text
stringlengths 2
1.05M
| repo_name
stringlengths 5
101
| path
stringlengths 4
991
| language
stringclasses 3
values | license
stringclasses 5
values | size
int64 2
1.05M
|
|---|---|---|---|---|---|
Cellular ras and cyclin D proteins each play critical roles in the control of cellular proliferation. Evidence increasingly indicates an important connection between these two molecules. Extra cellular growth signals control ras activity; while ras activity stimulates cyclin D levels. These two proteins function to regulate cell cycle progression by regulating the activity of cell cycle control proteins in late GI-phase; when the cell makes a commitment to another round of DNA synthesis and cell division. We now report the possible involvement of ras and cyclin D1 in the control of cell cycle progression at an unexpected cell cycle point; late S- and G2-phases. With a cell cycle analytical procedure based upon time lapse analysis of asynchronous cultures coupled with quantitative fluorescence analytical procedures, we report here that cyclin D1 is expressed at high levels late in S-phase and throughout G2-phase. In this study we will test our hypothesis that ras activity and cyclin D expression late in the cell cycle might play a critical role in the control of cell cycle progression. To conclusively demonstrate that ras is active in late S- and G2- phases, ras activity will be analyzed by its association with target peptides. In Specific Aim 1, the signaling pathway downstream of ras will also be analyzed late in the cell cycle. In Specific Aim 2, we will determine to what extent ras activity leads to cyclin D1 expression in late cell cycle stages by comparing ras activity to cyclin D1 mRNA levels. In Specific Aim 3, the biological importance of ras activity and cyclin D1 expression late in the cell cycle will be analyzed. Experiments are designed to demonstrate that cyclin D1 made in G2-phase effects cyclin D1 levels in G1 phase. In addition, we will test the possibility that cyclin D1 produced prior to mitosis influences entry into quiescence and the length of the next G1- phase. These studies have the potential to broaden our understanding of the role of ras activity throughout the cell cycle in the control of cellular proliferation.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Melissa Nierle
Melissa began learning mobile development on both Android and iOS platforms in 2014. She ultimately fell in love with iOS when Apple debuted Swift at the 2014 WWDC. Melissa graduated from Virginia Commonwealth University last May with a degree in Computer Science. After college, she moved to Charlottesville VA where she currently works her dream job as a Software Engineer at WillowTree, Inc.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
[Nosospecific features of the dynamics of immunological parameters in young children with acute respiratory virus infections of varying etiology].
The study of acute viral respiratory infections has shown that in the course of these infections fluctuations in the content of antigen-nonspecific immunocytes and immunoglobulins occur, depending on the etiology of the disease. This dependence should be taken into consideration in the evaluation of the immune status of young children with acute viral respiratory infections.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Background
==========
Obesity is a universal disease of increasing prevalence with alarming proportions worldwide, including in countries that recently had hunger and chronic malnutrition as main public health problems \[[@B1]\]. Obesity is the major risk factor for hypertension, being responsible for 20% to 30% of disease cases. In 2009, hypertension accounted for 7.5 million (12.8%) deaths worldwide \[[@B2]\].
Among the methods used to assess body fat, anthropometric indicators stand out and, because they are inexpensive and noninvasive and have good accuracy, are recommended by the World Health Organization for assessing the nutritional status and health risk of populations \[[@B3]\]. Body fat percentage (%BF) is usually assessed by anthropometry by measuring skinfolds due to their high correlation with body fat \[[@B4]\]. The correct measurement of skinfolds demands substantial time and requires a high degree of training and expertise of evaluators \[[@B5]\], which impair the use of these measures in multidisciplinary epidemiological surveys that collect large amounts of data about a given population \[[@B6]\].
Clinical studies have developed equations to assess %BF by means of anthropometric indicators of obesity, such as body mass index (BMI) and waist circumference (WC), which are more easily collected than skinfolds \[[@B7]-[@B9]\]. These equations show a strong association with body fat when estimated by more accurate methods, such as dual energy X-ray absorptiometry (DEXA) and hydrostatic weighing.
The % BF estimation allows for more precise analysis of body components than simply BMI and WC measures. Through % BF, lean body mass and fat mass can be estimated \[[@B10]\]. In this sense, if equations that estimate % BF have good predictive capacity for hypertension, they can, while analyzing body composition, identify people at risk for hypertension.
Physical education, sports, and nutrition professionals routinely assess body fat in populations. These professionals have been associated with health teams; for example, in 2008, the Brazilian government regulated these professions into primary health care teams \[[@B11]\]. The identification of discriminatory power and the screening features of %BF equations using indicators such as BMI and WC can be useful for professionals that take care of a large number of individuals. If these equations show good predictive and screening characteristics, health professionals will be able not only to use anthropometry as a tool for assessing obesity but also to identify people at risk for hypertension and refer them for monitoring and diagnostic tests. Moreover, the evaluation of the specific role of anthropometric indices on the development of hypertension may help to better understand the pathogenesis of arterial hypertension, and to provide more accurate means for prevention \[[@B12]\].
This study aims to analyze the discriminatory power and screening properties of %BF assessed by equations with BMI and WC in the identification of hypertension. In addition, the associations between high %BF and hypertension are assessed in a sample of adults in southern Brazil.
Methods
=======
Population and sample
---------------------
This cross-sectional population-based study originated from the health survey *EpiFloripa Adults 2009* conducted in Florianópolis, Santa Catarina, southern Brazil, between September 2009 and January 2010. Florianópolis is the capital of the Brazilian state of Santa Catarina and has close to 420,000 inhabitants; it is also the Brazilian capital with the best social and health indicators \[[@B13]\].
The sample size was calculated to estimate the prevalence of each health outcome investigated in the survey, given a reference population of 249,530 adults from 20 to 59 years of age, a confidence level of 95%, 50% prevalence for unknown health outcomes, an error sample of 3.5 percentage points, a design effect (deff) estimated at 2 due to cluster sampling, and percentage of losses estimated at 10%. Based on these parameters, a sample size of 1,720 individuals was obtained. However, considering the multiple objectives of the *EpiFloripa* study, this study interviewed 32 adults in each of the 63 census sectors, thus increasing the sample size to 2,016 individuals.
Sampling was conducted in two stages. In the first, the 420 urban census sectors of the city were stratified according to deciles of the family head income (R\$ 192.80 to R\$ 13.209.50 \[Brazilian currency\], US\$ 1 = R\$ 1.7 during the data collection period); 60 sectors were randomly selected (sampling fraction equal to seven), consisting of six sectors in each decile. In the second stage, the sampling units were the households. In this step, the number of permanent private households in each sector was updated by the study supervisors. The number of dwellings ranged from 61 to 810, giving a variation coefficient of occupied households between sectors of 55%. To decrease this, and considering the geographical proximity and income decile, it was decided to group some census sectors and divide others, resulting in 63 census sectors with a variation coefficient of 32%. Eighteen households from each of these geographical units were randomly selected.
Eligibility, exclusion, and loss criteria
-----------------------------------------
All adults aged 20 to 59 years living in selected households were eligible for the study. The exclusion criteria for carrying out anthropometric measurements and blood pressure measures were bedridden subjects, amputees, plastered and pregnant women, and those who had given birth in the six months preceding the interview. Individuals with neurological disorders that might interfere with their understanding the questions regarding the survey interview were also excluded. One resident who was not found in at least four visits, one in the weekend and another at night, was considered lost.
Data collection
---------------
Data collection was carried among all adults living in selected households. To this end, 35 interviewers were selected. A personal digital assistant (PDA) was used to record and store data. All interviewers were intensively trained for the fieldwork; the survey pretest was conducted among 30 adults not sampled, and the pilot study was conducted among 100 individuals.
Outcome
-------
The dependent variable was hypertension (yes/no), which was defined as systolic pressure ≥ 140 mmHg and/or diastolic pressure ≥ 90 mmHg, and/or self-report of taking some antihypertensive medication, and/or diagnosis of hypertension by a doctor \[[@B14]\].
Blood pressure levels were measured twice, and the average measurements were used in the study. The resting time was approximately 30 minutes before the first measurement and approximately 15 minutes between measures. Blood pressure was measured in accordance with the recommendations of the Brazilian Guidelines on Hypertension \[[@B15]\]. For this purpose, blood pressure was measured on the right arm, which rested on a table at heart level with the palm facing upward. The individual remained sitting with his feet planted on the ground. At the beginning of the interview, the individuals were advised to refrain from smoking and drinking coffee, *chimarrão*, or black tea, and to empty their bladder. Electronic sphygmomanometers with a digital readout system (Techiline®, São Paulo, Brazil), previously and properly calibrated by the National Institute of Metrology, Standardization and Industrial Quality (Inmetro), were used to measure blood pressure levels.
Anthropometric variables
------------------------
Anthropometric measurements of body mass, height, and WC were evaluated according to standardized procedures \[[@B16]\], and the mean of two measurements was used in the study.
Body mass was measured with the digital scale model HCM 5110M (GA.MA Italy Professional®, Bologna, Italy), with a resolution of 100 grams and 150 kg capacity, which was calibrated before the survey. Height was measured using a stadiometer with a measuring tape at a resolution of 1 mm. The WC, taken without any clothing, was measured with an inextensible anthropometric tape (Sanny ®, São Bernardo do Campo, Brazil) with a resolution of 1 mm at the narrowest waist.
%BF was calculated based on equations with BMI \[[@B8]\] and WC \[[@B9]\]. The equation using BMI developed with a sample composed of white Americans and Africans showed a determination coefficient of R = 0.86 and a standard error of 4.98% when compared to the body composition analysis of the four-compartment model evaluated by means of DEXA (bone density) and hydrostatic weighing (water and body volume) \[[@B8]\]. The equation of Gallagher et al. \[[@B8]\] is as follows: *%BF = 64.5 - 848 x (1/BMI) + 0.079 x age - 16.4 x sex + 0.05 x sex x age + 39.0 x sex x (1/BMI)*. In the indication of sex, the values are 1 for men and 0 for women; age is given in complete years.
The equation with WC developed with healthy adults from Glasgow, Scotland, showed a determination coefficient of R = 77.8%, with %BF estimated by means of hydrostatic weighing, and a standard error of 4.10% for men, and a determination coefficient of R = 70.4% and a standard error of 4.70% for women \[[@B9]\]. The equation of Lean et al. \[[@B9]\] differs between men and women. *For men: %BF = (0.567 x WC) + (0.101 x age) - 31.8. For women: %BF = (0.439 x WC) + (0.221 x age) - 9.4*. WC must be in cm, and age in complete years.
BMI was calculated (weight/height ^2^) and ranked according to the literature \[[@B3]\] into obesity (BMI ≥ 30 kg/m^2^), overweight (BMI of 25.0 to 29.9 kg/m^2^) normal weight (BMI ≥ 18.5 and \<25 kg/m^2^), and underweight (BMI \<18.5). WC was assessed based on cutoff points in relation to risk of metabolic complications, and ranked into very high risk (men ≥ 102 cm, women ≥ 88 cm), high risk (men ≥ 94 cm, women ≥ 80 cm), and no risk (men \<94 cm, women \<80 cm) \[[@B3]\]. The inter-and intra-examiner technical error of measurement (TEM) was calculated according to the recommendations of Gore et al. \[[@B5]\]. The maximum inter-examiner TEM (1.86%) and intra-examiner TEM (1.18%) was found in the WC measure, which indicated an adequate level of interviewers for anthropometric measurements.
Control variables
-----------------
The control variables included demographic data, such as age, which was expressed in complete years and categorized as 20--39 and 40--59 years. The self-reported skin color was collected based on the categories proposed by the IBGE \[[@B17]\] and classified as white, light-skinned black, dark-skinned black, yellow, and indigenous. The socioeconomic variables were educational level assessed by the complete years of schooling and *per capita* family income in reais (R\$, the Brazilian currency; US\$ 1 = R\$ 1.7 during the data collection period).
Smoking was assessed by the categories nonsmoker, former smoker, light smoker (less than 10 cigarettes daily), and moderate/heavy smoker (more than 20 cigarettes daily). The Alcohol Use Disorders Identification Test (AUDIT) was used to identify people with problematic alcohol use, using the cutoff point to classify subjects into no (score 0--7) and yes (score ≥ 8) \[[@B18]\]. Physical activity was assessed according to the leisure domain of the questionnaire used in the surveillance system of risk and protective factors for chronic diseases through a telephone survey (VIGITEL), considering as inactive those who practiced no physical exercise or practiced less than once a week in the three months preceding the interview \[[@B19]\]. Food habits were assessed based on the regular consumption of fruits and vegetables (≥ 5 days per week) according to the VIGITEL questionnaire \[[@B20]\].
Statistical analysis
--------------------
Descriptive statistics using the mean, standard deviation, and absolute and relative frequency was applied. To compare continuous variables between sexes, Student's t-test for independent samples was used. To determine differences between sexes in the distribution of categorical variables, the chi-square test was used. The ROC curve was calculated to analyze the discriminatory power of %BF in the identification of hypertension and to find the best cutoffs to identify this association \[[@B21]\]. In this study, this cutoff point was the one with the best accuracy, i.e., with fewer false positives and false negatives. The larger the area under the ROC curve (AUC), the greater the discriminatory power of the %BF equation to identify hypertension. The confidence interval was calculated at 95% (95% CI), which determines whether or not the predictive capacity is due to chance, and the lower limit should not be less than 0.50 \[[@B22]\]. The differences between the AUC values of the different %BF equations were compared using the nonparametric test \[[@B23]\]. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR +), and negative likelihood ratio (LR-) of all the best cutoffs of %BF were calculated to identify hypertension.
The association between hypertension and high %BF estimated by the cutoff points calculated in this study was analyzed by Poisson regression, estimating the crude and adjusted prevalence ratios and 95% CI. Three models of adjusted analysis were developed to determine the magnitude of association between excess fat and hypertension. Model 1 was adjusted by sociodemographic variables (age, skin color, educational level, and *per capita* family income). Model 2 was adjusted by sociodemographic variables and health behaviors (smoking, problematic alcohol use, practice of physical activities during leisure time, and regular consumption of fruits and vegetables). Model 3 was adjusted by sociodemographic variables, health behaviors, height, and BMI (for %BF equation with WC) or WC (for %BF equation with BMI). All analyses were stratified by sex and carried out considering the design effect and sampling weight. To calculate the screening properties of %BF equations, the MedCalc software version 12.1.4 was used. For association analyses, the Stata 9.0 software was used.
Ethical aspects
---------------
The study was approved by the Ethics Committee on Human Research of the Federal University of Santa Catarina (No. 351/08). All the subjects who participated in the study signed an informed consent form.
Results
=======
The response rate of this study was 85.3% (*n* = 1720). The men had higher *per capita* family income, body mass, height, WC, and systolic and diastolic blood pressure values than the women (p \<0.05). The men also had a higher prevalence of moderate/heavy smoking (13.1%), problematic alcohol use (29.7%), inadequate consumption of fruits and vegetables (86.6%), overweight (37.4%), and high %BF (43.1% for the equation with WC) compared to the women (8.0%, 9.6%, 76.9%, 26.4%, and 33.3%, respectively). On the other hand, the women had a higher prevalence of physical inactivity (58.6%) and abdominal obesity (20.4%) than the men (46.3% and 11.2%, respectively) (Table [1](#T1){ref-type="table"}).
######
Characteristics of the adult population
**Variables** **Women** **Men**
--------------------------------------- ----------- ---------------------------- ------- -----------------------------
***Total*** 959 761
*Age (years)* 959 38.5 (37.8- 39.3) 761 37.4 (36.5- 38.2)
*Educational level* 958 11.6 (11.3- 11.9) 758 11.7 (11.4 - 12.0)
*Per capita family income* (R\$)*†* 940 1.311.3 (1.219-3- 1.403.3) 745 1586.5 (1.420.0- 1.753.1)\*
*Body mass (kg)* 925 65.3 (64.4- 66.2) 752 77.9 (76.9- 78.9)\*
*Height (cm)* 928 160.4 (160.0- 160.9) 756 173.2 (172.7- 173.7)\*
*Body mass index (kg/m*^*2*^*)* 923 25.4 (25.1- 25.7) 751 25.9 (25.6- 26.2)
*Waist circumference (cm)* 920 79.3 (78.4- 80.1) 751 88.4 (87.5- 89.2)\*
*Fat percentage (equation with BM I)* 923 33.0 (32.5-33.4)\* 751 20.9 (20.5-21.3)
*Fat percentage (equation with WCI)* 920 34.0 (33.5-34.5)\* 751 22.1 (21.6-22.6)
*Systolic blood pressure (mmHg)* 928 127.5 (126.2- 128.6) 754 139.8 (138.4- 141.1)\*
*Diastolic blood pressure ( (mmHg)* 928 81.9 (81.0- 82.8) 754 88.7 (87.6- 89.7)\*
**n** **% (95% CI)** **n** **(95% CI)**
*Skin color*
White 802 83.7 (79.8- 87.5) 642 84.1 (79.9 -- 87.6)
Light-skinned black 73 8.0 (5.7- 10.2) 74 10.1 (6.8- 13.4)
Dark-skinned black 53 5.3 (3.0- 7.6) 34 4.5 (2.6- 6.6)
Yellow 15 1.7 (0.8 - 2.5) 02 0.3 (0.1 - 0.6)
Indigenous 12 1.3 (0.6 - 2.1) 08 1.0 (0.3 - 1.7)
*Age group*
20-39 years 500 53.9 (49.6-58.1) 432 57.7 (52.3-63.0)
40-59 years 459 46.1 (41.9-50.3) 329 42.3 (37.0-47.7)
*Smoking*
No smoker 548 57.4 (53.2- 61.5) 378 51.3 (46.1- 56.5)
Former smoker 238 25.1 (21.2- 28.9) 211 27.3 (22.3- 32.4)
Light smoker 92 9.5 (7.6- 11.4) 66 8.3 (6.1- 10.4)
Moderate / heavy smoker 77 8.0 (6.1- 9.9) 101 13.1 (10.2- 15.8)\*
Problematic alcohol use
No 870 90.4 (87.7- 93.0) 533 70.3 (66.1- 74.6)
Yes 89 9.6 (7.0- 12.3) 228 29.7 (25.3- 35.9)\*
*Physical activity at leisure time*
Active 400 41.4 (36.6- 46.1) 406 53.7 (48.1- 59.2)
Inactive 558 58.6 (53.8- 63.3)\* 354 46.3 (40.7- 51.8)
*Food habit*
Adequate 222 23.1 (19.8- 26.3) 101 13.4 (10.1- 16.8)
Inadequate 736 76.9 (73.7- 80.2) 660 86.6 (83.2- 89.9)\*
*BMI*
\<18.5 kg/m^2^ 26 2.8 (1.6- 4.0) 8 1.0 (0.2- 1.7)
18.5 -- 24.9 kg/m^2^ 493 54.1 (50.0- 58.2) 346 46.9 (42.6- 51.0)
25.0 -- 29.9 kg/m^2^ 249 26.4 (23.4- 29.3) 282 37.4 (34.1- 40.7)\*
≥ 30.0 kg/m^2^ 155 16.7 (13.7- 19.6) 115 14.7 (11.8- 17.4)
*WC (cm) ‡*
No risk 536 58.6 (53.8- 63.4) 541 73.1 (69.2- 76.9)
High risk 188 21.0 (17.8- 24.1) 119 15.7 (12.9- 18.5)
Very high risk 196 20.4 (17.1- 23.6)\* 91 11.2 (8.8- 13.6)
*Fat percentage (equation with BMI)*
Normal 568 62.4 (58.2-66.5) 451 61.0 (56.7-65.4)
Increased 364 37.6 (33.4-41.7) 299 39.0 (34.6-43.3)
*Fat percentage (equation with WC)*
Normal 610 66.7 (62.2-71.2) 421 56.9 (52.3-61.4)
Increased 309 33.3 (28.7-37.7) 329 43.1 (38.5-47.7)\*
*Hypertension*
No 642 69.5 (65.4- 73.6) 360 48.4 (44.2- 52.5)
Yes 286 30.5 (26.4- 34.6) 394 51.6 (47.5- 55.7)\*
CI 95%: confidence interval of 95%; $\overset{―}{X}$**-** mean; \*significant difference between sexes (p\<0.05); †R\$: Brazilian currency, 1US\$ = 1,7R\$ during the data collection period; BMI: Body mass index; WC: waist circumference.
In both sexes (Table [2](#T2){ref-type="table"} and Figure [1](#F1){ref-type="fig"}), all %BF equations showed significant discriminatory power for hypertension (i.e., AUC \> 0.5). The AUC did not differ between sexes or between %BF equations.
######
Screening properties of %BF estimated by equation using BMI and WC to detect hypertension
**AUC (95% CI)** **Cutoff** **Sensitivity(95% CI)** **Specificity (95% CI)** **PPV (95% CI)** **NPV (95% CI)** **LR+ (95% CI)** **LR- (CI 95%)**
------------------------- ------------------- ------------ ------------------------- -------------------------- -------------------- -------------------- ------------------ ------------------
*Women*
%BF (equation with BMI) 0.73 (0.70- 0.76) 34.0 68.1% (62.3- 73.4) 68.2% (64.4- 71.8) 49.1% (44.1- 54.2) 82.6% (79.0- 85.7) 2.1 (1.9- 2.4) 0.5 (0.4- 0.6)
%BF (equation with WC) 0.73 (0.70- 0.76) 34.1 71.0% (65.4- 76.2) 65.8% (61.9- 69.5) 48.2% (43.3- 53.1) 83.5% (79.9- 86.7) 2.1 (1.9- 2.3) 0.4 (0.4- 0.5)
*Men*
%BF (equation with BMI) 0.70 (0.67- 0.73) 20.4 71.4% (66.6- 75.8) 59.8% (54.5- 65.0) 66.0% (61.2- 70.5) 65.7% (60.3- 70.9) 1.8 (1.6- 2.0) 0.5 (0.4- 0.6)
%BF (equation with WC) 0.69 (0.66- 0.73) 20.7 69.7% (64.8- 74.2) 63.4% (58.1- 68.4) 67.6% (62.8- 72.1) 65.6% (60.3- 70.6) 1.9 (1.7- 2.1) 0.5 (0.4- 0.6)
AUC: area under the curve, 95% CI: 95% confidence interval, PPV: positive predictive value, NPV: negative predictive value, LR+: positive likelihood ratio, LR-: negative likelihood ratio.
Note: The cutoff points units are: kg/m^2^, No significant difference between area under the curve by women and men, and by age (p\>0.05).
{#F1}
Table [2](#T2){ref-type="table"} shows the screening properties for hypertension of the cutoffs of %BF estimated by the equation with BMI and WC. For women, the cutoff of %BF estimated by the equation with BMI with greater screening capacity (highest sensitivity values) for hypertension was 34.0%. This cutoff point showed high sensitivity (68.1%) and high NPV (82.6%). Additionally, this cutoff point showed LR+ of 2.1 and LR- of 0.5. In women, the cutoff of %BF estimated by the equation with WC with greater screening capacity for hypertension was 34.1%. This cutoff point showed sensitivity of 71.0% and NPV of 83.5%. LR+ and LR- were 2.1 and 0.4, respectively.
In men, the cutoff of %BF estimated by the equation with BMI with greater screening capacity for hypertension was 20.4%. This cutoff point had sensitivity of 71.4%, NPV of 65.7%, LR + of 1.8, and LR- of 0.5. For men, the cutoff of %BF estimated by the equation with WC with greater screening capacity for hypertension was 20.7%. This cutoff point showed sensitivity of 69.7% and NPV of 65.6%. LR+ and LR- were 1.9 and 0.5, respectively (Table [2](#T2){ref-type="table"}).
Figures [2](#F2){ref-type="fig"} show the measures of association between high %BF and hypertension. In all groups analyzed, adjusting the model by sociodemographic variables (model 1) and health behaviors (model 2) slightly modified the strength of association between high %BF and hypertension in both sexes compared to the unadjusted model. However, by adjusting the model simultaneously by sociodemographic variables, health behaviors, height, and WC or BMI (model 3), a reduction in this association was observed. The measures of association between exposure and outcome were higher for women than for men.
{#F2}
Discussion
==========
The predictive capacity of the %BF equations analyzed in this study was significant in identifying subjects with hypertension (i.e., AUC \> 0.50). The literature \[[@B24],[@B25]\] shows that a good screening test, in addition to having significant predictive capacity, should be inexpensive, easy to apply, and noninvasive, which are characteristics present in equations analyzed. However, another characteristic of a good screening test is high sensitivity so as to minimize the number of false negatives \[[@B24]\]. In this study, for women and men, the equations showed high sensitivity.
Screening is the search for any sign or symptom that might be indicative of a probable disease in asymptomatic subjects. In this study, screening is the identification of high %BF as indicative of hypertension. The purpose of screening is to refer people with any signs of the disease for better assessment, with monitoring and diagnosis from a qualified professional. Therefore, screening tests should be more \"sensitive\" and diagnostic tests more \"specific\" \[[@B25]\]. Thus, the %BF estimated by the equations analyzed and the cutoff points established in this study may be useful in screening hypertension in women and men. For women, the % BF equation with WC showed higher sensitivity values than the % BF equation with BMI. For men, the % BF equation with BMI showed higher sensitivity values than the % BF equation with WC.
One possible explanation for differences in sensitivity values between equations may be the origin of the population under study. The equation with WC used in this study was created from a sample composed of adults from Scotland, whose population is predominantly Caucasian \[[@B9]\]. The equation with BMI used in this study was developed with a sample of white Americans and African Americans \[[@B8]\]. The literature indicates that there are differences in fat distribution according to ethnicity. Asians, for example, have a higher adiposity degree for a given BMI compared to the white population \[[@B26]\]. The Brazilian population is very heterogeneous in terms of ethnicity, which can be verified by the distribution of the skin color variable.
The present study is consistent with other works in reporting that high body fat is associated with hypertension \[[@B27]-[@B29]\]. The crude measures of association for both equations and sexes indicate prevalence approximately twice as high of subjects with high %BF of having hypertension when compared to those with normal %BF. After adjusting by sociodemographic variables and health behaviors, this association was little changed, indicating that regardless of age, skin color, educational level, socioeconomic level, and lifestyle variables, excess fat is strongly associated with hypertension. This highlights why obesity is a major risk factor for hypertension, causing up to 30% of disease cases \[[@B2]\].
As in other studies that investigated the association between obesity and noncommunicable chronic diseases \[[@B28]-[@B30]\], this study found that by adjusting the analysis model by anthropometric indicators (BMI, WC, and height), the association between hypertension and high %BF decreased. This suggests that there is a high correlation between the anthropometric markers analyzed \[[@B29]\]. For example, an elevated BMI may be due to the accumulation of abdominal fat; high WC levels may be indicative of excess total body fat.
Through % BF, it is possible to estimate other body composition components \[[@B10]\]. Moreover, analyzing only the absolute WC and BMI values does not allow estimating lean body mass and fat mass. Thus, it is believed that the % BF estimation should also be considered in body fat and obesity evaluations at population level as widely performed with WC and BMI \[[@B3]\].
This study has some limitations: 1) the cross-sectional design does not allow establishing causal relationships between hypertension and high %BF so reverse causality cannot be ruled out; 2) the analysis of %BF conducted by means of anthropometric indicators of obesity is less accurate than other methods aimed at assessing body composition; and 3) chronic diseases, such as hypertension, are multifactorial, and in addition to anthropometric measurements, other factors, such as heredity, should be considered in future studies.
Conclusions
===========
Screening for hypertension using %BF estimated by equations with BMI and WC should be performed carefully, taking into account the properties of each measure. In practical terms, the screening of hypertension through %BF is more useful in women, regardless of age, if the equation with WC is used. In men, regardless of age, the screening is most useful if the %BF equation with BMI is used. Moreover, there is greater prevalence of hypertension in adults with high %BF values compared to those with lower %BF measurements.
The findings of this study show that while people with obesity are identified through % BF equations, there are individuals at risk of hypertension. This information may be relevant to health systems in countries of low and middle income that do not have enough financial and material resources for the accurate diagnosis of obesity and hypertension.
Competing interests
===================
The authors declare that they have no competing interests.
Authors' contributions
======================
DASS conceived the study, supervised data collection and data analysis, and drafted the manuscript. ELP assisted in the statistical analysis, contributed to the interpretation of the results and drafted the manuscript. MAP is the day-to-day project manager, assisted in the statistical analysis and contributed to the interpretation of the results. All authors read and approved the final manuscript.
Acknowledgments
===============
The authors thank the Brazilian Institute of Geography and Statistics for their support in training, to Professor Dr. Nilza Nunes da Silva, School of Public Health, University of São Paulo, for contributions in the sampling and the Municipal Health Department of Florianopolis for their assistance in the conduction of the research. This project was funded by the National Council for Scientific and Technological Development - CNPq (No. 485327/2007-4).
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Bobby Lee, CEO of China's first Bitcoin exchange BTCC, says Bitcoin's struggles are serious but ther
Is Bitcoin on its death bed?
That was the question posed during a Sept. 21 panel at Tech Crunch Disrupt, a conference in San Francisco, as Bitcoin proponents speculated on the digital currency’s lackluster performance for venture capitalists and whether it would ever see a comeback.
The panelists included Wences Casares, CEO for the bitcoin bank Xapo; Bobby Lee, CEO of BTCC, China’s first Bitcoin exchange; and The New York Times Journalist Nathaniel Popper, author of Digital Gold, a book chronicling the birth of Bitcoin.
While optimistic, all three said they’d been dismayed by the currency's deteriorating value over the past year or two — and Casares estimated its plight would likely worsen before it improved.
“As an industry, we are paying the price around the hype of bitcoin about two years ago,” Casares said.
Referencing investment figures, he noted venture capitalists have poured more than $600,000 million into Bitcoin businesses since the currency launched.
“Everybody’s expectations were that this was going to change [world monetary systems] in six months, and that didn’t happen,” Casares said.
At present, one Bitcoin is valued at about $230, a far cry from its peak valuation in 2013 when its exchange rates totaled more than $1,200 per coin. Some analysts, Lee said, even believe the currency may bottom out at zero — a figure he doubts, yet doesn’t rule out either.
Making matters worse is another troubling notion about what might happen if Bitcoin’s slump continues. In his remarks, Casares said there is a very real scenario where Silicon Valley’s tech companies stop providing services for Bitcoin in favor of more lucrative business models. Bitcoin needs infrastructure to work, and this infrastructure means apps, financial platforms and support from traditional banking institutions.
“I would say that I’m the most biased Bitcoin person I can imagine, the most pro-Bitcoin person I can imagine,” Casares said. “And even then, I always tell people that they shouldn’t own an amount of Bitcoin they can’t afford to lose because I think there is a non-trivial chance that that amount goes to zero.”
Lee said the tragedy in Bitcoin’s possible demise would be the missed opportunity to benefit from an independent monetary system that relies on an unbiased code base, as opposed to typical currencies that rely on government management and consumer perceptions.
Despite this, the three unanimously endorse the idea that blockchain, the coding framework behind Bitcoin, would likely never go away. As a transactional database synced among all of its users, blockchain could be repurposed for other uses like personal identification or varieties of digital record keeping. And the state of Vermont has asked a coalition of stakeholders to consider whether the technology could help manage state records. Similarly, Popper suggested that blockchain could be a foundation for iteration. Bitcoin, the three agreed, could be the predecessor of a more successful currency, rebranded and ubiquitously accepted by major financial institutions.
Whatever the case, Lee said he and other advocates of the service believe the system has fundamentally changed the concept of monetization. Lee likened its transparency and innovation to the beginning of the World Wide Web.
“It will matter for sure!” Lee said. “Bitcoin is not going to go away in the same way the Internet is not going to go away.”
This story was originally published by Government Technology.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Car crash and injury among young drivers: contribution of social, circumstantial and car attributes.
The objective of the study was to assess the independent contribution of individual, car and circumstantial features in severe and fatal car crashes involving young drivers. A prospective longitudinal, register-based cohort study was conducted at national level (in Sweden), in which people born in the years 1970-1972 (n = 334070) were followed up for the period 1988-2000 (aged 16-18 years in 1988) for their first two-car crashes leading to severe or fatal injury. Ten variables descriptive of the driver (sociodemographics), the car (safety level) and the crash have been analysed using multiple logistic regressions for male and female drivers separately, compiling crude and adjusted odds ratios with 95% CI. When controlling for other features, none of the variables descriptive of male and female drivers' socio-demographic characteristics impacts significantly on the odds of being severely injured or dying in a car-to-car crash. After adjustment, significant excess risks are observed for speed limits higher than the lowest one, type of crash other than rear end collision and road and light conditions other than favourable (dry and daylight), for both male and female drivers. For males only, cars from all car safety levels have significantly higher odds than those from the safest category. Among male and female young drivers, class differences in the risk of being severely injured in a traffic injury are substantial. Yet, despite this imbalance, crash characteristics (for males and females) and safety level of the vehicle driven (for males) remain the most determinant factors of crash severity. Understanding the social patterning of road traffic injuries is a challenge for public health and it seems that qualitative and quantitative differences in crash exposure offer part of the explanation. Young drivers from all social groups need, however, to be sensitized to the risk factors.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Quantitative analysis of mannitol polymorphs. FT-Raman spectroscopy.
Mannitol is a polymorphic excipient which is usually used in pharmaceutical products as the beta form, although other polymorphs (alpha and delta) are common contaminants. Binary mixtures containing beta and delta mannitol were prepared to quantify the concentration of the beta form using FT-Raman spectroscopy. Spectral regions characteristic of each form were selected and peak intensity ratios of beta peaks to delta peaks were calculated. Using these ratios, a correlation curve was established which was then validated by analysing further samples of known composition. The results indicate that levels down to 2% beta could be quantified using this novel, non-destructive approach. Potential errors associated with quantitative studies using FT-Raman spectroscopy were also researched. The principal source of variability arose from inhomogeneities on mixing of the samples; a significant reduction of these errors was observed by reducing and controlling the particle size range. The results show that FT-Raman spectroscopy can be used to rapidly and accurately quantitate polymorphic mixtures.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Faces of Federation
A letter from our CEO
Faces of Federation
I started working at Federation in July of last year. I am the Program Assistant for the FACT (Forensic Assertive Community Treatment) team.
I am one of the first faces you see at our Richmond Hill site. It’s eventful and exciting most days. Though the FACT team meets with the individuals in the community, some are scheduled to come into the office for weekly groups. I kindly greet them with water or a cup of coffee and direct them to their scheduled group location. I provide assistance when individuals are in crisis either in person or on the phone until they are transferred to staff. I set up transportation to the site and make other appointments off-site as needed. I keep track of staff daily visits with client’s, track prescriber visits, sign for medication, track individual’s Medicaid status, you name it…I get it done.
I knew of Federation before I started working here. My sister was fortunate enough to receive services from Federation at their Babylon location. I have 5 sisters, and she was the oldest sister. I’m the 2nd to last sister. She was diagnosed with Schizophrenia later in life—in her forties. It was there the whole time but we never understood it. Once she was diagnosed, I became educated and then I was able to help navigate services for her. Over the years she struggled with paranoia and substance abuse. Sometimes she would accept help from others before me because of the paranoia…but I idolized her. Unfortunately, she passed away in 2013 from medical issues.
One of the things I respect about Federation is that they go out into the community and bring the services to the individuals to get them the help they need. As I was preparing for my interview with Federation, I went online and read their mission statement which describes the services and their philosophy. When you get here and actually see what they do to help people… it’s nothing short of amazing.
I have a very strong connection here because of my sister. I always look to be of service to others and help in any way I can. Helping people resolve any issue, even the little ones, makes me feel good. It’s my calling. Consequently, I’m also the peacemaker in my family.
Don’t take anything for granted about your mental, physical, or spiritual state because everyone is in a different position. Always be willing to encourage each other because without encouragement, you’ll stay stuck where you are. My Motto is, “be the change you wish to see in the world”.
Working at Federation is not only a career to me, but also a way that I give back to my community.
My first year of retirement was horrendous. I never realized how much your identity is tied to what you do for a living. When I retired, my father had a stroke (he’s ok) and my mother broke her back at the same time. At that time, I was just freefalling.
I had seen an article about the Foster Grandparent program in Newsday and I thought, “This is perfect!” I am a retired school teacher having taught 1st, 2nd, 4th, and 5th grades. I tried substitute teaching but that was too much like teaching. I started volunteering in the Foster Grandparent program this past November. As a volunteer, I get to work with the children, but I get to focus on their emotional needs. As a teacher that was always the most frustrating for me—not having the time to devote to each child’s emotional well-being. I don’t have all the authority now but I can make a difference. I try to connect with each one, so they feel special in their own way, every day.
I have them call me nanny. It’s wonderful.
This has been my therapy. I have my identity back. I am volunteering in the same school that I went to in 4th and 5th grade. I’ve come full circle and I’m giving back to my community. It’s been so rewarding.
You don’t need to be an expert in anything, just do it. It’s so simple. Everyone has something to offer these children. Kids just need someone to cheer them on. I’m like Jiminy Cricket, helping them stay focused. I realize how much I am helping the teachers as well. Now they can teach because they have me to support the children in the classroom as well. This program is truly a win-win for everyone.
As long as I am physically able, I will still be volunteering. I feel like I’ve been given a gift!
My Name is Laura and I am a Face of Federation.
My name is Marsha and I am a Face of Federation.
I came from Pilgrim State. At the time, I was battling alcoholism, bulimia, and anorexia. I had struggled for quite a few years. I was floundering around, drinking, drinking, drinking. I was married for 25 years and my husband was a heavy drinker. I would try and keep up with him. My life was just a mess. Before that I had gone to many different hospitals, maybe 15 at least. Finally, I went to one and the counselor there asked me if I would like to go to Pilgrim, a long-term care facility. As soon as I heard the word care, I knew it was a good thing. But it was scary going in there. My brother wrote me letters every day asking if I was safe. Eventually he came and got me. That was about 9 years ago. I left Pilgrim and came to one of Federation’s homes on the north shore. I couldn’t believe it when we drove up there…the beautiful trees and the horses.
I walked in and said, “Oh my God.”
It was a home.
Federation’s MRS team has helped me so much and continues to encourage my independence. That’s my basket there behind the couch and I take it with me and do my own grocery shopping.I get to pick out the items that I want. I also teach an adult education crocheting class one night a week at the local high school. We all sit in a little group and they tell me what they want to learn. I teach them different stiches, but I’ve learned so much from them as well. This is my second semester teaching. I was nervous at first but my dad encouraged me. He’s my motivator. He told me to just be myself. He’s so proud of me and it’s so gratifying to be able to make money for things that I want. Eventually I’d love to sell some of the items that I’ve made.
What does it mean to be free? Wow! It’s a blessing. I didn’t think I would ever see my family again before this.
Don’t ever give up. And I still never give up, it’s an ongoing thing. Don’t give up because the miracle will happen. I know what that means. This is a miracle sitting here talking to you.
I want people to know that I am kind. I am caring. I will always listen to someone if they ever have a problem. I will be there.
I’ve been working for Federation for 5 years. I was a member of the Patchogue PROS program and they helped me get a job here. Before that, it was bad. I was homeless, living in the woods until a police officer spotted me and took me to a shelter. I lived there for a year. From the shelter, I went to Concern and lived there and that’s when I started coming to Federation. At the time I was depressed…deeply depressed. I was so down on myself and I didn’t think I would ever work again. It took me five years with one therapist and at first I would go there and literally cry. She would listen to me and let me cry. She would always tell me I’m not worthless. She was trying to boost my confidence but I couldn’t accept it at the time. I had a bad life- I had survived abuse and bad relationships. It took me 5 years to get to this point, but now, I feel great about myself. I can work. I am worth it! I don’t put myself down anymore. I met my husband, the love of my life, and I am a good wife. PROS helped me gain confidence. It helped me learn to be around people. I was always so self-conscious and I thought people were always talking about me. PROS helped me realize that no one is talking about me– I was putting all of that on myself. I am so glad that I came to Federation. They were there for me. They would listen no matter what and they always had time for me. Here, I learned to put myself first–to do things that I want to do and to stop being a follower. I love working here.
Keep your head up and depend on your support team. Keep moving forward and don’t move back. Things are going to happen don’t let them become bigger than what they are. Keep yourself first.
My name is Chi Qui and I am a Face of Federation.
My name is Daniel and I am a FACE OF FEDERATION
Working one– on-one with people has empowered me to be as full and strong and clear as possible. They walk into this room and it’s just me here. Each day, I’m invited to reach into my own heart and try to connect with them…because if you feel connected, you can grow. It’s such an honor that people are willing to speak with me about vulnerable and personal pieces of themselves. As the months go on and the relationships develop, we’ve started to see some real changes rooting in our clients and even though they may seem small, they are actually really big. A lot of times they can’t see it and it’s my job to reflect that to them. It’s an amazing opportunity to watch people transform their lives and grow in a positive direction but also to be there to catch them if they fall.
I just started a mindfulness meditation group here to help members navigate through their mental illness. We’re learning meditation techniques and concepts, as well as incorporating in art and music. All these things can help bring us back to center, increase our focus, awareness, and compassion for ourselves. These qualities can help us cope with anxiety, depression, and the myriad of challenges that come with mental illness. Mindfulness and meditation are ways to come back to the present and see things openly, clearly, and with love.
I learned at an early age the importance of money and spending wisely. I was raised by a single mother who was able to support us through the help of government safety net programs so I understand just how important these services can be and how managing your finances can be difficult and overwhelming for anyone. For the past 6 years, I’ve been the Program Manager of the Financial Management program. I oversee the Representative Payee Program, the Community Trust Program and the Veterans Fiduciary Program. All combined, our programs help with managing finances and entitlements, budgeting, and providing fiduciary services to over 550 individuals with disabilities or who are veterans. For some, this can mean making sure rent is paid and they have a roof over their head, or are able to buy food and pay their bills. I’m so lucky because I get to come to work every day and help others get their lives on track by doing what I love which is managing money in smart ways. This past November, I celebrated my 25th year working at Federation. I get involved in as much as I can with the agency because I believe in what we do. I’m a member of the Safety Committee, the Incident Review Committee, and always volunteer to help out with fundraising and events. I am so proud of the work we do here and how our programs work collaboratively to help people rebuild their lives.
My name is Joe and I am a FACE OF FEDERATION
My name is Michelette and I am a FACE OF FEDERATION
Surround yourself with support, whether it is in a program like this or somewhere else. There is always someone willing to listen and to help you. No matter what situation you are going through, there is always someone there to help.
I had been living in a shelter before I came to Federation and I had been receiving services. But it wasn’t really enough. I didn’t understand what I was going through and I wasn’t dealing with my mental illness very well. I was going to therapy and was pregnant at the time. When I was able to secure housing and leave the shelter, I was overwhelmed with all the things I had to do. I was juggling being a young mom, with two small children to care for and maintaining a household on my own. It was a lot for me and I found myself slowly breaking down. I knew I needed to find another outlet that would help me; that would reinforce that I was doing a good job and that I could achieve the goals I had too. Because I knew… the more I took care of myself and my needs, the better I would be at raising my children. Finding Federation’s PROS program has been a blessing. I’m not alone now because I have a good support network here. Now, I’m in school to become a social worker and I am working on learning to drive and get my license. I still have my moments where I don’t feel good about myself and I feel like I’m not doing enough. But now, in the back of my mind, I know I’m doing a pretty good damn job. When I met the people here at Federation, it just made me feel so much better about myself. Now I have the support of everyone here when I am at my best, and when I am not at my best and that has made all the difference.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
IRRELEVANT-FORMALS
Let fn be a function of n arguments. Let x be the ith formal of fn.
We say x is ``irrelevant in fn'' if x is not involved in either the
guard or the measure for fn, x is used in the body, but the value of
(fn a1...ai...an) is independent of ai.
The easiest way to define a function with an irrelevant formal is
simply not to use the formal in the body of the
function. Such formals are said to be ``ignored'' by Common Lisp
and a special declaration is provided to allow ignored formals.
ACL2 makes a distinction between ignored and irrelevant formals. Note
however that if a variable is declared ignored or ignorable,
then it will not be reported as irrelevant.
An example of an irrelevant formal is x in the definition of fact
below.
Observe that x is only used in recursive calls of fact; it never
``gets out'' into the result. ACL2 can detect some irrelevant
formals by a closure analysis on how the formals are used. For
example, if the ith formal is only used in the ith argument position
of recursive calls, then it is irrelevant. This is how x is used
above.
It is possible for a formal to appear only in recursive calls but
still be relevant. For example, x is not irrelevant below, even
though it only appears in the recursive call.
(defun fn (i x) (if (zerop i) 0 (fn x (1- i))))
The key observation above is that while x only appears in a
recursive call, it appears in an argument position, namely i's, that
is relevant. (The function above can be admitted with a :guard
requiring both arguments to be nonnegative integers and the :measure(+ i x).)
Establishing that a formal is irrelevant, in the sense defined
above, can be an arbitrarily hard problem because it requires
theorem proving. For example, is x irrelevant below?
(defun test (i j k x) (if (p i j k) x 0))
Note that the value of (test i j k x) is independent of x -- thus
making x irrelevant -- precisely if (p i j k) is a theorem.
ACL2's syntactic analysis of a definition does not guarantee to
notice all irrelevant formals.
We regard the presence of irrelevant formals as an indication that
something is wrong with the definition. We cause an error on such
definitions and suggest that you recode the definition so as to
eliminate the irrelevant formals. If you must have an irrelevant
formal, one way to ``trick'' ACL2 into accepting the definition,
without slowing down the execution of your function, is to use the
formal in an irrelevant way in the guard. For example, to admit
fact, above, with its irrelevant x one might use
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Biological membranes are constituted by lipid bilayers as their basic structure. Lipid bilayers, which are sheet-like assemblies of amphiphilic lipid molecules held together by hydrophobic interactions between their acyl chains, form the boundaries between intracellular cytoplasm and the cell's outside environment, as well as between the interior of many of the cellular organelles and the cytoplasm. This lipid bilayer structure was first recognized as the basis for cell membrane architecture in 1925;\[[@CIT1]\] however, only in 1972, Singer and Nicholson\[[@CIT2]\] first proposed a fluid mosaic model, to explain the membrane structure.
According to this model, lipids and proteins diffuse freely within the plane of the cell membrane. Since then, large membrane domains (e.g., basal, lateral, and apical membrane regions of glandular, endothelial, and epithelial cells) and lateral microdomain structures (e.g., lipid rafts, caveolae, and coated pits) have been discovered, which reveal the complex nature of the cell membrane structure.\[[@CIT3]\] Membrane lipids belong to three groups: glycerol-based lipids (phospholipids), ceramide-based sphingolipids, and cholesterol. Phospholipids are further divided into different groups, depending on their hydrophilic head groups: phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (which are largely present in the cellular membrane); in addition phosphatidylinositol and cardiolipin are present in smaller quantities. Membrane constituents are not always homogeneously arranged in the bilayer membrane of biological cells, but rather organized in complex lateral microdomains. This polymorphic nature of lipid arrangement, in addition to a significant variety of lipids, with distinctly different physical properties (i.e., cross-sectional area, fluidity, electric charge, molecular weight), make the lipid membranes extremely intricate structures. Furthermore, the covalent association of proteins and carbohydrates adds to the complexity of this membrane's structure. As a consequence of this intricacy of the cell membrane structure, along with the highly dynamic nature of the lipid--lipid and lipid--protein interactions in the cell membrane, the biophysical interactions with drugs and drug delivery systems are very difficult to investigate. Therefore, simplified artificial membrane systems, mimicking the natural bilayer lipid membrane, have been developed.
In this article, we show how differential scanning calorimetry studies of biophysical interactions with lipid model membrane systems permit to better elucidate the absorption process of a drug by a biological membrane after the release of the drug from a delivery system or after the dissolution process.
Biomembrane Models {#sec1-1}
==================
Biomembrane models are systems in which the lipid organization mimics the arrangement of lipids in natural cell membranes. Supported lipid bilayers,\[[@CIT4]\] lipid monolayers,\[[@CIT5][@CIT6]\] and liposomes\[[@CIT7]\] are widely used biomembrane models. In this contest just a brief description of liposomes, which are extensively used in our research, will be provided.
Liposomes are spherical lipid vesicles, with internal aqueous compartments. This simple structure still possesses two fundamental properties of the biological membranes: (i) due to the hydrophobic effects, membranes tend to form closed shapes, which are called vesicles; (ii) lipid molecules can move around (diffuse) rather rapidly and freely within the membranes, as they are usually in the fluid state.\[[@CIT8]\]
The use of a liposome as a tool to determine the ability of biologically active compounds (BA), to interact, dissolve, and penetrate a lipidic bilayer has been studied over the years, and a vast amount of research has been carried out in an attempt to evaluate the ability of liposomes (MLV or LUV), to operate both as a barrier in mimicking biological membranes or as a carrier in the transport of BA. The structural units of liposomes are amphiphilic molecules, especially phospholipids. The most abundant lipids in liposomes are phosphatidylcholines (PCs), in which a glycerol bridge links a hydrophobic part with a hydrophilic polar head group. In contact with water, PCs form bilayers, due to their molecular tubular shape, differently from detergents, which form micelles because of their conical shape. Other polar lipids such as sphingolipids and amphiphiles can be introduced in the liposomal bilayers. Cholesterol or other sterols, isolated from natural sources, and several lipid conjugated polymers, may be found in the liposome bilayers. The phospholipids exhibit thermotropic mesomorphism. When heated, they undergo a number of phase changes before reaching the fusion. Frequently occurring among them are the lamellar subgel L~c~ and the gel L~β~ phases, which are stable at low temperature, and the lamellar liquid crystalline L~α~ phase, stable at higher temperatures. The biological significance of the latter phase is well known, as it is accepted that the cellular membranes are liquid crystalline bilayers with proteins embedded in them.\[[@CIT9]\]
The thermodynamic properties of hydrated lipids depend on the molecular structure and on the composition of the lipid dispersion. The phosphatidylcholine phase behavior is affected by hydrocarbon chain length, unsaturation, asymmetry, and branching, as well as the type of chain--glycerol linkage and the position of chain attachment to the glycerol backbone, the head group modification, the stereochemical purity, and the morphology of the lipid aggregates (unilamellar and multi-lamellar vesicles). In addition the phase behavior is influenced by the composition of the aqueous dispersing medium.\[[@CIT10]\]
A lipid thermodynamic database (LIPIDAT) collects, in one central location, all information on lipid mesomorphic and polymorphic transitions and miscibility. The database is considered comprehensive for glycerophospholipids, sphingolipids, glycoglycerolipids, and biological membrane lipid extracts.\[[@CIT11]\]
This thermotropic behavior is investigated in depth by the calorimetric technique applied to the studies on lipids and biomembranes. A pronounced and easily detectable effect of solutes on lipid phase behavior is the shift, upward or downward, of the transition temperature. However, the other thermodynamic characteristics of the lipid phase transitions, enthalpy, transition width, and maximum specific heat, can be also influenced by solutes.
As the biomembranes are constituted by a multitude of lipids, these studies were mainly carried out on synthetic and a single kind of lipids, so that the interaction between BA and lipids could be easily considered.
It has been several years since our research group is involved in the study of the release of drugs from delivery systems to biomembrane models using the DSC technique. In this article the main results obtained from such studies will be presented. The steps of the protocol used are as follows:
To evaluate the interaction between the drug under study and the biomembrane modelsTo determinate the real amount of drug present in the phospholipid and the aqueous phases of the biomembrane model dispersionTo evaluate the factors affecting the kinetic of absorption of the free drug by biomembrane modelsTo ascertain that the delivery system does not interact with the biomembrane modelsTo evaluate the release of the drug from the delivery system to the biomembrane model
In addition a brief description of the DSC technique will be provided
Differential Scanning Calorimetry {#sec1-2}
=================================
Differential scanning calorimetry (DSC) is the most frequent technique used for determining the thermal effects of a variety of materials, including biological systems that are characterized by an enthalpy change and temperature variation. Besides being involved in the determination of the effect of hydration, pH, solvent, and kind of composition, on the phase transition, and of the changes of enthalpies of model lipid membranes and phospholipid bilayers, it is used in the thermal characterization of complex processes such as the denaturation of proteins and to study glass transition of polymers. Differential scanning calorimetry scans temperature and measures the difference between the heat flows to a sample and a reference pan that is under the same temperature program, at atmospheric pressure, and measures the heat capacity of a material. Differential scanning calorimetry measures the heat flow going into or being released by a material. From that, the heat capacity at constant pressure (*Cp*) can be calculated. Heat capacity units are cal °C^−1^ or J °C^−1^. It measures the amount of heat input (q) required to raise the temperature of a specimen by one degree Celsius while at constant pressure. Heat capacity is usually normalized by dividing the specimen heat capacity by the number of grams, to get the heat required to raise one gram of specimen by one degree Celsius. This corresponds then to the specific heat capacity *Cp*. If desired, the heat capacity can be normalized by the number of moles. Heat capacity is defined by *Cp* = (δ*q* / δ*T*)*p*,where T is the temperature and *q* is the heat input.
If the temperature changes from T~0~ to T~1~, the enthalpy of the reaction $\left( {\mathrm{\Delta}H} \right)\quad{is}\quad\mathrm{\Delta}H\quad = \quad\int_{T_{0}}^{T_{1}}CpdT$
Usually, ∆T is small, and *Cp* is independent of temperature between *T*~0~ and *T*~1~ . The integral thus reduces to ∆*H* = *Cp* (*T*~1~ - *T*~0~) = *Cp∆T*.\[[@CIT12]\]
Interaction Drug / Biomembrane Model {#sec1-3}
====================================
The first step to be taken into account in the study of the release of a BA from a delivery system to a biomembrane model is the evaluation of the interaction of the BA with the biomembrane model.
In order to evaluate this interaction, the lipid vesicles are usually prepared in the absence and in the presence of increasing amounts of BA, and the measurement of the effect of the BA on the thermotropic behavior of the phospholipid bilayers (T~m~ and ∆H), applying the van't Hoff model, is carried out.\[[@CIT13]\] It is, in fact, known that, for dilute solutions, the presence of a solute in the solvent can modify the thermodynamic parameters (such as the melting temperature) of the solvent. The solute acts as an impurity toward the solvent and the modification is dependent on the amount of the solute. In a similar way, the presence of BA in the ordinate lipidic structure can affect the thermodynamic parameters of the transition from the ordinate gel phase to the disordered liquid crystalline phase.\[[@CIT14]--[@CIT17]\] The effect is correlated to the amount and to the collocation (for similar compounds) of BA in the lipidic structure.
The biomembrane models (MLV or LUV) are generally prepared following the methods reported a little later in the text, depending on the solubility of the BA:
\(a\) BA soluble in organic solvent: To prepare the MLV, the phospholipid and the BA are separately dissolved in an organic solvent (generally chloroform / methanol, 1 : 1). Aliquots of the phospholipid solution are distributed in glass tubes in order to have the same amount of phospholipid in all the tubes. In the same tubes aliquots of the BA solution are added in order to have an increasing amount of BA. The solvents are removed under a nitrogen stream (at a temperature higher than the transition temperature of the phospholipid),and then, by freeze drying. To the obtained films a known amount of aqueous solvent at a well-defined pH (generally 50 mM Tris, pH 7.4) is added. The samples are vortexed for one minute and heated for one minute at a temperature higher than the transition temperature, thrice, and then left for one hour in a thermostated bath (at a temperature higher than T~m~). The latter step permits two important processes: the homogeneous repartition of the BA between the lipidic and the aqueous phases and the aggregation of eventual small unilamellar vesicles (SUV).
For the LUV preparation, the MLV, with or without the BA, are repetitively (19 times) passed under moderate pressure at a temperature at least 5°C above the T~m~ through polycarbonate membranes (pores diameter 100 nm) in an extruder system (LiposoFastTM Basic, Avestin Inc.).\[[@CIT18][@CIT19]\] The membrane pores are almost cylindrical, and the vesicles (unilamellar or multi-lamellar) that are larger than the mean pore diameter are reduced in size and lamellarity during the passage through the pores, resulting in a final vesicle size that corresponds to the mean size of the pores.\[[@CIT20][@CIT21]\]
\(b\) BA soluble in aqueous solvent: To obtain the MLV, a phospholipid solution in an organic solvent is prepared. A BA solution in an aqueous solvent is prepared. Aliquots of the phospholipid solution are distributed in glass tubes so as to have the same amount of phospholipid in all the tubes. The solvents are removed under a nitrogen stream (at a temperature higher than the transition temperature of the phospholipid), and later, by freeze drying. To the obtained films, defined amounts of the BA solution are added, in order to have an increasing amount of BA. The samples are vortexed for one minute and heated for one minute, at a temperature higher than the transition temperature, thrice, and then left for one hour in a thermostated bath (at a temperature higher than the T~m~). The LUV is prepared as described herewith.
To determine the real amount of phospholipid present in each sample, the phospholipid phosphorous content is assessed in the preparation by a phosphate assay, after destruction with perchloric acid.\[[@CIT22]\]
The samples are submitted to DSC analysis and the transition temperature is reported as a variation with respect to the T~m~ of the biomembrane models prepared without BA, as a function of the amount of the BA. Usually, a linear correlation between the transition temperature variation and the amount of BA exists, as shown in [Figure 1](#F0001){ref-type="fig"}, where the transition temperature variation is reported as ∆T / T~m~^0^ (∆T = T~m~-T~m~^0^; where T~m~ is the transition temperature of the biomembrane models prepared in the presence of BA and T~m~^0^ is the transition temperature of the biomembrane models prepared without BA). The calorimetric curves obtained from these experiments will be used as reference in the experiments, where the release of a BA from a delivery system to the biomembrane models is studied, as successively described.
![Depression of biomembrane model transition temperature as a function of the molar fraction of BA compound present in the aqueous lipid dispersion. Adapted from Castelli *et al*.\[[@CIT23]\]](JPBS-3-77-g001){#F0001}
Partition of the Drug between the Lipidic and the Aqueous Phases {#sec1-4}
================================================================
When the interaction BA / biomembrane model is evaluated, the repartition of the BA between the phospholipid bilayers and the aqueous medium where the biomembrane models are dispersed have to be taken in consideration.
The obtained graph described earlier \[[Figure 1](#F0001){ref-type="fig"}\] reflects the effect exerted not by the entire amount of BA present in the biomembrane model sample (aqueous lipidic dispersion), but only the effect exerted by the amount of BA present in the phospholipid bilayer. Then, the amount of BA in the phospholipid phase, which really causes the effect has to be determined.
To conduct this, the biomembrane model prepared in the presence of different molar fractions of BA is ultracentrifuged. The supernatant (containing the BA in the aqueous phase) is separated from the pellet (containing the BA in the lipidic phase), whose volume is corrected for the entrapped aqueous volume. The two aliquots are freeze dried and the obtained powders are solubilized in the opportune solvent. The amounts of BA in the two phases are determined by UV / VIS spectrometry. Then, the graph in [Figure 1](#F0001){ref-type="fig"} can be corrected by multiplying the values of the molar fractions (corresponding to the transition temperature variation) for the H~2~O / lipid partition coefficient, and subsequently, the effect on the transition temperature can be attributed to the real amount of BA present in the lipidic phase. In this manner, the obtained line (line b of [Figure 2](#F0002){ref-type="fig"}) can be used as the real calibration curve. The values of this curve permit to transform the effect exerted on the transition temperature of the biomembrane model with the amount of BA present in the phospholipid bilayer.\[[@CIT23]--[@CIT25]\]
![Calibration curve relating the depression of biomembrane model transition temperature to increasing concentration of BA present in: (a) the aqueous lipid dispersion; or (b) effectively dissolved in the lipid matrix. Adapted from Castelli *et al*.\[[@CIT23]\]](JPBS-3-77-g002){#F0002}
In addition, the log P value can give useful information on the lipophilic character of the BA and it can be obtained from the bibliographic data or otherwise it can be assessed by using computational approaches (see for example Pallas 3.0 (CompuDrug International, Inc. San Francisco USA); OSIRIS Property Explorer).\[[@CIT26]\]
Transfer of a BA from a Drug Delivery System to a Biomembrane Model {#sec1-5}
===================================================================
The use of biomembrane models is not limited to getting information on the interaction of BA with the biomembranes. They can, in fact, be used to evaluate the release of drugs from drug delivery systems. Usually, the release kinetic of a drug from a delivery system (hydrogel polymeric systems, nanoparticles, and so on) is evaluated by the use of dissolution systems, which allow to get a graph, where the amount of drug released is plotted as a function of time. This route to evaluate the release does not take into account the absence of a system that is able to take up the drug released during the time, which is instead possible in the presence of a biomembrane model.
To follow the release kinetic with an *in vivo*-like system, the differential scanning calorimetry can be used based on the following protocol.
First of all, from the experiments where the interaction between the BA and the biomembrane model is studied, the molar fraction of the drug that has a strong interaction with the biomembrane model, but at the same time, produces a well-defined calorimetric curve, is chosen as a reference curve for the highest interaction between BA and the biomembrane model. This curve will be considered in all these experiments as the curve toward which that of the biomembrane model should tend if the BA was transferred to the lipid bilayers.
Then, before following the transfer of a BA from a delivery system to a biomembrane model, the release (dissolution) and the interaction of the BA left in contact with the biomembrane model has to be considered. This experiment can clarify the effect, due to the dissolution and the migration and the successive uptake by the biomembrane model in the absence of a delivery system where the BA is molecularly dispersed. The experiments can be summarized as follows:
An exact amount of the drug is weighted at the bottom of a DSC aluminum pan and a defined amount of biomembrane model dispersion is addedAn exact amount of drug loaded delivery system (containing the drug molar fraction chosen) is weighted at the bottom of a DSC aluminum pan and a defined amount of biomembrane model dispersion is addedThe unloaded delivery system (with the same amount of that at point b) is weighted at the bottom of a DSC aluminum pan and a defined amount of biomembrane model dispersion is added
The pans are sealed and submitted to DSC analysis as follows: (a) A heating scan at the rate of 2°C/minute in a range of temperature starting about 20°C below the transition temperature of the phospholipid employed and ending about 20 C above the transition temperature of the phospholipid employed; (b) Next, the samples are left at this temperature for 60 minutes; (c) A cooling scan to bring the sample back to the starting temperature. These steps are repeated, at least, eight times. By this procedure the interaction of the delivery system and of the drug with the biomembrane model is followed both during the heating step and during the isotherm step, when the phospholipids are in a disordered liquid-crystalline phase. In fact, when the phospholipids are in a disordered phase, the drug is more able to penetrate the multibilayer (MLV) or the bilayer (LUV) and eventually to bind the phospholipids and localize among them. This process is slowed during the cooling step. The degree of interaction of the drug with the phospholipid and then the release from the carrier is quantified through the variation of the biomembrane model transition temperature.
The protocols reported earlier in the text are aimed at obtaining the following information:
When the free drug is put in contact with biomembrane dispersion, we can not only follow the uptake of the drug by the biomembrane model \[[Figure 3a](#F0003){ref-type="fig"}\], but also the dissolution and diffusion processes through the aqueous phase of the drug, which, in this case, are affected by the uptake process. We can also measure the effect of the pH on the dissolution of the drug and consequently on its interaction with the biomembrane model.When the drug loaded delivery system is put in contact with biomembrane model dispersion we can evaluate the uptake of the drug released from the delivery system, the process of hydration of the dissolution of the delivery system, the drug diffusion through the delivery system, and successively through the aqueous phase \[[Figure 3b](#F0003){ref-type="fig"}\]. In this case even the effect of the pH on these processes can be evaluated.When the unloaded delivery system is put in contact with the biomembrane model dispersion, we can evaluate the eventual effect of the system on the thermotropic parameters of the biomembrane model. In case we obtain no effects, we can ascertain that when we put the loaded delivery system in contact with the biomembrane model, the effect on the transition temperature is exerted just by the drug. In this process even the effect of the pH can be monitored.
{#F0003}
Depending on the use of MLV and LUV, different information can be obtained. Let us consider the use of MLV first.
The permeation of a multi-lamellar vesicle by a BA, which is in the proximity of the biomembrane model, determines interesting effects on the thermotropic behavior of the membrane. The time variation of the specific heat profile can be used to get information on the BA diffusivity within the multi-lamellar vesicle, as shown in [Figure 4](#F0004){ref-type="fig"}. At an early stage of the process the calorimetric curve is similar to that of the pure lipid, with a sharp maximum near the T~m~ of the pure phospholipid; at intermediate times a splitting of the calorimetric peak is observed due to the local inhomogeneities of the composite membrane; finally, in the late stages of the process, the two peaks merge forming a single peak that has shifted to a lower temperature than that of the pure phospholipid phase transition.\[[@CIT27]\]
![Upper part: the concentration (Ф) profile of a BA inside a multi-lamellar vesicle at different times. *r* is the multi-lamellar vesicle radius. At *t* = 0 all the BA molecules are in the external aqueous medium (A). At intermediate times (B) one observes a nonlinear concentration gradient throughout the membrane which becomes linear in the late stages (steady-state C). At *t* = ∞ the BA concentrations in the external and internal aqueous medium become identical (D). Lower part: the corresponding variation of the specific heat (*Cp*) with temperature (*T*) at different times. *T*~m~^0^ is the melting temperature of the unperturbed multi-lamellar vesicle. Adapted from Raudino *et al*.\[[@CIT27]\]](JPBS-3-77-g004){#F0004}
Both, when the BA is in a free form or it is contained in the delivery system, three different cases can take place.
The BA does not transfer or transfers in a very low amount, through the aqueous medium, to the biomembrane model.After the first incubation period, the BA transfers through the aqueous medium into the outer MLV layers, and successively, it transfers to the inner layers.The BA quickly transfers, partially or completely, to all the MLV layers.
Then, the examination of the calorimetric curves permit us to determine which of the three cases occurs \[[Figure 5](#F0005){ref-type="fig"}\]. Let us consider the case (a) the condition of non-transfer of the drug to the MLV is evidenced by the unchanged calorimetric curve during the entire incubation time.
![Panel A. Calorimetric curves during the permeation kinetic of a drug released from a delivery system through multi-lamellar vesicles. The arrows mark the position of the multi-lamellar vesicles at t = 0. Adapted from Raudino *et al*.\[[@CIT27]\] Panel B. Schematic representation of what happens in the calorimetric pan. In (a) the drug is not released from the delivery system and the calorimetric curve remains unchanged. In (b), initially, the drug is released from the delivery system and transferred to the external bilayers of MLV and a double peak is observed in the calorimetric curve; as the time passes the drug localized also in the internal bilayers and a unique peak is observed in the calorimetric curve. In (c) the drug released from the delivery system quickly localizes uniformly in all the bilayers and a unique peak is observed from the first times of contact](JPBS-3-77-g005){#F0005}
In the case (b), the calorimetric curve associated to the early time of contact between the delivery system and the MLV, is very similar to that of the MLV; as the time passes the main peak splits into two peaks, caused by the inhomogeneous distribution of the BA in the MLV; in particular the BA mostly localizes in the outer bilayers; the successive scans allow the BA to pass into the inner layers by a flip-flop mechanism, in a series of mobile equilibria, among the BA loaded layers, the BA unloaded layers, and the aqueous medium. Such equilibrium brings to the final state and the two peaks merge in an unique peak due to the homogenous distribution of the BA in the multi-lamellar bilayers. The occurrence of case (c) is evidenced by the presence of an unique main peak which, quickly or slowly, moves to a lower temperature than that of the pure phospholipid.
As stated before, by using the MLV we were able to detect the uptake process of a BA (free or delivery system released) by the biomembrane model, by considering the T~m~ shift. If the T~m~ moved toward the value observed when the same amount of BA was placed in the MLV during their preparation, we considered it a complete transfer of the BA into the inner lipid layers.
To be sure that such a process was complete and to better define if the limiting step of the transfer process could be attributed to the dissolution and migration in the aqueous medium, rather than the permeation and partition into the lipid multilayers, LUV were employed.
The LUV, having only one bilayer, do not show the problem of the BA transfer from the aqueous medium to the outer bilayers and then to the inner bilayers; then we can consider, by studying their behavior, the transfer limitation due to the medium surrounding the vesicles.
[Figure 6](#F0006){ref-type="fig"} shows the three possibilities that can occur when a BA (free or loaded in a delivery system) is left in contact with the LUV.
![Calorimetric curves during the permeation kinetic of a drug thought unilamellar vesicles. The arrows mark the position of the unilamellar vesicles at t = 0. In (a) the drug is not released from the delivery system and the calorimetric curve remains unchanged. In (b) the drug is slowly released from the delivery system and transferred to LUV and the calorimetric peak slowly moves to lower temperature. In (c) the drug is quickly transferred from the delivery system and transferred to LUV and the calorimetric peak quickly moves to lower temperature. Adapted from Raudino *et al*.\[[@CIT27]\]](JPBS-3-77-g006){#F0006}
As stated before for MLV, in the case (a) the BA is not able to reach the LUV surface even after several incubation periods at a temperature higher than the T~m~ . In this case, processes such as low dissolution rate and unfavorable partition between delivery system and water avoid the BA-LUV interaction.
If the BA dissolves in the medium surrounding it or it is released by the delivery system and migrates to the LUV surface interacting with it, we can differentiate if the limiting step is the process of dissolution or release with respect to the interaction with the LUV bilayer by comparing the curves (b) and (c). In b, it is evidenced that the slow interaction BA-LUV can be ascribed to a lower availability of the drug near the LUV surface; while the curves (c) indicate a fast interaction that can be ascribed to the fast absorption caused by the high availability of the BA.
The interaction observed when a fixed amount of BA is put in contact with an MLV or LUV, compared with that observed when the BA is loaded in the vesicles during their preparation, gives useful information about the processes of dissolution, release, and uptake.
The comparison between the effect exerted by a BA on MLV or LUV (curves (b) and (c) in Figures [5](#F0005){ref-type="fig"} and [6](#F0006){ref-type="fig"}) allows to determine if the limiting step is the uptake or the transfer process and also gives information about the ability of the BA to cross the lipid layers penetrating inside the MLV. In fact, depending on the rate of interaction, if the transfer of BA from the outer to the inner layers of the MLV is complete, beside a uniform distribution, we will obtain a calorimetric curve similar to that of LUV and to those of MLV, prepared in the presence of the same amount of BA.
This protocol was used for instance to follow the release of model drugs from an inulin-based hydrogel (intended to release the drug in the colon), α,β-polyasparthydrazide (PAHy) hydrogels, α,β-poly(N-hydroxyethyl)-[DL]{.smallcaps}-aspartamide (PHEA) hydrogels, Eudragit microparticles, and poly(lactide-co-glycolide) micropheres.
With regard to the release of the drug (diflunisal) from the inulin-based hydrogel, the influence of the drug loading of the hydrogel swelling degree and of the pH on the release was evidenced.\[[@CIT28]\] In that study, DMPC unilamellar vesicles were used as the biomembrane model. The results obtained at pH 7.4 suggested that with a drug loading of 10.4% (w/w) the hydrogel swelled, but diflunisal, that was not so abundant inside the polymeric network, it would take time to dissolve and migrate through the network. When hydration and swelling occurred, the release would become faster. For the hydrogel with the highest drug loading (24%, w/w) we observed an initial fast release, due to the free drug molecularly dissolved inside the polymer; the following release was also fast, but not complete, perhaps due to the high amount of drug loaded in the hydrogel that could affect the swelling and so the release; or it could be also possible that during dissolution the drug started to crystallize due to the high concentration, forming large crystals that obviously dissolved slowly. The best profile of release was obtained with a drug loading of 17% (w/w); wherein besides a fast initial release, a complete release of the drug occurred, probably due to a good balance between drug dispersion in the polymeric network and swelling of the hydrogel. At pH 4, the diflunisal release from the hydrogel with a drug loading of 10.4% (w/w) was low for all the experimental period, due to the low amount of drug present in the hydrogel, the lower swelling at such a pH, and the low-aqueous solubility of the drug; all these factors contributed to reducing the release of diflunisal. The release of the drug from the hydrogel with a drug loading of 24% (w/w) was slower than that with a drug loading of 17% (w/w), and incomplete, thus indicating that the formation of drug aggregates together with migration through the polymeric network, made it difficult for the dissolution process to occur. Seventeen percent (w/w) represented the best loading, allowing a complete release and transfer of the diflunisal to the biomembrane model.
Dipalmitoylphosphatidylcholine (DPPC) LUV and DSC were employed to study the suitability of the hydrogels obtained by chemical crosslinking of α,β-polyasparthydrazide (PAHy) by glutaraldehyde, as carriers for prolonged release of poorly soluble drugs, and the modulating effects exerted by polymer crosslinking.\[[@CIT23]\] It emerged that by increasing the polymer crosslinking degree the total amount of transferred drug and the release velocity were decreased. This behavior may be caused by the increase in the number of cruciate bonds in the hydrogels, which cause a free volume reduction, obstructing the passing drug.
Successively, PAHy hydrogels were crosslinked with different agents (ethyleneglycoldiglycidylether (EGDGE) polyvinylalcohol (PVA) and glutaraldehyde (GLU)) and different degree of crosslinking and the release of diflunisal by these hydrogels was carried out with the aim to evaluate the effect of the crosslinking agent and the degree of crosslinking on the release. It appeared evident that the total amount of drug transferred and the release rate were affected by the polymer crosslinking degree (it increased with the crosslinking degree) as well as on the nature of the crosslinking agent.\[[@CIT29]\]
The study of the ketoprofen release from a derivative of the α, β-polyapartylhydrazide polymer containing hexadecylamine to biomembrane models made of DMPC / DMPA vesicles permitted (i) to demonstrate that the polymer was able to release the drug and (ii) to explain how the release could happen; it was in fact, proposed that the hexadecylamine moiety penetrated into the lipidic bilayers, followed by the delivery of the drug. In this manner the micelles could improve the localized release close to the biological target.\[[@CIT30]\]
The analysis of the release of ketoprofen from polymeric micelles made of PHEA-C16 and PHEA-PEG2000C16 to DMPC / DMPA vesicles permitted to hypothesize a likely mechanism of drug migration from the micelles to the vesicles: We can suppose that the C16 chains interact with the lipidic bilayer, thus causing the opening of the micellar structure and facilitating drug penetration in the lipidic vesicle.\[[@CIT31]\]
Biomembrane models made of DPPC MLV were used\[[@CIT32]\] to study the release of moxifloxacin from uncrosslinked and crosslinked (glutaraldehyde as crosslinking agent) chitosan microspheres intended for pulmonary administration. The results showed that uncrosslinked microspheres swelled rapidly and dissolved, releasing free chitosan that was able to interact with the liposomes (increase of ∆H value), probably altering the biomembrane permeability to the drug. Crosslinked microspheres did not show this property.
The release of diclofenac from Eudragit RS100^®^ microparticles and the effect of the pH on such a release was also investigated.\[[@CIT33]\] In such a study of DMPC MLV (as biomembrane models), microparticles containing two different amounts of diclofenac (14.26 and 25.0%) and two different pHs (7.4 and 4.0) were used. At pH 7.4, the release process for the microparticles loaded with a higher amount of drug appeared to be faster with respect to the lower loaded microparticles, both being slower than the free drug. In fact, the drug dissolved easily in the external pH 7.4 medium and was readily absorbed by the biomembrane model. Drug release from the microparticles was hindered by the acidic pH, which prevented its dissolution and migration through the aqueous medium to reach the model membrane. The results obtained from this study suggested that the process of drug dissolution through a polymeric matrix could be affected by the amount of drug loaded, but mainly by the pH of the dissolution medium.
The release of flurbiprofen, an acidic drug, from Eudragit RS100^®^ and Eudragit RL100^®^ nanosuspensions, was studied at pH 7.4 and the results obtained from DSC, where a biomembrane model (DMPC MLV) was used, and the dialysis experiments were compared.\[[@CIT34]\] The results showed a plateau in the dissolution profile of flurbiprofen from the nanoparticles, which was related to an equilibrium among the drug release, the drug ionization in the dissolution medium, and the saturation of the binding sites on the surface of polymer particles. This behavior was ascribed to the fact that the dissolved drug that got ionized in the neutral dissolution medium was readsorbed onto the polymer particles because of the presence of opposite electrical charges. In the dialysis experiments the driving force leading to flurbiprofen release from the nanoparticles was the volume and light alkaline pH of the dissolution buffer; the absence of an uptaking system in the external medium made the release profile more strictly dependent on the nature of the polymers. In fact the two polymers showed similar time-release curves, but with a higher amount of drug released from the more permeable RL matrix. Although, when the biomembrane model was used, the drug release profile was conditioned by the MLV bilayers to capture and retain the drug molecules after their release from the polymeric system. In these experiments the volume of the dissolution medium was much smaller with respect to that of the dialysis experiments. The equilibrium among the drug bound to the nanoparticles surface, the fraction dissolved in the medium, and the amount captured by MLV were strongly affected by the affinity of the drug for the RS or RL polymers. As a consequence, the behavior observed for RL and RS nanosuspensions was quite different. In fact, although the maximum released amount was higher for the RL system due to its higher water permeability, the MLV incubated with RS nanoparticles showed a quicker uptake of the dissolved drug. The comparison of the results obtained from the two different kinds of experiments permitted us to conclude that although in the dialysis tests the permeability of RS and RL polymers was the limiting step of the release of an acidic drug such as flurbiprofen, in the smaller space of the DSC pan, the affinity equilibrium for a nanoparticle surface or MLV bilayers played a big role in determining the overall drug release profile.
Similar results were obtained in a study where the release of ibuprofen from Eudragit RS100^®^ and Eudragit RL100^®^ nanosuspensions was studied.\[[@CIT35]\]
Transfer of a BA from a Lipophilic Drug Delivery System to Biomembrane Models {#sec1-6}
=============================================================================
The previous model can also represent a useful approach in studying the transfer of a drug from a lipophilic carrier to the biomembrane model, taking advantage of the use of a drug-loaded MLV, using the following protocol: In the calorimetric pan, equimolar amounts MLV, loaded with a known molar fraction (X = n) of the BA, which mimics a lipophilic carrier, and of the drug-unloaded MLV (X = 0), which mimics the biomembrane model, are put in contact and submitted to calorimetric analysis, in which a heating scan is followed by an isothermal period of one hour at a temperature higher than that of the phospholipid and then by a cooling scan, several times.
Three different cases can occur: (a) the drug does not transfer from the loaded to the unloaded MLV, (b) the drug slowly transfers from the loaded to the unloaded MLV, and (c) the drug quickly transfers from the loaded to the unloaded MLV. The analysis of the calorimetric curves and their comparison with the calorimetric curve (reference curve) obtained from the MLV prepared in the presence of BA at X = n/2 gives us information on which of the cases occurs \[[Figure 7](#F0007){ref-type="fig"}\]. The curve X = n/2 should be obtained if 50% of BA is contained in the loaded MLV transferred to the unloaded MLV.
{#F0007}
If case (a) occurs the calorimetric traces are characterized by two peaks, simply resulting from the sum related to the unloaded and loaded MLV, which were put in contact. This curve remains unaltered for all the calorimetric scans without reaching the reference curve (shape or position).
If event (b) takes place, the calorimetric curves exhibit two peaks related to the unloaded and loaded MLV that were put in contact, in which, as the incubation time passes, the drug transfers from the loaded to the unloaded MLV and the two peaks approach each other (the peak related to the loaded MLV loses the BA and moves toward a higher temperature; whereas, the peak related to the unloaded MLV is enriched with BA and moves toward a lower temperature) and merge in a unique peak, which overlaps the reference curve.
The case (c) is characterized by a single calorimetric peak, due to the fast transfer of the BA from the loaded to the unloaded MLV and with a fast transfer from the outer to the inner bilayers, which gradually moves toward lower temperature. If the transfer is complete the calorimetric curve reaches the reference curve.
This protocol was used with gemcitabine and acyclovir prodrugs obtained by the conjugation of the drug with Squalene.\[[@CIT36][@CIT37]\] These prodrugs were obtained with the aim of increasing the lipophilic character of the drug. It was found that the affinity of the prodrugs to the biomembrane models was much stronger with respect to the free drug and the prodrugs were released from the loaded MLV to the unloaded MLV very gradually, suggesting that the liposomes could be used as a carrier for the sustained release of the prodrugs.
In a recent article of our research group it was shown that trimethylresveratrol transfers slowly from the lipophilic carrier to the biomembrane models; whereas resveratrol exhibits a quicker kinetics of transfer.\[[@CIT38]\] These behaviors can be explained by the different lipophilicity of the two compounds. Trimethylresveratrol being more lipophilic than resveratrol has a bigger affinity for the lipophilic environment, with respect to resveratrol; hence, it leaves the lipophilic carrier slower than resveratrol. In a recent research\[[@CIT39]\] the transfer of omega-3 fatty acids from a lipophilic carrier to biomembrane model was studied. From that study it has emerged that docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) possessing the same carbon atoms, but differing in the unsaturation (DPA with five double bonds and DHA with six double bonds) show different behaviors. In fact, the transfer from the loaded to the unloaded MLV is slow and not complete for DPA, but quick and complete for DHA. The smaller and slower transfer of DPA was attributed to its stronger affinity for the lipophilic environment of MLV.
Toward Modelization of the Combined Release-uptake Kinetics {#sec1-7}
===========================================================
The great deal of experimental study described in the previous sections can be exploited in order to gain quantitative information about a number of useful parameters related to the release-uptake process in biological systems. This goal can be accomplished by developing a non-trivial mathematical modelization of the involved coupled processes. Here we sketch the minimal physical effects to be considered in a minimal but realistic picture. The starting point for any release kinetics is the transport equation
$$\frac{\partial C_{i}}{\partial t}\quad = \nabla J_{i}\left( C_{i} \right) + F\left( C_{i} \right)$$
which states that the time variation of the concentration *C~i~* of a generic i-th species depends upon the difference between the ingoing and outgoing flux *J~i~(C~i~)* inside a generic volume element of the system (the term ∇*J~i~(C~i~)*, the symbol ∇ meaning spatial difference) augmented by a term that describes the concentration variation related to eventual chemical reactions (the term *F(C~i~)*. The flux J~i~(C~i~) can originate from different causes. In the simplest case it originates from the concentration gradients (Fick's law: *J~i~(C~i~)* ≈ *D~i~gradC~i~*, where *D~i~* is the diffusion coefficient of the i-th species). Things are generally more intricate because the diffusion coefficient *D~i~* may depend on the swelling degree of the carrier's matrix (see, e.g., Grassi *et al*,\[[@CIT40]\]), moreover, other complex effects, such as hydrodynamic effects, may contribute.
A similar equation must be used to deal with the uptake of a diffusing molecule. There is, however, a key difference, because a key contribution comes from the 'immobilization' of the processes occurring when the diffusant is trapped at a generic binding site. These immobilization effects can be described in a variety of ways, one of the simplest ones is to introduce a fictious chemical reaction, which destroys the diffusing particles when they hit the binding sites within the target. Such an effect modifies the local concentration of the diffusant, and therefore, the whole diffusant motion. In the case of a prescribed distribution of irreversible traps, the kinetic term to be added to the diffusion equation takes the simple form: *F(Ci)* ≈ *k* *(C*($\overset{\rightarrow}{r}$)-- *C~i~)C~i~*, where *C*($\overset{\rightarrow}{r}$)is the spatial distribution of the target's binding sites and *k* is the kinetic constant of the binding process (therefore the quantity *C*($\overset{\rightarrow}{r}$)-- *C~i~* describes the number of unoccupied binding sites). The above-mentioned model leads to two coupled diffusion-type equations (associated with the release and uptake processes, respectively) that can be easily solved.
Once the time-varying local concentration of the diffusant has been calculated, we can easily calculate the variation of the calorimetric properties in each region of the sample. Indeed, as previously stated, the transition temperature and the associated enthalpy of a system (e.g., a multi-lamellar liposome) depend on the local concentration of a foreign compound; such a relationship is empirically determined by calibration curves. Thus the real calorimetric signal calculated at different times is proportional to the space concentration of the diffusant averaged over the whole sample.
The advantage of the above sketched mathematical model is twofold:
It enables one to numerically derive useful parameters such as the diffusion mobility of a drug in different matrices (e.g., a multi-lamellar liposome), the water-lipid partition coefficient, the release kinetic constant from a dissolving matrix, and so on.To test the validity of release-uptake mechanisms by the fitting of theoretical and experimental curves.
Studies along these lines will be discussed in a near future.
In conclusion, the use of biomembrane models and differential scanning calorimetry are useful approaches to study the release of a BA from a delivery system, as also the uptake of the BA from biomembranes models. In our researchers we have studied the release of BA from several kinds of delivery systems and we have obtained useful information, not only on the kinetics of the release, but also on the uptake of the BA by the biomembrane. The described approach can be applied to study the BA release from delivery systems other than those described in this article. For example, in some of our studies we have employed the differential scanning calorimetry to characterize solid lipid nanoparticle (SLN) and nanostructured lipid particle (NLP) colloidal carriers,\[[@CIT41][@CIT42]\] developed as alternative systems to the existing traditional carriers (emulsions, liposomes, and polymeric nanoparticles), especially for the delivery of lipophilic compounds and recently, due to its versatility, we have applied the described approach to follow the release of drugs from SLN and NLP, and their uptake by biomembrane models.
**Source of Support:** Nil
**Conflict of Interest:** None declared.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Q:
appcompat-v7:27.1.1 conflicts with play-services:11.0.1
I am working on a new app. Presently I am trying to add dependency.
implementation 'com.google.android.gms:play-services:11.0.1'
When I do I get a gradle compile error on implementation 'com.android.support:appcompat-v7:27.1.1' saying:
All com.android.support libraries must use the exact same version specification (mixing versions can lead to runtime crashes). Found versions 27.1.1, 26.1.0. Examples include com.android.support:animated-vector-drawable:27.1.1 and com.android.support:mediarouter-v7:26.1.0
Any ideas how to best resolve this issue?
Gradle file
apply plugin: 'com.android.application'
android {
compileSdkVersion 27
defaultConfig {
applicationId "com.example.boulbabazitouni.getdevicelocation_time"
minSdkVersion 21
targetSdkVersion 27
versionCode 1
versionName "1.0"
testInstrumentationRunner "android.support.test.runner.AndroidJUnitRunner"
}
buildTypes {
release {
minifyEnabled false
proguardFiles getDefaultProguardFile('proguard-android.txt'), 'proguard-rules.pro'
}
}
}
dependencies {
implementation fileTree(include: ['*.jar'], dir: 'libs')
implementation 'com.android.support:appcompat-v7:27.1.1'
implementation 'com.android.support:support-vector-drawable:27.1.1'
implementation 'com.android.support:mediarouter-v7:27.1.1'
implementation 'com.android.support.constraint:constraint-layout:1.1.0'
testImplementation 'junit:junit:4.12'
androidTestImplementation 'com.android.support.test:runner:1.0.2'
androidTestImplementation 'com.android.support.test.espresso:espresso-core:3.0.2'
implementation 'com.google.android.gms:play-services:11.0.1'
}
A:
The problem is that you have some transient dependencies in this libraries. Whenever this happens you can explicitly add the conflicting dependencies and match them with your current version:
implementation 'com.android.support:animated-vector-drawable:27.1.1'
implementation 'com.android.support:mediarouter-v7:27.1.1'
implementation 'com.android.support:support-v4:27.1.1'
| null |
minipile
|
NaturalLanguage
|
mit
| null |
[Change in liver size caused by antitubercular combination therapy].
In 23 patients undergoing antituberculous combination treatment, an ultrasonographic study of the dimensions of the liver was carried out every two weeks for the first two to three months of treatment. Starting with the fourth to sixth week on the therapeutic regimen, significant increases in the width of the left, and the length of the right liver lobes amounting to an average of 1 cm (11%) were established. Differences in the time course of changes in liver size were not to be found, neither in connection with adverse reactions, nor as a function of sex. Between the age of the patient and the depth parameters of the right liver lobe, however, significant positive regressions were observed with the course of treatment. Patients older than 40 years experienced a more marked increase in liver size under therapy. Patients with a history of alcohol abuse and those with side effects, have, on average, larger livers. Slow acetylators manifest a slightly greater increase in the size of the liver during treatment than do rapid acetylators. None of the patients investigated revealed any clinically relevant hepatotoxic side effects. There was no strict correlation between transient transaminase elevations and ultrasonographic changes in the hepatic architecture.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
INTRODUCTION {#s1}
============
Cell migration is a complex biological process that supports or underlies a diverse range of physiological or pathological events and functions including embryonic development, immune responses and tumor metastasis. While the continuous inward movement of actin filaments provides driving forces for cell migration, a transmission mechanism is required between the motile and stationary parts in the cytoskeleton-adhesion linkage ([@BIO016428C8]; [@BIO016428C7]). We have recently reported that p130Cas (Crk-associated substrate, hereafter referred to as Cas) is involved in such a transmission as it supports cell migration by linking the actomyosin-driven actin retrograde flux to the cell-extracellular matrix adhesions ([@BIO016428C14]). We have shown that both the Src-mediated tethering and the actomyosin-driven displacement of Cas are involved in the mechanism that drives cell migration. Detailed analysis regarding the process of Cas displacement has revealed that upon phosphorylation of the substrate domain (CasSD), Cas molecules move inward in association with the actin retrograde flux, and get dissociated from focal adhesions. However, it remains unclear how actin cytoskeletons are linked to Cas molecules with phosphorylated CasSD.
In search for such a molecule or molecular complex that can interact with both actin filaments and phosphorylated Cas simultaneously, we consolidated previous reports on actin-associating proteins that may bind to phosphotyrosine-containing polypeptides. Tensin 1 is a focal adhesion protein that has been reported to associate with actin filaments through its actin-binding domains located in the amino-terminal and central regions of the molecule ([@BIO016428C5]; [@BIO016428C2]; [@BIO016428C19]). In addition, tensin 1 has the phosphotyrosine-binding SH2 (Src homology 2) and PTB (phosphotyrosine-binding) domains ([@BIO016428C18]). It has been documented that tensin 1 co-immunoprecipitates with Cas *in vitro*, although physiological role of the tensin 1-Cas interaction has not been defined ([@BIO016428C9]). Therefore, we tested tensin 1 as a molecule that links actin cytoskeletons to phosphorylated Cas.
RESULTS AND DISCUSSION {#s2}
======================
Cas, but not its phosphorylation-defective mutant, co-localizes with tensin 1 at focal adhesions in the regions close to leading edge {#s2a}
-------------------------------------------------------------------------------------------------------------------------------------
We first examined whether tensin 1 co-localized with Cas in relation to Cas phosphorylation. To this end, we analyzed mouse embryonic fibroblasts (MEFs) derived from Cas knockout (CasKO) mice ([@BIO016428C11]) expressing Cerulean-tagged tensin 1 (Cerulean-tensin 1) together with green fluorescent protein (GFP)-tagged Cas wild-type (GFP-CasWT) or its phosphorylation-defective mutant (GFP-Cas15YF) ([@BIO016428C14]) using a confocal microscope. We observed that GFP-CasWT and Cerulean-tensin 1 co-localized at focal adhesions in the regions close to leading edges of migrating cells ([Fig. 1](#BIO016428F1){ref-type="fig"}A, top panels). In contrast, Cerulean-tensin 1 was poorly localized at focal adhesions in GFP-Cas15YF-expressing CasKO MEFs, and there was no apparent co-localization of Cerulean-tensin 1 and GFP-Cas15YF ([Fig. 1](#BIO016428F1){ref-type="fig"}A, bottom panels). Furthermore, indirect immunofluorescence staining using an anti-phospho-Cas antibody (pCas-165) ([@BIO016428C6]; [@BIO016428C17]) showed a correlation between GFP-CasWT-Cerulean-tensin 1 co-localization and Cas phosphorylation ([Fig. 1](#BIO016428F1){ref-type="fig"}A, top panels). These findings suggest that tensin 1 co-localizes with Cas at focal adhesions in the leading regions of migrating cells, depending on Cas phosphorylation. Fig. 1.**Cas co-localizes with tensin 1 at focal adhesions in the regions close to leading edge of migrating cells depending on Cas phosphorylation.** (A) Confocal images of CasKO MEFs expressing Cerulean-tensin 1 together with either GFP-CasWT (top panels) or GFP-Cas15YF (bottom panels) after immunostaining against phosphorylated Cas. Monolayers of GFP-CasWT- or GFP-Cas15YF-expressing CasKO MEFs transfected with Cerulean-tensin 1 were subjected to wound healing experiments. Migrating cells were fixed, subjected to immunofluorescence staining and viewed with a confocal microscope. Magnified images of boxed regions are shown in insets. Merged images of the boxed regions are also shown (blue: Cerulean-tensin 1, red: phospho-Cas, green: GFP-CasWT or GFP-Cas15YF). Scale bar: 5 μm. Arrows indicate the direction of cell migration. (B) Anti-FLAG immunoprecipitates from the lysate of HEK293T cells expressing Cerulean-tensin 1 together with either FLAG-CasWT or FLAG-Cas15YF were analyzed by immunoblotting. HEK293T cells were co-transfected with Cerulean-tensin 1 together with either FLAG-CasWT or FLAG-Cas15YF. 24 h after transfection, cells were lysed and subjected to anti-FLAG immunoprecipitation followed by SDS-PAGE and anti-FLAG or anti-GFP immunoblotting. Anti-β-actin blot provided a loading control. Cerulean-tagged proteins were detected using an anti-GFP antibody that cross-reacted to Cerulean (anti-GFP blot). (C) Schematic representation of truncated mutants of tensin 1. SH2, Src-homology 2 domain; PTB, phosphotyrosine-binding domain. (D) Confocal images of CasKO MEFs expressing GFP-CasWT together with Cerulean-tensin 1 (top panels), Cerulean-tensin 1-ΔSH2PTB (middle panels) or Cerulean-tensin 1-SH2PTB (bottom panels). Monolayers of GFP-Cas-expressing CasKO MEFs transfected with either Cerulean-tensin 1, Cerulean-tensin 1-ΔSH2PTB or Cerulean-tensin 1-SH2PTB were subjected to wound healing experiments. Migrating cells were then viewed with a confocal microscope. Magnified images of boxed regions are shown in insets. Merged images of the boxed regions are also shown (blue: Cerulean-tensin 1, Cerulean-tensin 1-ΔSH2PTB or Cerulean-tensin 1-SH2PTB, green: GFP-CasWT). Scale bar: 5 μm. Arrows indicate the direction of cell migration. (E) Anti-FLAG immunoprecipitates from the lysate of HEK293T cells expressing FLAG-CasWT together with either Cerulean, Cerulean-tensin 1, Cerulean-tensin 1-ΔSH2PTB or Cerulean-tensin 1-SH2PTB were analyzed by immunoblotting. HEK293T cells were co-transfected with FLAG-CasWT together with either Cerulean only, Cerulean-tensin 1, Cerulean-tensin 1-ΔSH2PTB or Cerulean-tensin 1-SH2PTB. 24 h after transfection, cells were lysed and subjected to anti-FLAG immunoprecipitation followed by SDS-PAGE and anti-FLAG or anti-GFP immunoblotting. Anti-β-actin blot provided a loading control. Cerulean-tagged proteins were detected with anti-GFP blot as in B. Asterisks indicate the IgG bands (∼26 kD and ∼52 kD) and unidentified non-specific bands (∼125 kD). B and E represent one of three independent experiments with similar results.
To biochemically analyze the interaction between tensin 1 and Cas, we conducted a co-immunoprecipitation assay using human embryonic kidney (HEK) 293T cells expressing Cerulean-tensin 1 together with FLAG-tagged wild-type Cas (FLAG-CasWT) or Cas15YF (FLAG-Cas15YF). We found that Cerulean-tensin 1 was co-immunoprecipitated with FLAG-CasWT ([Fig. 1](#BIO016428F1){ref-type="fig"}B, left lane). In contrast, Cerulean-tensin 1 was poorly co-immunoprecipitated with FLAG-Cas15YF ([Fig. 1](#BIO016428F1){ref-type="fig"}B, right lane). These results suggest that the interaction between Cas and tensin 1 is dependent on Cas phosphorylation, while the apparently faint association between FLAG-Cas15YF and Cerulean-tensin 1 leaves the possibility of the existence of an additional mechanism of Cas-tensin 1 binding independent of Cas phosphorylation.
The SH2PTB domains of tensin 1 are responsible for its interaction with phosphorylated Cas {#s2b}
------------------------------------------------------------------------------------------
The SH2 and PTB domains of tensin 1 (hereafter referred to as tensin 1-SH2PTB) are reportedly responsible for its association with phosphotyrosine-containing proteins ([@BIO016428C5]; [@BIO016428C2]; [@BIO016428C19]). We therefore examined whether tensin 1-SH2PTB played a significant role in the association between phosphorylated Cas and tensin 1 by testing tensin 1 (full-length) and its deletion mutants, tensin 1-ΔSH2PTB and tensin 1-SH2PTB ([Fig. 1](#BIO016428F1){ref-type="fig"}C). In contrast to Cerulean-tensin 1 (full-length) ([Fig. 1](#BIO016428F1){ref-type="fig"}D, top panels) and Cerulean-tensin 1-SH2PTB ([Fig. 1](#BIO016428F1){ref-type="fig"}D, bottom panels), Cerulean-tensin 1-ΔSH2PTB was poorly localized at focal adhesions and did not exhibit apparent co-localization with GFP-CasWT ([Fig. 1](#BIO016428F1){ref-type="fig"}D, middle panels) in the leading regions of migrating cells when they were co-expressed in CasKO MEFs. Consistently, co-expression experiments using HEK293T cells revealed that Cas co-immunoprecipitated with tensin 1 and tensin 1-SH2PTB ([Fig. 1](#BIO016428F1){ref-type="fig"}E, lanes 2 and 4), but very poorly with tensin 1-ΔSH2PTB ([Fig. 1](#BIO016428F1){ref-type="fig"}E, lane 3). These results indicate that SH2PTB domains are crucial for tensin 1 to associate with Cas at focal adhesions in the leading regions, while the apparent co-localization of GFP-CasWT and Cerulean-tensin 1 or Cerulean-tensin 1-ΔSH2PTB in the central regions of cells ([Fig. 1](#BIO016428F1){ref-type="fig"}D, top and middle panels) may denote Cas-tensin 1 interaction independent of the SH2PTB domains of tensin 1. Based on the significance of Cas dynamics at focal adhesions in cell migration ([@BIO016428C14]), we specifically focus, in this study, on behaviors of Cas and tensin 1 in the leading regions.
We then examined whether tensin 1-SH2PTB alone bound to Cas in a CasSD phosphorylation-dependent manner. We prepared a bacterially expressed recombinant protein in which tensin 1-SH2PTB was fused to GST (glutathione-S transferase), and conducted a GST pull-down assay. We found that FLAG-Cas was brought down with GST-tensin 1-SH2PTB ([Fig. S1](Fig. S1), lane 2). Furthermore, FLAG-Cas 'pull-down' with GST-tensin 1-SH2PTB was remarkably enhanced when Cas phosphorylation was increased by treating the cells with phenylarsine oxide (PAO), the tyrosine phosphatase inhibitor ([Fig. S1](Fig. S1), lane 4). These findings support the notion that tensin 1 associates with Cas through the binding between tensin 1-SH2PTB and phosphorylated Cas.
Exogenous expression of tensin 1-SH2PTB interferes with Cas-driven cell migration {#s2c}
---------------------------------------------------------------------------------
Tensin 1 has been reported to positively regulate cell migration ([@BIO016428C4]; [@BIO016428C3]). Consistently, we observed that the silencing of tensin 1 impeded cell migration in a wound healing assay ([Fig. S2](Fig. S2)). We postulated that the tensin 1-SH2PTB-mediated interaction between tensin 1 and Cas ([Fig. 1](#BIO016428F1){ref-type="fig"}E,F) might be responsible for the linkage of phosphorylated Cas to actin cytoskeletons that drives cell motility ([@BIO016428C14]). To test this, we examined whether the exogenous expression of tensin 1-SH2PTB protein ([Fig. S3](Fig. S3)) that binds to phosphorylated Cas ([Fig. S1](Fig. S1)) but lacks the actin-binding motifs modulated Cas-driven cell migration. As shown in [Fig. 2](#BIO016428F2){ref-type="fig"}A and B, the expression of mCherry-Cas in CasKO MEFs significantly promoted the cell migration (compare columns 1 and 4 in [Fig. 2](#BIO016428F2){ref-type="fig"}B). While the expression of GFP-tensin 1-SH2PTB significantly slowed down the migration of CasKO MEFs expressing either mCherry alone (columns 1, 2 and 3 in [Fig. 2](#BIO016428F2){ref-type="fig"}B) or mCherry-Cas (columns 4, 5 and 6 in [Fig. 2](#BIO016428F2){ref-type="fig"}B), it was more prominent in the latter (CasKO MEFs expressing mCherry-Cas). The negative effect of GFP-tensin 1-SH2PTB expression on the migration of CasKO MEFs indicates that the SH2PTB domains of tensin 1 is also involved in Cas-independent regulation of cell motility. Nevertheless, the promoting effect of mCherry-Cas expression on cell migration was eliminated by the expression of GFP-tensin 1-SH2PTB (compare columns 3 and 6 in [Fig. 2](#BIO016428F2){ref-type="fig"}B). This suggests that tensin 1 serves as a major mediator of the association between phosphorylated Cas and actin cytoskeletons during cell migration. Fig. 2.**Exogenous expression of tensin 1-SH2PTB interferes with Cas-driven cell migration.** (A) Representative images of cells either non-transduced, transduced with GFP or GFP-tensin 1-SH2PTB at 0, 5 and 10 h after wounding. Scale bar: 50 μm. Monolayers of mCherry-(left panels) or mCherry-Cas-(right panels) expressing CasKO MEFs, either non-transduced or adenovirally transduced with GFP only or GFP-tensin 1-SH2PTB, were subjected to wound healing experiments. Migrating cells were viewed with a microscope. (B) The cell migration velocity was defined by the distance over which nuclei moved during recording. Error bars represent s.e.m. The attached letters (a,b,c) indicate the groups statistically determined by a one-way ANOVA followed by Tukey--Kramer post hoc testing (*n*\>30 in each group). Columns that do not share the same group letters are significantly different from each other (*P*\<0.01), whereas there is no significant difference between the letter-sharing columns. Similar results were obtained from three independent experiments.
Exogenous expression of tensin 1-SH2PTB slows down the inward flux of Cas molecules, but not the retrograde actin flow {#s2d}
----------------------------------------------------------------------------------------------------------------------
We previously reported that the inward movement of Cas molecules correlated with the myosin-driven actin retrograde flow that promoted focal adhesion disassembly and cell migration ([@BIO016428C14]). We therefore examined whether the exogenous expression of tensin 1-SH2PTB, which impeded Cas-driven cell migration ([Fig. 2](#BIO016428F2){ref-type="fig"}B), disrupted the correlation between the actin retrograde flow and the movement of Cas molecules. The movement of Cas molecules and the retrograde flow of actin were monitored at focal adhesions in the leading regions by tracking speckles of photoactivatable GFP-Cas (PA-GFP-Cas) and photoactivatable mCherry-actin (PA-mCherry-actin). Consistent with our previous observation ([@BIO016428C14]), the movements of Cas molecules and actin molecules appeared to be correlated in the control CasKO MEFs expressing Cerulean alone ([Fig. 3](#BIO016428F3){ref-type="fig"}A,B,E; [Movie 1](Movie 1)). By contrast, the inward movements of Cas molecules were impeded whereas the actin retrograde flow appeared unaffected in CasKO MEFs expressing Cerulean-tensin 1-SH2PTB ([Fig. 3](#BIO016428F3){ref-type="fig"}C,D,E; [Movie 2](Movie 2)). These findings indicate that the expression of tensin 1-SH2PTB disrupts the correlation between the actin retrograde flow and the movement of Cas molecules at focal adhesions. Fig. 3.**Exogenous expression of tensin 1-SH2PTB disrupts the correlation between the inward fluxes of actin and Cas molecules.** (A,C) Representative images of migrating cells expressing PA-GFP-Cas and PA-mCherry-actin together with either Cerulean only (A) or Cerulean-tensin 1-SH2PTB. (C). Monolayers of PA-GFP-Cas- and PA-mCherry-actin-expressing CasKO MEFs transfected with either Cerulean only or Cerulean-tensin 1-SH2PTB were subjected to wound healing experiments. Migrating cells were analyzed by PA-TIR-FSM as described in Materials and Methods. Scale bar: 5 μm. Arrows indicate the direction of cell migration. (B,D) Kymographs drawn on the movement of actin and Cas molecules along the white dashed lines in A and C. The arrows represent the retrograde movement of actin and Cas molecules. Vertical scale: 5 min; horizontal scale: 2 μm. (E) The rates of PA-GFP-Cas and PA-mCherry-actin movement were quantified based on the kymographs in B and D. Data show the mean±s.e.m.;\*\*\**P*\<0.001; n.s.: not significant (*n*\>20 in each group); Student\'s *t*-test. Similar results were obtained from three independent experiments.
Exogenous expression of tensin 1-SH2PTB hampers the dissociation of Cas molecules from focal adhesions {#s2e}
------------------------------------------------------------------------------------------------------
To further examine the effect of the exogenous expression of tensin 1-SH2PTB on the dynamic behavior of Cas molecules at focal adhesions of migrating cells from a different aspect, we analyzed the molecular turnover. To this end, we conducted fluorescence recovery after photobleaching (FRAP) experiments using a total internal fluorescence reflection (TIRF) microscope ([@BIO016428C14]). We found that the recovery of fluorescence from GFP-Cas was significantly encumbered by the exogenous expression of tensin 1-SH2PTB ([Fig. 4](#BIO016428F4){ref-type="fig"}A,B). When the mobile fraction (*M*) and the half-recovery time (*T~1/2~*) were calculated from the fluorescence recovery curves ([Fig. 4](#BIO016428F4){ref-type="fig"}B), there was a significant increase in *T~1/2~* as well as a significant decrease in *M* in tensin 1-SH2PTB-expressing cells as compared with their control cells ([Fig. 4](#BIO016428F4){ref-type="fig"}C,D). These results suggest that the expression of tensin 1-SH2PTB impeded the exchange of Cas molecules at focal adhesions. In particular, the decrease in *M* value relates to the hampered displacement of Cas molecules from focal adhesions ([@BIO016428C14]) in tensin 1-SH2PTB-expressing cells. By contrast, the turnover rate of paxillin at focal adhesions was not apparently affected by the expression of tensin 1-SH2PTB ([Fig. S4](Fig. S4)). This indicates that the retarding effect of tensin 1-SH2PTB expression on the molecular turnover at focal adhesions is specific for Cas. These results strengthen the notion that tensin 1 links phosphorylated Cas to actin cytoskeletons, and mediates the dissociation of Cas molecules from focal adhesions. Fig. 4.**Exogenous expression of tensin 1-SH2PTB stabilizes Cas residence at focal adhesions.** (A) Representative FRAPs of GFP-tagged Cas expressed in migrating CasKO MEFs co-expressing Cerulean only (top panels) or Cerulean-tensin 1-SH2PTB (bottom panels). Pseudocolor images representing fluorescence intensities of GFP-Cas before (−10 s), immediately (0 s), 15 s, 30 s, 40 s, and 60 s after photobleaching are shown. Scale bar: 1 μm. (B) Mean fluorescence intensities *I(t)/I*~−10~ of individual focal adhesions of cells co-expressing Cerulean only (green triangle) or Cerulean-tensin 1-SH2PTB (purple diamond) are plotted against time. (C,D) Mobile fraction, *M* (C) and half-recovery time, *T~1/2~* (D) were obtained as described in Materials and Methods. Data show the mean±s.e.m.; \*\*\**P*\<0.001; \*\**P*\<0.01 (*n*\>50 in each group); Student\'s *t*-test. Similar results were obtained from three independent experiments. (E) A model for the actin-Cas linkage. Tensin 1 links phosphorylated Cas to inwardly moving actin cytoskeletons at focal adhesions, thereby supporting cell migration.
Src-Cas-tensin 1-actin linkage as a transmission that reconciles the inwardly moving actin filaments and the stationary adhesion complex {#s2f}
----------------------------------------------------------------------------------------------------------------------------------------
In our present study, we identify tensin 1 as the molecule that supports the displacement of Cas from adhesion complexes by linking inwardly moving actin cytoskeletons to phosphorylated Cas ([Fig. 4](#BIO016428F4){ref-type="fig"}E). Whilst the effect of actomyosin on cellular motility may differ depending on cell types ([@BIO016428C13]) and there appears to be a variation of molecular mechanisms of cell migration, we have previously reported that Cas supports cell migration through the association with Src and actomyosin contraction at focal adhesions ([@BIO016428C14]). Src tethers Cas molecules to the adhesion complexes and phosphorylates the tyrosine residues in their substrate domains. Phosphorylated Cas then binds to tensin 1 and constitutes a cytoskeleton-adhesion linkage. Thus, continuous actin inward flux leads to the displacement of Cas molecules from the adhesion sites. Based on the temporal nature of Src-Cas and Cas-tensin 1 associations, the Src-Cas-tensin 1-actin linkage could serve as a transmission that reconciles the motile and the stationary parts of the cell, and underpins the locomotive machinery to support the cell migration ([Fig. 4](#BIO016428F4){ref-type="fig"}E; [Movie 3](Movie 3)).
MATERIALS AND METHODS {#s3}
=====================
Cell culture and retroviral infection {#s3a}
-------------------------------------
CasKO MEFs and HEK293T cells were cultured in Dulbecco\'s modified Eagle\'s Medium (DMEM) (Nissui Pharmaceutical, Tokyo, Japan) containing 10% fetal bovine serum (FBS) (Gibco, Grand Island, NY) supplemented with 100 units/ml of penicillin, 100 mg/ml streptomycin (Gibco), 2 mM L-glutamine (Gibco), and 0.18% sodium bicarbonate under standard cell culture environment at 37°C supplied with 5% CO~2~. Retroviral infection was performed as described previously ([@BIO016428C12]).
Antibodies, chemical reagents and plasmids {#s3b}
------------------------------------------
Anti-phospho-Cas polyclonal (pCas-165) (Cell Signaling Technology, Danvers, MA), anti-Cas polyclonal (αCas3) (Upstate Biotechnology, Lake Placid, NY), anti-β-actin monoclonal (Sigma-Aldrich, St. Louis, MO), anti-FLAG monoclonal (Sigma-Aldrich), anti-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (Santa Cruz Biotechnology, Santa Cruz, CA), anti-GFP monoclonal (Clontech Laboratories, Mountain View, CA) antibodies were used for immunoblot, co-immunoprecipitation (Co-IP) and immunofluorescence analyses. Cerulean is a GFP analog and recognized by the anti-GFP antibody, which we used to detect Cerulean-tagged proteins by immunoblotting. All chemicals were purchased from Sigma-Aldrich unless otherwise stated.
The retroviral expression vectors for GFP-CasWT, GFP-Cas15YF and PA-GFP-Cas were constructed as described previously ([@BIO016428C14]). To generate the expression vectors for Cerulean-tensin 1 variants, chicken tensin 1 was used as a polymerase chain reaction (PCR) template and cloned into pCAGGS ([@BIO016428C15]). The expression plasmids for FLAG-CasWT and FLAG-Cas15YF were constructed using pcDNA3 (Invitrogen) as a parent vector. To prepare the retroviral expression vectors for paxillin-mCherry, PA-mCherry-actin and mCherry-Cas, pBabe-blasticidin was used as a parent vector. To construct the silencing vector for tensin 1, mouse tensin 1 target sequence (5′-GCCTTTGTTTCTGCATCATGT-3′) was cloned into pSuper-puromycin (Oligoengine, Seattle, WA). pET-41 (Novagen, Madison, WI) was used as a parent vector for bacterial expression of GST proteins (GST only and GST-tensin 1-SH2PTB).
Immunofluorescence analysis {#s3c}
---------------------------
The immunofluorescence staining was performed as described previously ([@BIO016428C10]). The samples were viewed with a confocal microscope (A1R, Nikon) equipped with oil-immersion (NA 1.40, 100×; Plan Apochromat VC, Nikon) and air (NA 0.95, 40×; Plan Apochromat, Nikon) objectives. Acquired images were analyzed off-line with the public domain ImageJ program (NIH).
Co-immunoprecipitation (Co-IP) assay {#s3d}
------------------------------------
Co-IP assay was conducted to biochemically analyze the interaction between FLAG-tagged Cas variants and Cerulean-tagged tensin 1 variants using an anti-FLAG (M2) Affinity Gel (Sigma-Aldrich) according to manufacturer\'s instructions.
Adenoviral transduction {#s3e}
-----------------------
The recombinant adenovirus expressing GFP-tensin 1-SH2PTB was generated using the ViraPower Adenoviral Expression System (Invitrogen, Thermo Fisher Scientific, Inc.). GFP only recombinant adenovirus was prepared as described previously ([@BIO016428C1]). The adenoviruses were purified with AdEasy Virus Purification Kits (Agilent Technologies, Palo Alto, CA) before use. The purified GFP-tensin 1-SH2PTB adenovirus was then used to transduce the target cell lines at a multiplicity of infection (MOI) of 50 plaque-forming unit (pfu) for 4 days.
Photoactivation total internal reflection fluorescent speckle microscopy (PA-TIR-FSM) {#s3f}
-------------------------------------------------------------------------------------
CasKO MEFs stably co-expressing photoactivatable (PA)-GFP-Cas and PA-mCherry-actin were transfected with Cerulean-tensin 1-SH2PTB or Cerulean only expressing vectors. To record the retrograde flow of actin and the inward movement of Cas simultaneously, PA-TIR-FSM was performed using a Ti-E inverted microscope (Nikon) equipped with an electron multiplying charge coupled device camera with a 512×512-pixel chip (iXon3 897, Andor Technology, Belfast, UK), 1006 NA 1.49 objective lens and fiber-coupled 488-nm and 559-nm lasers to excite GFP and mCherry, respectively. Photoactivation was done by directing laser with 405 nm wavelength onto the cell. The TIRF images of GFP and mCherry were then recorded every 10 s for 25-30 min. NIS elements software (Nikon) was used for image acquisition, and ImageJ software was used for image processing and final figure preparation.
Wound healing assay {#s3g}
-------------------
Wound healing assay was performed as described previously ([@BIO016428C14]). Cells were grown overnight in DMEM containing 10% FBS. A Chamlide magnetic chamber (Live Cell Instrument, Seoul, Korea) with a collagen (10 μg/ml)-coated glass bottom was used to form a monolayer, which was scratched by a pipette tip and viewed with a microscope. Differential interference contrast (DIC) images were taken every 10 min for 10 h. Analysis of migration speed was performed using ImageJ software with a manual tracking plug-in. The displacement of the nuclei at each time point was plotted and the migration rate was quantified by the slope of the plotted points.
TIRF-FRAP experiments {#s3h}
---------------------
TIRF-based FRAP (TIRF-FRAP) analysis was conducted as described previously ([@BIO016428C14]).
GST pull-down assay and quantitative PCR analysis {#s3i}
-------------------------------------------------
GST pull-down assay was performed as described elsewhere ([@BIO016428C16]). To measure mRNA expression levels, quantitative PCR analysis was performed as described previously ([@BIO016428C12]). The primers used for mouse tensin 1 were 5′-GCCCTCGGCTGTGTATTTAT-3′ (forward) and 5′-AGCCATACAATGGATCGTGA-3′ (reverse). The primers used for mouse GAPDH were 5′-CAACTACATGGTCTACATGTTC-3′ (forward) and 5′-CGCCAGTAGACTCCACGAC-3′ (reverse).
We thank Prof. Michael P. Sheetz and Prof. Chwee Teck Lim for their consistent support and useful discussion.
**Competing interests**
The authors declare no competing or financial interests.
**Author contributions**
Z.Z. and Y.S. conceived the project and designed the experiments; Z.Z. and S.H.T. performed the experiments; Z.Z. and S.H.T. analyzed the data; H.M., K.A. and K.K. helped acquire data; Z.Z., H.H. and Y.S. wrote the manuscript.
**Funding**
This work was supported by the Biomedical Research Council \[grant number R-154-000-423-305\]; and the Seed Fund \[grant number R-714-004-007-271\] from The Mechanobiology Institute, Singapore.
**Supplementary information**
Supplementary information available online at <http://bio.biologists.org/lookup/suppl/doi:10.1242/bio.016428/-/DC1>
[^1]: Present address: R-Pharm Japan, and Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550 Japan.
[^2]: These authors contributed equally to this work
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Mike Pence was greeted with a display of LGBT+ solidarity upon arrival in Iceland, after the Nordic island’s president wore a rainbow bracelet to their meeting and businesses displayed Pride flags outside buildings.
The US vice-president, visiting the capital Reykjavík as part of a whirlwind European tour, has a history of supporting anti-LGBT+ policies, including as Indiana governor when he voted against a ban on discrimination against people based on their sexual orientation. He also opposed the repeal of a law preventing openly gay people serving in the military.
Pulling up to Höfði House – the venue of President Ronald Reagan’s historic 1986 meeting with Soviet leader Mikhail Gorbachev – Mr Pence was met by half a dozen Pride flags planted conspicuously outside an office block opposite the building.
Ægir Már Þórisson, director of IT company Advania, told local news outlet Monitor: “We just felt the need to celebrate diversity today and wanted to show that by flying the flags.”
Another business, Efling union - headquartered nearby - also flew the rainbow flags, which are global symbols of LGBT+ pride.
Meeting Mr Pence inside Höfði House, President Guðni Jóhannesson was spotted wearing a rainbow bracelet on his right wrist. Iceland’s first lady, Eliza Reid, wore a similar bracelet to the meeting.
It came a day after the Trump administration claimed Mr Pence could not be “anti-gay” because he had agreed to meet the Irish taoiseach and his same-sex partner during a trip to Ireland.
Related: Pence says government 'will never ever penalise anyone for their religious beliefs' (EPA)
Mr Pence was the first US vice-president to visit Iceland, a country of just 350,000 people, since George HW Bush came to Reykjavik in 1983.
But the size and standards of Mr Pence's security detail, which included military jets and armed personnel, required adjustments by the nation of just 350,000 people.
The guards protecting Mr Pence got backup from a police force that only allows elite "Viking SWAT" members to carry guns.
Icelandic authorities also gave US personnel special permission to carry firearms, while bomb-sniffing dogs were cleared to enter the country because of a strict quarantine for imported animals.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Homes for sale in Peccole Ranch in Las Vegas, NV
There are currently 51 MLS Listings in the search: Homes for sale in Peccole Ranch in Las Vegas, NV. Click on a listing to view property details, photos, virtual tour and map. If you would like to change or expand your search criteria, try using our Advanced Search.
Lovely two story home located in a gated community, La Ventana! The home has been freshly updated with plush new carpet, stainless steel appliances, and interior paint. The house has an open concept f...
WOW, stop the car and check out this remodeled single story home! Massive remodel almost completed includes new paint interior and exterior, new floors, new bathrooms, new kitchen with new appliances,...
Cozy 3 bedroom 2 story home located close to the heart of Las Vegas, shopping center, nice neighborhood, with Swimming /Spa , well trimmed front yard. All offers must be with loan approval. Buyers an...
Fully upgraded & ready for move-in! Three bedroom home in gated Ascot Park in Peccole Ranch. Open & high ceilings provide a grand entrance into the formal living & dining space. Separate family room, ...
LOCATED IN GATED COMMUNITY OF STONE RIDGE IN PECCOLE RANCH. UPSTAIRS UNIT WITH 1-CAR GARAGE FEATURES 2 BEDROOMS, 2 FULL BATHS AND SPACIOUS LIVING AREA. KITCHEN WITH NEW STAINLESS STEEL APPLIANCES INCL...
Beautiful home in Peccole Ranch. Looking for a great buyer for lasting memories! Tile throughout with a easy floor plan featuring 2 bedrooms and two baths just had the pool and deck are newly plastere...
Stunning freshly updated home in the highly sought after neighborhood, Peccole Ranch! Brand new wood laminate downstairs and plush carpet upstairs! The stunning kitchen is fit for any chef featuring b...
A very rare and spacious 4 bedroom home plus a Loft with open floor plan that boast an amazing foyer in the entry with a gorgeous chandelier. Two master bedrooms with separate shower/bathtub & walk-in...
Spectacular 2 Story Luxury Home in a Gated Community in Peccole Ranch! 5 Bedrooms (one downstairs), 3 Bathrooms, a Loft ,Grand Entry with a 2 Story Formal Living Room, Formal Dining Area & a Massive ...
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Stubbington
Stubbington is a small Hampshire village which is located between Southampton and Portsmouth on the south coast of England. It is within the borough of Fareham but is part of the parliamentary constituency of Gosport.
History
Both Stubbington and neighbouring Crofton were mentioned in the Domesday Book (the 11th century UK census) as small districts belonging to the estates of Titchfield Abbey.
The earliest known cricket match to have been played in Hampshire took place on Tues 22 May 1733 in the village. It was between Married v Single. The Married team won. Details were found by Martin Wilson in the American Weekly Mercury, a Philadelphia newspaper dated 20 to 27 September 1733. Mr Wilson subsequently found an earlier version of the report in an English newspaper, the 18 June 1733 edition of Parker's Penny Post.
During the 19th century, Stubbington engulfed Crofton and the small fishing village of Hill Head. The Crofton name still remains in the name of many local facilities, such as the Crofton School and Crofton Old Church.
At the start of the 20th century, the village still consisted of just a few dozen cottages and farms. By 1939, the population had risen to around 2,500 and a number of small shops had opened surrounding the village green. This remains the central focus of the village to the present day, with a war memorial situated on the central village green.
The Church
The 'Crofton Old Church' at Crofton is one of the oldest known inhabited sites in the area. It was mentioned in the Domesday Book and it is thought to date back to the reign of King Alfred in the 9th Century. It is believed to have caught the eye of Samuel Pepys in 1662 and was extensively renovated during the 13th Century. A new church (Holy Rood) was built in Stubbington which took over the function of Crofton Church in 1878.
The War Memorial and Village Pump
In 1922 a wooden War Memorial was built to commemorate those from Stubbington and Hill Head who fell in the First World War. Their names were carved into the roof of the memorial although over the years they have been worn away. The Memorial takes the form of a shelter over the village pump, and today it is one of few pre-war structures standing in the vicinity of Stubbington Village Centre. The names carved into the roof of the memorial have now been cleaned and can be seen clearly.
Present day
The population of Stubbington has risen to over 15,000, with new housing estates taking over a number of the surrounding fields. The town has a number of modern shops as well as a range of other facilities, including a doctor, dentist, library, community centre and seven schools. The former Royal Navy site of HMS Daedalus lies between Stubbington and neighbouring Lee-on-the-Solent, and a small part is currently being developed, however more is scheduled for further development that could further expand the town.
Neighbouring areas
The nearest village is Titchfield. Also near Stubbington is the area of Fareham called Hill Head and the town of Lee-on-the-Solent.
Schools
Crofton School (Secondary Comprehensive)
Crofton Anne Dale Infant School
Crofton Anne Dale Junior School
Crofton Hammond Infant School
Crofton Hammond Junior School
See also
Crofton School
List of places of worship in the Borough of Fareham
Stubbington House School
References
External links
Category:Borough of Fareham
Category:Villages in Hampshire
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Q:
Calendar Selection
Greetings,
Might be having a brain fart this morning, but I need a way to execute some JavaScript at the conclusion of an operation taking place inside an ASP .NET Ajax Update Panel. How can this be accomplished?
Thanks,
jason
Updated based on responses:
I was not entirely clear, as both initial answers were correct given what I was asking. In my case I ONLY want the JS to run when a particular event for the control inside the UpdatePanel is executed, sorry for the confusion.
A:
Sys.WebForms.PageRequestManager.getInstance().add_endRequest(endRequest);
function endRequest(sender, args) {
// Executed when ajax request finishes, you could check the sender variable
// in order to identify which update panel fired the request
}
| null |
minipile
|
NaturalLanguage
|
mit
| null |
The city could eventually see a major sidewalk improvement project on High Street — thanks to a $750,000 earmark inserted by state Rep. Patricia A. Haddad into a $12 billion transportation bond bill.
That bill was unanimously approved by the House on Wednesday night.
The Taunton funding component would create handicapped-accessible curb ramps at crosswalks, improvements to existing sidewalks and the installation of new sidewalks where needed.
Haddad, D-Somerset, said she's hopeful the Senate will approve the current version of the bill. Bond bills, she said, usually have a life span of five years.
"There's still a lot of work to be done," she said.
Haddad said she also included funding for bike path and sidewalk improvements in Somerset and Swansea. When it comes to crafting such bond bills, she said, the challenge is deciding which improvement project is most worthy.
"You always ask, 'What is it you need?'" Haddad said.
The sidewalks on High Street — which extends three long, residential blocks from Ingell to Cohannet streets — is a mishmash of dirt, grass and deteriorating walkways.
Haddad said she and state Rep. Shaunna O'Connell, R-Taunton, worked together, contacting Mayor Thomas Hoye Jr. to determine how the local transportation-related funding should be spent.
"It's great news," Hoye said, acknowledging that portions of sidewalk on High Street are in poor condition.
The mayor said the earmark is consistent with his administration's overall strategy of assuring that Taunton sidewalks become fully compliant with the Americans with Disabilities Act.
Haddad said her goal is to encourage more people to take advantage of the outdoors and, especially in the case of Taunton, to be able to do so safely.
Taunton lawyer Joseph deMello, who in 2011 filed a lawsuit against the city on behalf of Nancy Gero, a wheelchair-bound Taunton resident, welcomed the news.
"It's beneficial to everyone in the city," he said.
Each time Nancy Gero leaves her house, deMello said, she risks her life navigating the city's sidewalks.
Her wheelchair has been snagged on railroad tracks, where the disintegrating sidewalks and steel rails create impregnable obstacles.
More than once, passing motorists have stopped to help free her from a difficult situation before it turned to tragedy. Often she abandons the sidewalks and takes to the street.
She is suing the city, asking them to fix their sidewalks, so all residents can travel unfettered. If state funding is approved, some paths of travel may soon reopen for Gero.
deMello, who has muscular dystrophy and is himself reliant on a wheelchair, said any kind of infrastructure improvement doesn't just improve personal safety. It also enhances a neighborhood's overall quality and appearance.
He said the Gero case — in which deMello is seeking damages from the city for alleged failure to comply with ADA rules — has moved from the mediation phase and has been placed on the full trial calender with the U.S. District Court.
Page 2 of 2 - "It will go to litigation," he said.
deMello said he intends to prove that Taunton still has "miles and miles of sidewalks that should, and could have by now, been (made) accessible."
He said he's completely satisfied with the results of the city's $2.1 million Downtown Sidewalks Improvement Project. "So far they've turned out very nicely, and they do comply," deMello said.
Riding around the city by car can be a frustrating experience for deMello. It's hard to travel more than a few blocks without spotting numerous ADA violations.
He points out illegal grades at driveway curb-cuts and broken sections of blacktop sidewalks he estimates to be more than a half-century old.
On County Street, a major thoroughfare, the sidewalk shrinks to a foot or less at spots. Sections have gaps between them, and deep ruts can easily trap a wheelchair.
Along Oak Street, blocks from Taunton's temporary City Hall, double poles limit sidewalk space, where the sidewalk exists. At one point, the sidewalk disappears for hundreds of feet next to a city park. Gero has to swing her chair out onto the road to travel from her home to City Hall.
"Nancy is fearless," deMello said. "But she says she has to be, or she wouldn't get anywhere in this city."
| null |
minipile
|
NaturalLanguage
|
mit
| null |
(File photo)
China could further ease its visa policies to facilitate labor flow from ASEAN countries into China's aging society, suggested a consultant of the State Council.
Addressing the annual Conference on China’s Economy and International Cooperation in Beijing, the consultant, Wang Huiyao, proposed that a demonstration zone of China-ASEAN free labor flow be established.
“China has an aging society, while ASEAN countries are rich in labor population. There are maybe 200,000 more Filipino housekeepers in China, who may not be holding work visas. Tens of thousands of Vietnamese technicians are working in Guangxi. All this shows that we have a sound cooperation basis with ASEAN countries for mid- and high-level work forces,” Wang said.
“Cooperation on human resources could be the biggest growth opportunity for China-ASEAN cooperation under the Belt and Road Initiative,” added Wang, who is also director of the Center for China and Globalization.
By easing visa policies, Wang explained, the inflow of human labor could solve the labor shortage facing some coastal cities in China.
Wang stressed that tourism will be an additional key component of promoting the Belt and Road Initiative among ASEAN countries.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Censoring the Military Embeds
One could devote a lifetime—or at least the better part of a year—to chronicling all the propaganda-like tricks the Bush administration and the military have pursued over the past few years. Here’s a new one, courtesy of Rod Norland, Newsweek‘s former bureau chief:
The military has started censoring many [embedded reporting] arrangements. Before a journalist is allowed to go on an embed now, [the military] check[s] the work you have done previously. They want to know your slant on a story — they use the word slant — what you intend to write, and what you have written from embed trips before. If they don’t like what you have done before, they refuse to take you. There are cases where individual reporters have been blacklisted because the military wasn’t happy with the work they had done on embed.
What’s fun here is that the two sides in the ongoing debate over the Iraq war can see this development with radically different eyes. The pro-war camp—that is, the camp that believes that the war’s basically going well despite some setbacks, and that we can pacify Iraq and “win” if only the American public would just backbone up for the long haul, and that only the media can “lose” this war by reporting too much bad news and causing people to doubt the wisdom of the occupation—well, they’ll likely applaud this decision and say that the military has no obligation to take on reporters working at cross-purposes with the war effort.
The anti-war camp, of course, will say that accurate reporting is necessary so that the public can see that this war is an utter failure and our continuing presence only making things worse and getting people killed, and that having the military censor the media will only obfuscate that reality and prolong our futile presence in Iraq. I’m certainly of that camp, and think the accuracy of those “cheerleading” journalists who would no doubt be approved by military censors tends to leave much to be desired… Needless to say, this isn’t a good development at all.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Cheap Home Interior Design
Sponsored Links
Fresh cheap home interior design is one of the best Pics @ yoob4.org. full interior design renovation in singapore for residential and commercial projects design consultation layout space planning more, need inspiration for decorating your home garden at look4design you can easily navigate to view a wide variety of exhibitors in the area of home and interior design, interior design ideas home decorating photos and pictures home design and contemporary world architecture new for your inspiration, who we are our ability to stay abreast of the latest in interior design industry coupled with the ingenuity and imagination of our experienced professionals has made j design group a dominant player in this market
Interior Design Quattrozero Restaurant Edinburgh
diy home décor is always popular here the simple and easy decorating projects will not cost you a lot but a little creativity can make your home refreshing and interesting, color psychology color psychology in interior design can the psychology of color help you decorate your home yes color psychology can help you create a desired mood in interior design
if you want to look for a simple way to protect your little plants from the unwanted guests you can try making chicken wire cages chicken wire is perfect, online interior design for real people chat now with a professional interior designer for 19 or begin your room project for as low as 79, thinking about a design for your new home and looking for software to visualise your design ideas for this article we take a look at 10 of the best programs for budding residential architects to design their own home, french interiors french interior design french home decor french interior design is bold sophisticated and chic it is also very quirky and personal as youll see in these articles and photos of real french homes
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Wednesday, November 24, 2010
Scenario: You want to deploy a SQL Compact / .NET based application, using private deployment only. Your application depend on a certain .NET Framework version. The table below illustrates your options, as you can see there are special considerations, if your clients only have .NET 4.0 and not .NET 3.5 SP1 installed.
Also, notice that all files required for private deployment are included in the private folder in either Program Files or Program Files (x86) (C:\Program Files\Microsoft SQL Server Compact Edition\v4.0\Private) for version 4.0.
Tuesday, November 16, 2010
As you may know by now, the major new feature of SQL Server Compact 4.0 is support for ASP.NET starter websites. In addition, the Entity Framework support has been improved with the following features:
- Support for Code First development (requires EF 4 Feature CTP 4), allowing you to create database and schema in code.
. Support for paging (can be implemented with Skip and Take in LINQ).
- Support for server generated keys (IDENTITY)
The purpose of this post is to show how to use Entity Framework 4 with SQL Server Compact 4.0 and ASP.NET without having the full support for SQL Server Compact 4.0 in VS 2010.
I will cover the following scenarios in the sample application:
1: Migrate data and schema for the solution from either SQL Server Compact 3.5 or SQL Server 2005 or later.
3: Create a layered application, where the UI has no knowledge of Entity Framework, in order to improve testability, minimize UI code and allow the Data Access layer to be replaced with another Data Access Technology (unlikely, I know )
4: Provide the initial implementation of a music track list displayed in a grid, which can be sorted and paged.
7: Use various extension methods, that make your life with Entity Framework smoother.
For this sample I am using the Chinook database from CodePlex, which is delivered in script format and as a 3.5 SDF file. The Chinook database schema represents a digital media store, including tables for artists, albums, media tracks (3500 tracks), invoices and customers.
Creating the database (optionally migrating from 3.5 or Server)
Depending on your starting point, there are many ways to get to a 4.0 database.
If you have a 3.5 database, you can use SqlCeCmd40.exe to upgrade a copy of this database to 4.0:
Have a 3.5 database handy with the exact same table definition (schema) as the 4.0 database. After generating the EDM based on the 3.5 database, tweak the model to work with a 4.0 database. Let’s see how this is done:
Start by creating an empty solution, named Chinook, to hold our projects:
Then add a C# Class library project to the solution, and name it Chinook.Data:
Remove Class1.cs, then go to file system, and copy the Chinook.sdf (the 3.5 version) to the solution folder (C:\projects\chinook).
(I have also copied the 4.0 version, so I can easily find it later). Now we can add the EDM based on the 3.5 database file:
Name the model ChinookModel.edmx and click Add. In the next step, select Generate From Database, and click Next.
On the “Choose you data connection” step, create a new connection to the Chinook.sdf 3.5 version database, using the SQL Server Compact 3.5 provider, and click Next:
Then you get this question:
(I suggest you reply No)
Select all tables, select pluralize and click Finish. Now we have our Model:
Now, let’s make the Model work with our SQL Server Compact 4.0 file. First, modify the connection string in app.config as follows:
Then modify the emdx file (right click the file, and select Open With.. XML Editor).
Verify your changes by opening the edmx file in the visual designer.
Creating the POCO Entities for use with Repository
Now let us create a separate class library for our POCO entities based on the model, This will allow us to reference this Model project from both the data access layer and the UI layer. In order to do this, follow the steps in this EF Team blog post, and you will end up with a solution structure like this:
Notice the following change,that was made to ChinookModel.tt in order to have the entities in a separate project:
string inputFile = @"..\Chinook.Data\ChinookModel.edmx";
Also, a reference to the Chinook.Model project was added to Chinook.Data:
And the Custom Tool Namespace for the Chinook.Model.Context.tt file was set to Chinook.Model:
Creating the Repository
Now, add a Chinook.Repository project to the solution, to create the data access methods used by the UI. This project should reference the Chinook.Model and the Chinook.Data projects. As always, remove the Class1.cs file. Now, we want to create a method that allows the UI to get a page of Track data for display in a GridView. This is an initial implementation (notice the parameters, which are passed by default when using and ObjectDataSource from the UI):
I will be present in the Technical Learning Centre, SQL Server Data Technologies & Developer Tools booth during the event, so feel free to come and have a chat about some of the technologies and tools, that the SQL Server Data Programmability team provides.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
No effect of highly dosed nitric oxide donor molsidomine on the angiographic restenosis rate after percutaneous coronary angioplasty: a randomized, placebo controlled, double-blind trial.
Nitric oxide (NO) counteracts several mechanisms involved in the restenotic process after coronary angioplasty. NO mediates an antiproliferative effect on smooth muscle cells, inhibition of leukocyte-vessel wall interactions, and platelet aggregation and adhesion. Because these effects are mainly dose dependent, NO-releasing drugs have to be applied at a high dose to have an effect on restenotic mechanisms. To study the effect of the NO donor molsidomine at a high dose of 8 mg tid on angiographic restenosis rate in a randomized, placebo controlled, double-blind trial. One hundred and sixty-six patients with de novo stenosis were randomly assigned to molsidomine or placebo treatment for six months (83 patients each). The primary end point was the angiographic restenosis rate at six months. The secondary end points were major adverse cardiac events (MACE) including death, myocardial infarction and revascularization. Analyses were performed by intention to treat. There were no differences in clinical, procedural and angiographic data, including minimum lumen diameter and reference diameter. Provisional stenting was performed in 28% of patients receiving molsidomine and 25% of patients treated with placebo. All other patients were treated with standard balloon angioplasty. Reangiography rate was 89.3% (molsidomine 90 lesions, placebo 97 lesions). Restenosis rate (greater than 50% diameter stenosis) was not significantly different (molsidomine 25.6% and placebo 29.9%). Patients receiving molsidomine improved significantly more in their anginal class than patients receiving placebo (P<0.026). Occurrence of MACE did not significantly differ between both groups (molsidomine 26.8% and placebo 34.9%, P=0.26). Treatment with the NO donor molsidomine at a high dose of 8 mg tid for six months after coronary angioplasty has no effect on the angiographic restenosis rate. Due to the vasodilating effect of NO, the anginal status improves slightly more in patients receiving molsidomine.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
A non-genomic signaling pathway shut down by mating changes the estradiol-induced gene expression profile in the rat oviduct.
Estradiol (E(2)) accelerates oviductal egg transport through intraoviductal non-genomic pathways in unmated rats and through genomic pathways in mated rats. This shift in pathways has been designated as intracellular path shifting (IPS), and represents a novel and hitherto unrecognized effect of mating on the female reproductive tract. We had reported previously that IPS involves shutting down the E(2) non-genomic pathway up- and downstream of 2-methoxyestradiol. Here, we evaluated whether IPS involves changes in the genomic pathway too. Using microarray analysis, we found that a common group of genes changed its expression in response to E(2) in unmated and mated rats, indicating that an E(2) genomic signaling pathway is present before and after mating; however, a group of genes decreased its expression only in mated rats and another group of genes increased its expression only in unmated rats. We evaluated the possibility that this difference is a consequence of an E(2) non-genomic signaling pathway present in unmated rats, but not in mated rats. Mating shuts down this E(2) non-genomic signaling pathway up- and downstream of cAMP production. The Star level is increased by E(2) in unmated rats, but not in mated rats. This is blocked by the antagonist of estrogen receptor ICI 182 780, the adenylyl cyclase inhibitor SQ 22536, and the catechol-O-methyltransferase inhibitor, OR 486. These results indicate that the E(2)-induced gene expression profile in the rat oviduct differs before and after mating, and this difference is probably mediated by an E(2) non-genomic signaling pathway operating on gene expression only in unmated rats.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
2009/1/22 James Fee <james.fee at rsparch.com>:
> -----Original Message-----
>> From: discuss-bounces at lists.osgeo.org [mailto:discuss
>bounces at lists.osgeo.org] On Behalf Of Frank Warmerdam
>> Sent: Thursday, January 22, 2009 2:21 PM
>> To: OSGeo Discussions
>> Subject: Re: [OSGeo-Discuss] Top ten myths for open source in geo?
>>>> Another common one in general is "open source is just for that geeky
>> linux operating system, I want to use windows!" to which the response
>> will hopefully reference some particular windows packaging efforts
> like
>> OSGeo4W as well as indicating that most projects do offer binaries for
>> windows. I often try to make the point that OSGeo and FOSS4G is
> available
>> for many operating systems, and that using open source GIS software
> does
>> not mean pushing linux down peoples throats.
>> This is the biggest issue I find myself needing to "educate" potential
> users of open source solutions. Many open source server projects are
> much easier to install than their proprietary counterparts.
>>> --
> James Fee
> RSP Architects Ltd.
> 502 South College Avenue, Suite 203, Tempe, AZ 85281
> 480-889-2095 (w)
> 602-819-2142 (m)
> _______________________________________________
> Discuss mailing list
>Discuss at lists.osgeo.org>http://lists.osgeo.org/mailman/listinfo/discuss>
If you undestand Spanish this[1] speech by the chair of the GIS
department of the Barcelona port (on the 2nd Spanish FOSS4g
conference) is really interesting.
It was one of the best presentations I've seen recently and raises all
the fears or doubts (also the good points) he has about Free Software
for a large organization like the BCN port.
Briefly (minute 21 aprox):
* TCO
* Future sustainability of a project (not only for FOSS!)
* Need of professionals on his IT team with expertise on their technologies
* Obsolescence risk (he has a Smallworld system for 14 years)
* He doesn't find a BCN company offering support for FOSS
* He doesn't find good documentation or good training on FOSS
* He finds better admin tools on propietary software
Cheers
[1] http://www.sigte.udg.es/jornadassiglibre2008/blog/?p=32
--
Jorge Gaspar Sanz Salinas
Ingeniero en Geodesia y Cartografía
http://geomaticblog.net/people/xurxo
| null |
minipile
|
NaturalLanguage
|
mit
| null |
A hand-reared penguin that was terrified of water has learned how to swim with the help of her keeper.
The aquaphobic bird, named Charlotte, refused to get into the penguin pool with the rest of her colony and made desperate attempts to avoid the water. But after having one-on-one swimming lessons to conquer her fear, Charlotte now loves her time in the pool.
Head keeper, Alastair Keen, donned a wetsuit and goggles to tempt the water-shy bird into the penguin pool at Birdland Park and Gardens in Gloucestershire.
And after a few days training, Charlotte is now diving happily into the pool and darting through the water with her dive companion.
The first King penguin to be born in England in 7 years, Charlotte’s egg was artificially incubated after several previous eggs had been broken by other penguins.
She was then hand-reared by Alastair with round-the-clock care and grew up believing the 35-year-old keeper was her mother and father.
But after being introduced to the other penguins at the park, it became clear Charlotte was reluctant to join them in the pool.
‘Charlotte hadn’t had contact with water for 9 months as chick feathers aren’t waterproof,’ says Alastair. ‘She’d never experienced it, it was a complete shock to her.’
In the wild, penguins naturally follow their parents into the water, but being hand-reared Charlotte didn’t have the benefit of a large family group to help her.
Simon Blackwell, manager at Birdland, said: ‘We realised Charlotte was scared of water when we released her to be with the other penguins. When she came to the edge of the pool to put her feet in the water she ran away. We pushed her into the pool and she panicked so much we realised we needed to approach it in a different way.
‘Because she followed Alastair in the enclosure quite regularly it was obvious that he was going to have to don a wetsuit and get into the smelly, fishy water.’
Keeper Alastair gives Charlotte a swimming lesson
Committed keeper Alastair rose to the challenge. ‘The first day she just sat and watched me in the pool so we decided to lift her in,’ he says. ‘Once she got her head underwater and realised she could hold her breath, she could see underwater, something just twigged and she was brilliant.’
Alastair shared pictures of their exploits on his Facebook page and the cute penguin has become a poster girl for the park.
Charlotte is now as happy in the penguin pool as she is on dry land – but has one trick left to learn.
‘She’s become a brilliant swimmer now,’ says Alastair. ‘You see her exhibiting natural behaviours like cleaning herself on the water. Now she just needs to learn to feed in the water – we’re yet to see her catch a fish.’
Get in touch
Search
We work hard to achieve the highest standards of editorial content, and we are committed to complying with the Editors’ Code of Practice (https://www.ipso.co.uk/IPSO/cop.html) as enforced by IPSO.
If you have a complaint about our editorial content, you can email us at [email protected] or write to Complaints Manager, TI Media Limited Legal Department, 161 Marsh Wall, London, England, E14 9AP. Please provide details of the material you are complaining about and explain your complaint by reference to the Editors’ Code.
We will endeavour to acknowledge your complaint within 5 working days and we aim to correct substantial errors as soon as possible.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Treatment of mice with a herbal preparation (mentat) protects against radiation-induced mortality.
The effect of various doses (0, 5, 10, 20, 40, 80, 100, 120 and 160 mg/kg b. wt.) of 50% ethanolic extract of mentat (a herbal preparation) was studied on the survival of mice exposed to 10 Gy of gamma-radiation. Treatment of mice with different doses of mentat consecutively for fi ve days before irradiation delayed the onset of mortality and reduced the symptoms of radiation sickness when compared with the non-drug treated irradiated controls. Most of the doses of mentat provided protection against the gastrointestinal (GI) death, however, the highest protection against GI death was observed for 80 mg/kg mentat. This was also true for bone marrow deaths, where the highest number of survivors were observed at 30 days post-irradiation in this group (i.e. 80 mg/kg) when compared with the other doses of mentat. The evaluation of acute toxicity showed that mentat was non-toxic up to a dose of 1.5 g/kg b. wt., where no drug-induced mortality was observed. The LD50 dose of mentat was found to be 1.75 g/kg b. wt. Our study demonstrates that mentat can provide good radioprotection at a dose of 80 mg/kg, which is far below its toxic dose.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Description from the manager
Description from the manager
This semi-detached cottage is situated close to Ruthwell in Dumfries and sleeps four people in two bedrooms. Dabbins Cottage is an all ground floor cottage, set on the owners' working livestock farm, 2.8 miles from the village of Ruthwell in Dumfries. This cottage sleeps four people in two bedrooms, consisting of one double and one twin, as well as a bathroom. The cottage also has an open plan living area with kitchen, dining area and sitting area with woodburning stove. Outside there is off road parking for two cars and a shared front garden with furniture. Dabbins Cottage is a lovely retreat for couples or families who wish to explore this area, which offers the towns of Annan and Dumfries, the Solway Coast Trail, as well as many castles, abbeys.
Region: From the lush green farmlands of the Borders to the ruggedness of the Highlands, the Scots are proud of their land and identity. Scotland also has some of Britain's best beaches with glorious stretches of clean sand over which to roam.
Town: Ruthwell is a small village located between the towns of Annan and Dumfries on the Solway Firth in Dumfries and Galloway. The village was home to Dr. Henry Duncan who founded the world's first commercial savings bank and the village is now home to the Savings Bank Museum. Annan is just seven miles away and offers traditional red stone buildings and a rich history of ship building and fishing, plus it is situated at the start of the Solway Coast Trail - a drive which takes you on quiet roads to a wealth of castles and abbeys.
Additional amenities include: cooker.TripAdvisor property ID 2407251 area, which offers the towns of Annan and Dumfries, the Solway Coast Trail, as well as many castles, abbeys.
Region: From the lush green farmlands of the Borders to the ruggedness of the Highlands, the Scots are proud of their land and identity. Scotland also has some of Britain's best beaches with glorious stretches of clean sand over which to roam.
Town: Ruthwell is a small village located between the towns of Annan and Dumfries on the Solway Firth in Dumfries and Galloway. The village was home to Dr. Henry Duncan who founded the world's first commercial savings bank and the village is now home to the Savings Bank Museum. Annan is just seven miles away and offers traditional red stone buildings and a rich history of ship building and fishing, plus it is situated at the start of the Solway Coast Trail - a drive which takes you on quiet roads to a wealth of castles and abbeys.
Interested?
From
$482
Reservation rules
3 night minimum staySaturday check-in only
Manager terms
All prices are inclusive of the booking fee. Winter Short Breaks (WSB) are available at many properties in the "Winter" period - subject to availability. Extra nights are charged pro rata of the weekly rental. Off Season Breaks (OSB) are available at many properties in parts of the "Low" and "Mid" periods - subject to availability. The price for a 3 night break is either 75% of the normal weekly rental or, if it is higher, the quoted Winter Short Break price. Extra nights are charged pro rata of the weekly rental. OSBs can be booked within a calendar month of the start date of the holiday. "Last Minute Breaks" (LMB) are available at most properties throughout the "LOW", "MID", "HIGH", "PEAK", "XMAS" and "NEW YEAR" periods. The price for a 3 night break is either 65% of the normal weekly rental or, if it is higher, the quoted Winter Short Break price. Extra nights are charged pro rata of the weekly rental. LMBs can be booked within one week of the start date of the holiday.
/ week - / week - manager terms applymanager terms apply
Request more information
Check-in*Check-out*
Guests*
First and last name*
Email*
Confirm Email*
Phone
Enter a brief message*
Talk to the manager
Call the manager
+44-1244-357716
* required
Contact the manager
You have gone over the limit for submitting inquiries in a certain amount of time. Please wait a moment before trying to submit another.
About Us
Love for FlipKey
As featured in USA TODAY and recommended by Travel + Leisure in its annual Villa Guide:
FlipKey Elsewhere
New to FlipKey?
FlipKey is a vacation rental marketplace with more than 300,000 rentals around the world. Find the perfect place to stay for your trip, and get great value along with the space, privacy and amenities of home.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
The Audacity of Iran's Foreign Minister
Iranian women wearing chadors in the Islamic tradition protesting in Tehran on April 16, 1979.AP
If the Persian language had a term for chutzpah, it should have been the title for Javad Zarif’s recent essay in The Atlantic. Written by Iran’s foreign minister and master propagandist, a man who has perfected the art of spoon-feeding credulous Westerners his spin, the article depicts an odious Iranian regime that has spread chaos and destruction throughout the Middle East as a magnanimous democratic force for regional stability.
The narrative spun by the foreign minister not only contradicts the historical reality of Iran’s behavior but is also at odds with the Farsi-language narratives of Iranian politicians who openly boast of the Islamic Republic’s hegemonic ambitions. Just three years ago, an Iranian official close to Supreme Leader Ayatollah Khamenei famously remarked, “Three Arab capitals [Beirut, Damascus, and Baghdad] have already fallen into Iran’s hands and belong to the Iranian Islamic Revolution.” The Yemeni capital of Sana’a, he added, would be the fourth. Add to that the mullahs’ racial and religious incitement for what Ayatollah Khomeini called, as far back as 1945, “the savages and camel herders” of Arabia, language that Iran’s clerical and political class continues to spew in their sermons and media.
Listening to Zarif, we are to believe that the Islamic Republic is promoting peace and understanding in the world, having been born of a glorious revolution that “freed its people from tyranny.” That the mullahs butchered tens of thousands of their own citizens and forced millions more into exile during this glorious revolution is conveniently forgotten. Also conveniently ignored by Zarif, in his lamentations that Iran suffered an unjust war with Iraq, is the fact that by calling for the overthrow of Saddam Hussein, and by urging their followers to spread the fire of the Islamic revolution to the “corrupt godless monarchies” of the Arabian Gulf, Iran’s mullahs succeeded in provoking an admittedly foolish Saddam into attacking them, and the Gulf monarchies into throwing their full weight behind Baghdad.
Since the early days of its revolution, Iran has worked to develop proxy forces, like Hezbollah, as a tool to export the Islamic Republic’s radical revolution to its Arab neighbors. The creation of these forces and the unleashing of their destructive potential on the Arab world may be Iran’s single greatest “achievement.” In its nearly 40-year history the Iranian revolution has no other claim to success, no achievement of any consequence to boast of except creating what are arguably the world’s most successful state-sponsored terrorist organizations.
The Islamic Republic created Hezbollah to capture and control the Lebanese state; this is the same Hezbollah that in 1983 killed 241 U.S. marines when it destroyed the American military barracks in Beirut. “Hezbollah of the Hejaz,” the Lebanese terror group’s Saudi affiliate, murdered 19 U.S. military personnel in the 1996 bombing of the Khobar Towers complex. Iran unleashed both Hezbollah and its own Revolutionary Guard to prop up the bloody dictatorship of Bashar al-Assad after the latter met his own people’s peaceful demands for reform with barrel bombs and chemical weapons, killing them by the hundreds of thousands.
Tehran also backed the Houthi militias that overthrew the internationally recognized government of Yemen and helped create the Shia militias in Iraq whose ethnic cleansing of Iraq’s Sunni population led directly to the creation of ISIS. In Bahrain, Kuwait, and Argentina, Tehran funded terror cells that planned and, in the cases of Bahrain and Argentina, successfully executed terror attacks against security personnel and a Jewish cultural center, respectively. The history of Iranian aggression is so long, so damning, and so well-documented that it’s hard to believe one even has to remind people of it today.
The hubris of a regime that prioritizes power projection abroad over the critical human-development requirements of its own people—a neglected population who are fed anti-American rhetoric and extremist ideology while suffering under stagnant wages and chronic unemployment—does not come without a cost. While the foreign minister touts Iran’s 1979 liberation, he makes no mention of the Green Revolution, which also sought to “free [the Iranian people] from tyranny.” His government’s rigging of the 2009 presidential elections sparked peaceful protests by millions of Iranian citizens that were ruthlessly suppressed through a state-directed campaign of intimidation, mass arrests, torture, and murder. It is doubtful that the thousands of political dissidents who have been guests of Tehran’s infamous Evin prison and Iran’s other notorious detention facilities ever felt “freed from tyranny.”
The tragedy of Iran’s Islamic revolution is that it traded one dictatorship for a far more brutal one, yet this does not stop Zarif from audaciously claiming that Iran is a democracy. The fact is, however, that Iran’s unelected Supreme Leader appoints the Guardian Council, an unelected theocratic body that decides who can and cannot run for president and parliament. This same Guardian Council also decides who sits on the Assembly of Experts, another unelected theocratic body that chooses the next Supreme Leader. In other words, the Supreme Leader has veto power over all of Iran’s organs of government. Elections, when they are held, are cleverly designed to create the illusion of political participation and pluralism. This does not stop apologists in the West from jumping on minor variations within the tightly controlled Iranian political spectrum as signs of “moderation” worthy of Western support—a game Iranians like Zarif are only too happy to indulge them in.
Iran is not only a destabilizing revolutionary power masquerading as a benevolent force for stability but also a dictatorship pretending to be a democracy. This hypocrisy is why nobody trusts the Islamic Republic. And when their foreign minister can shamelessly say what he says with a straight face while his masters in Tehran say and, more importantly, do the exact opposite, is it any wonder that the Arab Gulf states do not believe they can peacefully “share their neighborhood” with such a regime, or any wonder why they treat calls for dialogue with great skepticism?
We want to hear what you think about this article. Submit a letter to the editor or write to [email protected].
| null |
minipile
|
NaturalLanguage
|
mit
| null |
1. Field of the Invention
This invention relates to an attenuator circuit apparatus, and more particularly to an improvement of step attenuator circuit for attenuating in stages a signal such as a high frequency signal of a micro-wave band.
2. Description of the Related Art
Up to the present time, various step attenuators have been proposed to obtain an attenuated signal of plural bits with respect to a high frequency signal. Especially, when it is applied to a consumer appliance (for instance, a portable telephone), an essential condition is that it can be manufactured at a low price and in a small size. To reach these objectives an MMIC (Monolithic Microwave IC) attenuator which utilizes a GaAs FET (field effect transistor) is being developed.
These step attenuators can be divided roughly into two categories. One of them is the step attenuator in which the plural stages of the .pi.-type attenuator circuit are connected in series with respect to the signal path as shown in FIG. 1 ("FAST GaAs MMIC ATTENUATOR HAS 5-b RESOLUTION", MICROWAVE & RF OCTOBER 1991 pp.71-76). The other is the step attenuator in which the plural stages of the T-type attenuator circuit are connected in series with respect to the signal path as shown in FIG. 2 ("DC-12[GHz] 4-Bit GaAs Monolithic Digital Attenuator", Applied Microwave Winter 91/92 pp.60-67).
Thus, the step attenuator is usually composed of the .pi.-type attenuator circuits or the T-type attenuator circuits. In the case of .pi.-type attenuator circuit, there is a disadvantage that the insertion loss of it is larger in some degree (4 dB or more, at DC-10 GHz). This is mainly due to the increasing of the insertion loss which is caused by the electric power which leaks from these FETs, in view of the fact that there are two FETs connected in the shunt position with respect to the signal path. Therefore, this type is not suited for the realization of a step attenuator of plural bits, which requires a lower insertion loss.
On the other hand, in the case of the T-type attenuator circuit, the number of the FET which is connected in the shunt position with respect to the signal path is one. It is less than the number of the case of the .pi.-type attenuator circuit by one, therefore, the insertion loss can be restrained to a considerably small value (2 dB or less, at DC-2 GHz). Consequently, this type is suited for the realization of the step attenuator of plural bits, which requires the lower insertion loss.
However, in the case of the T-type attenuator circuit, there was a problem that the more the attenuation quantity increases the more the attenuation quantity is affected by the dispersion of the element precision. That is, if an attempt was made to attenuate the high frequency signal which is inputted to the 50 .OMEGA. terminated signal path by 16 dB with the T-type step attenuator 5, which is comprised of the three stages connected, the resistance value of the resistor r6a, which is connected in the shunt position with respect to the signal path, of the resistors composing the T-type attenuator circuit 5C which is connected to the third stage becomes a very little value, that is about 10 .OMEGA..
Therefore, when the ON resistance value of the FET16 located in the shunt position or the resistance value of the resistor r6a has fluctuated for some reason, the influence caused by the fluctuated quantity becomes large. For instance, when the resistance value has fluctuated by only 2 to 3 .OMEGA., this fluctuated quantity corresponds to 20 to 30% toward the resistance value of the resistor r6a. Hence, the attenuation quantity fluctuates extensively.
On the other hand, there is a limit to control very precisely the resistor and the FET which are located in the shunt position. Consequently, it is very difficult, in effect, to obtain a large attenuation quantity with a satisfactory precision by the T-type attenuator circuit.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Published by Dynamite Entertainment From October 2014Lineup Evil Dead/Army of Darkness seriesFormat: One-shot special issue Army of Darkness: Convention Invasion #1.
Following the fan-favorite Evil Dead film trilogy, Ashley J. Williams has had a long history with comic books.
After some pretty good comic book adaptations of The Evil Dead and Army of Darkness at Dark Horse Comics, Dynamite Entertainment launched an Army of Darkness ongoing title in 2004 to much success. These comics were fun, silly and very much true to the B-movie nature of the film series.
Ash and the Army of Darkness follows a complete reboot of
this long-running comic book series. This reboot of the comic was long time coming, it
was bound to happen as the series was starting to grew out of hand and
completely lose touch with what made it so great in the first place. The
series was getting harder and harder to follow thanks to several
crossovers and complete change of direction whenever a new creative
picked it up.
Dynamite wanted to offer a fresh new start to their Army of Darkness comics with a more serious tone, thanks to the
success of the Evil Dead remake.
After a trip across time and space in the Annual, Ash is now back to the present day working at S-Mart before facing an invasion of Deadites at a Comic Con for this short tale. This is the one-shot Army of Darkness: Convention Invasion!
This story is not really meant to be part of the main series, although you can sort of place it sometimes during the Annual before his arrival back to the past, right before the following story arc "Ash Gets Hitched".
Ash Williams is now seen working for S-Mart again, almost leaving his life fighting the Deadites behind him. When suddenly 3 nerds come looking for his help! There's a Deadite invasion slowly taking over a comic book convention nearby! And they knew about his epic ongoing fight versus the Army of Darkness from the comics! They made comics of Ash? Hey! What about his royalties?!
Anyways, turns out some sorcerer cosplayer took his role-playing a bit too far and has been seen using the Necronomicon to rise the Army of Darkness! Where did he get his hands on that priceless book, at the convention??
But the 3 kids were followed by a Deadite! They team up. Ash is captured by some skeletons and dragged underwater. Turns out Evil Ash is behind all this! And he's using the two other fake copies of the Necronomicon Ash left behind in the graveyard back in the past! And they seem to tap into that same power!!
Ash faces Evil Ashes while the kids go looking for the sorcerer...
Army of Darkness: Convention Invasion is a fun little one-shot. The comic was written by Michael Moreci who really captured the voice of Ash in this short little story, with art by Brent Peeples. It's just a simple little 48-page one-shot.
It's not meant to be taken too seriously. Ash even makes Evil Ash skips the entire explanation for all of this!
It's a funny silly story, not taking itself too seriously. It sort of reminded me of Knights of Badassdom, in a way!
It gets pretty meta with all the allusions to Ash's adventures and the comic book series. They even make fun of the way artists tend to exaggerate his chin. It plays with conventions, cosplay, etc.
Oh, and the cover by Robert Hack is pretty badass!
Overall, Army of Darkness: Convention Invasion is a fun little side romp, for fans of the series. Check it Out if you feel like it!
It plays with elements of the comics, conventions and fandom!
Nothing much really, but it was a nice distraction from the main and often too serious ongoing series.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Ordering a test swatch is a good idea! Color can look very different on fabric than what you see
on your monitor and there is simply no substitute to seeing your design on fabric
among other reasons.
This fabric is delivered smooth and crinkles when washed. Prints are likely to be off-grain.
Please note: We will print this item in as long a run
of fabric as possible. If flaws are present, extra may be printed. We may
need to divide your yardage into shorter, non-continuous pieces.
Click here
for more information or contact Customer Service.
By Amanda Jane Ogden
Description:
A repeat design of an English wild flower called Creeping Cinquefoil
I like this wild flower for its romantic name as much as for its distinctive five petal flower and five-segmented leaf. I drew the plant with botanical accuracy and used watercolour paint to add colour to the flowers, stem and leaves.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Moroccan police arrested a French citizen of Algerian origin near Tangiers at the weekend on suspicion of recruiting men to travel to Syria and Iraq to fight for al Qaeda, authorities said.
Advertising Read more
A statement issued by the Interior Ministry late Sunday described the suspect as a veteran member of the international terror network, who fought in Afghanistan,
Pakistan and Bosnia. It said he was charged with raising funds and manpower for fighting in Syria.
While Morocco has experienced few terrorist attacks compared to its neighbors, it is turning into a major source of recruits for conflicts in Mali, Syria and elsewhere.
Interior Minister Mohamed Hassad said on July 15 that 1,212 Moroccans belong to terrorist groups in Iraq and Syria and several Moroccans have committed suicide attacks there.
The worry in Morocco is that many of these trained fighters will one day return to carry out attacks in the kingdom.
Authorities have repeatedly announced the dismantling of cells recruiting for al-Qaida, especially in the northern cities.
According to the statement, the suspect arrived in Morocco on July 21, traveling via Tunisia and Libya and was arrested on Saturday in the main container port of Tanger-Med.
He was recruiting for the al-Qaida’s Syrian affiliate, the Nusra Front, authorities said.
(AP)
Daily newsletterReceive essential international news every morning Subscribe
| null |
minipile
|
NaturalLanguage
|
mit
| null |
A struggling restaurant would get to stay open, while the city of St. Paul takes a $487,000 loss under a deal that goes before the city council next week.
The non-profit Hmong American Partnership has offered to buy the University Avenue building where Mai Village is located for about $1.7 million dollars.
Dancers perform at Mai Village in February 2012 to help launch a branding campaign and bring attention to Asian-owned businesses in St. Paul during light rail construction. (MPR file photo / Nikki Tundel)
That would save the building from foreclosure, but St. Paul would get just pennies on the dollar for the $512,000 it’s owed as part of the mortgage. The restaurant owners would lose the building, but they’d get to keep doing business there.
“It allows the tax base in our city to continue on a really important corner, [and] a really great local business to continue operating,” said Council Member Melvin Carter, who represents the area. “What we get from saving Mai Village and keeping it there really outweighs what we’re giving.”
St. Paul would receive nothing if the foreclosure were completed as scheduled on April 25, because two other lenders have priority under the terms of the mortgage.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
details
Adds a sharp, classic style to any dash. A very low-profile bezel follows the curve of the lens to keep water from trapping. Rugged domed glass sheds water and is scratch-resistant. 2" diameter. Requires a 2.16" hole.
Description:
With a stylish white bezel design, these accurate,
reliable instruments will look great on any type of boat. Black on white graphics, enhanced with through-dial and perimeter lighting for easy readability, even at night. Tough domed glass sheds water and ...
Description:
Adds a sharp, classic style to any dash.
A very low-profile bezel follows the curve of the lens to keep water from trapping. Rugged domed glass sheds water and is scratch-resistant. 2" diameter. Requires a 2.16" hole.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Intrahepatic peribiliary glands of humans. II. Pathological spectrum.
The pathological spectrum of intrahepatic peribiliary glands is reviewed here. Several categories of histopathological changes such as necro-inflammation, cystic dilatation, hyperplasia and neoplasia have been identified in this glandular system. Necro-inflammation is associated with biliary tract diseases and chronic advanced liver diseases and may also appear in the livers of subjects with extrahepatic diseases such as sepsis. Cystic changes of microscopic sizes are not uncommon in autopsy livers of chronic advanced liver diseases, portal hypertensive diseases and also polycystic liver of adult type. Grossly recognizable cysts are, however, infrequent and occasionally cause compression of the adjoining bile ducts. Hyperplasia of these glands, which occurs consistently in hepatolithiasis and more variably in other conditions (e.g. biliary tract infection and submassive hepatic necrosis), may be associated with hypersecretion of seromucinous substances. Hyperplasia of peribiliary glands may then lead to mucin-related biliary diseases. In addition, these glands, particularly the hyperplastic ones, could be a precursor of cholangiocarcinoma. The pathological spectrum of the intrahepatic peribiliary glands is being expanded, although a clinical pathological correlation remains uncharted. Furthermore, age-related variations and non-specific reactive changes of these glands remain unexplored.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Is social media creating a digitally dependent culture?
November 8, 2013
Has social media invented a digital culture, or simply removed the red tape to a bevy of information? Credit: Stock.xchng
Unless you've taken a time machine back to the dark ages, you're well aware that social media is everywhere. The question many ask is whether social media has invented a digital culture or simply removed the red tape to a bevy of information.
Suzanne Scott, assistant professor of Film and Media Studies in the Department of English at Arizona State University, teaches two courses on the impact of new and digital media on the media industry and fan culture.
"People want to talk about social media as if it is groundbreaking, which it is on many levels, but ultimately, it is just an extension of something we've always been attracted to, like building out our network of friends and colleagues. Platforms like Facebook have just made it easier to curate and broadcast this information like never before," she said.
Networks such as Twitter have provided individuals with unprecedented access to celebrities and brands.
"Twitter is oriented around making connections outside of your circles. You may have gone to Comic Con and waited in line for an hour just to ask Dan Harmon a question about 'Community.' I, on the other hand, can simply tweet him a question and he is more inclined to respond."
Scott also references how social media is being used as an extension of the community following television shows. Shows such as The Walking Dead (#TheWalkingDead) and Scandal (#Scandal) list their tags at the bottom of the screen on each episode, encouraging the audience to go online to connect with fellow fans, producers and cast members. This increases the lifespan of a show that normally lasts only one hour each week.
But what happens when social media meets the classroom? Many professors will list electronic devices as unecessary distractions for their students during lectures. Realistically, that is probably true. Scott says that in her class, she notices students browsing the web, but that banning the devices altogether is not the solution. Instead, she sees it as a personal challenge.
"Simply telling students they can't bring their devices to class doesn't solve the problem. My goal is to find a way to turn this distraction into something that they critically engage with," she said.
For example, Scott encourages students to use YouTube and Google to find content related to the subject matter at hand that can be shared with the class. She also notices that students will search Twitter to see if there is a handle or hashtag they can follow. Students are also required to create a Storify page where they treat social media posts as scholarly evidence analyzing fan culture.
Job applicants try to make a good impression when meeting a prospective employer, but employers may be able to learn what applicants are really like by screening their social media posts. Unfiltered personal communications, ...
Recommended for you
It sounds like a science-fiction nightmare. But "killer robots" have the likes of British scientist Stephen Hawking and Apple co-founder Steve Wozniak fretting, and warning they could fuel ethnic cleansing and an arms race.
Photos. Messages. Bank account codes. And so much more—sit on a person's mobile device, and the question is, how to secure them without having to depend on lengthy password codes of letters and numbers. Vendors promoting ...
A startup team calls their work a product. They also call it a social movement. Many people in the over-7,000 islands in the Philippines lack access to electricity .The startup would like to make a difference. Their main ...
| null |
minipile
|
NaturalLanguage
|
mit
| null |
After the U.S. Vice President Mike pence visited the demilitarized zones between the South and North Korea and warned that the United States’ strategic patience with North Korea is over and sent a message to North Korea to not to test the resolve of President Trump, Russia has issued a warning to the United States against unilateral action in the region. Vice President Pence said, “In the past two weeks, the world witnessed the strength and resolve of our new president in actions taken in Syria and Afghanistan……North Korea would do well not to test his resolve or the strength of the armed forces of the United States.”
Speaking at a news conference, the Russian foreign minister Sergei Lavrov said that this is a very risky path. He added, “We do not accept the reckless nuclear missile actions of Pyongyang that breach UN resolutions, but that does not mean that you can break international law………I hope that there will not be any unilateral actions like the one we saw recently in Syria.” Russia has also warned the United States against further unilateral actions on Syria.
China is reportedly working with the United States to resolve the issue with North Korea. However, the North Korean regime has so far remained defiant. It test fired a ballistic missile to commemorate the 105th birthday of the country’s founder Kim Il-Sung but the test failed as the missile detonated immediately after launch.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
WASHINGTON – Today, U.S. Small Business Administration Administrator Jovita Carranza issued the following statement in response to President Donald J. Trump’s signing of the innovative United States-Mexico-Canada Agreement (USMCA):
“Today’s signing into law of the USMCA by President Trump is a landmark achievement that promises to create lucrative new opportunities for small businesses, including many minority-owned businesses. Thirty-six percent of Latino-owned businesses earn most of their revenue online, compared to 18% of other small businesses, and this new framework will make it easier to sell products to consumers in Canada and Mexico by eliminating complex and cost-prohibitive rules requiring small businesses to open foreign offices.
“As a result of this President’s leadership on trade, $68 billion in new economic activity will be generated, and an estimated 176,000 new jobs will be created, helping to further fuel upward mobility in communities that need it most.”
Click here to learn more about the USMCA.
About the U.S. Small Business Administration
The U.S. Small Business Administration makes the American dream of business ownership a reality. As the only go-to resource and voice for small businesses backed by the strength of the federal government, the SBA empowers entrepreneurs and small business owners with the resources and support they need to start, grow or expand their businesses, or recover from a declared disaster. It delivers services through an extensive network of SBA field offices and partnerships with public and private organizations. To learn more, visit www.sba.gov.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Image copyright AFP Image caption The Soyuz clears the pad and heads skyward
The European Space Agency has launched a second radar satellite into the EU's new Sentinel constellation.
Sentinel-1b was carried into orbit by a Soyuz rocket that flew out of Sinamary in French Guiana.
The new platform will monitor shipping lanes for pollution and icebergs, and survey land surfaces for evidence of subsidence - to name just three of the myriad applications for radar imagery.
Sentinel-1b will work alongside the 1a spacecraft, which was launched in 2014.
Operating in the same orbit but separated by 180 degrees, the pair will be able to map the entire Earth every six days.
This promises an avalanche of data - some five terabits per day - and both satellites are carrying laser communications systems to help get all the information to the ground.
The Sentinels are a flagship space project for the European Union, which has committed billions of euros to the endeavour.
The satellites fit into a programme the European Commission calls Copernicus, which draws together all sorts of data about the health of the Earth, not just from orbit.
Copernicus will support a multitude of services, ranging from air quality updates to crop-performance monitoring, from water-resource management to transport infrastructure planning.
Image copyright ESA Image caption Sentinel radar data reveals changes (blue) in the shape of Villarrica volcano in Chile
Esa is acting as the technical agent, procuring the satellites for the EU. Sentinel-1b is the fourth to launch, with more platforms to follow.
"At the moment, we have around 36,000 self-registered users (for Sentinel data), who have downloaded already about four million images, mainly from Sentinel-1a; although this is now picking up because Sentinel-2a (a visible colour camera) has just become operational as well," explained Esa's Earth-observation director Prof Volker Liebig.
The Soyuz' lift-off from French Guiana occurred at 18:02 local time (21:02 GMT), following three postponements in previous days due to meteorological and technical issues.
The 2.1-tonne Sentinel was ejected 23 minutes into the ascent. The planned injection altitude was 686km (426 miles).
"We will not start commissioning until we have raised ourselves to the proper orbit (693km), which could take two weeks, a maximum of three," Esa's Sentinel-1 project manager, Ramon Torres told BBC News.
"We will then go into detail with the calibration of the radar instrument. We plan the commissioning review (to declare Sentinel-1b operational) for 14 September."
Media playback is unsupported on your device Media caption Prof Volker Liebig: "We thought we'd reach the 'Big Data' region in one or two years"
Media playback is unsupported on your device Media caption Sentinel-1a images track the movement on Antarctica's Thwaites Glacier
Image copyright ESA Image caption Sentinels 1a and 1b are separated by 180 degrees and will map the entire Earth every six days
Four other satellites were put in orbit on the same Soyuz flight.
Three were university cubesats. One, however, was a French space agency mission called Microscope - a fundamental physics experiment.
This satellite will spend the next couple of years investigating the so-called "equivalence principle".
It is the concept in general relativity that holds that gravity accelerates all objects equally, regardless of their mass or composition.
The Apollo 15 astronaut Dave Scott famously demonstrated the principle on the Moon in 1971 when he dropped a geology hammer and a falcon feather. Both hit the surface of the airless body at the same time.
Microscope's examination will be much more exacting, of course. It will "drop" metal cylinders made from titanium-aluminium-vanadium and platinum-rhodium - to see if they also fall at the same rate in the vacuum of space.
The experiment can sense accelerations that are a millionth of a billionth of Earth's gravity.
Image copyright NASA Image caption Dave Scott: A hammer in his right hand, a falcon feather in his left
Image copyright CNES Image caption Microscope is a fundamental physics experiment
[email protected] and follow me on Twitter: @BBCAmos
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Abstract
Objective: The neurobiological mechanisms of deviant sexual preferences such as pedophilia are largely unknown. The objective of this study was to analyze whether brain activation patterns of homosexual pedophiles differed from those of a nonpedophile homosexual control group during visual sexual stimulation.
Method: A consecutive sample of 11 pedophile forensic inpatients exclusively attracted to boys and 12 age-matched homosexual control participants from a comparable socioeconomic stratum underwent functional magnetic resonance imaging during a visual sexual stimulation procedure that used sexually stimulating and emotionally neutral photographs. Sexual arousal was assessed according to a subjective rating scale.
Results: In contrast to sexually neutral pictures, in both groups sexually arousing pictures having both homosexual and pedophile content activated brain areas known to be involved in processing visual stimuli containing emotional content, including the occipitotemporal and prefrontal cortices. However, during presentation of the respective sexual stimuli, the thalamus, globus pallidus and striatum, which correspond to the key areas of the brain involved in sexual arousal and behaviour, showed significant activation in pedophiles, but not in control subjects.
Conclusions: Central processing of visual sexual stimuli in homosexual pedophiles seems to be comparable to that in nonpedophile control subjects. However, compared with homosexual control subjects, activation patterns in pedophiles refer more strongly to subcortical regions, which have previously been discussed in the context of processing reward signals and also play an important role in addictive and stimulus-controlled behaviour. Thus future studies should further elucidate the specificity of these brain regions for the processing of sexual stimuli in pedophilia and should address the generally weaker activation pattern in homosexual men.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Image copyright Geograph/Simon Mortimer Image caption The wire was pulled across Clyne Valley cycle path
A cyclist was thrown from his bike after riding into a piece of string tied at neck height across a Swansea cycle path.
David Stacey suffered head injuries and spent a night in Morriston Hospital after being knocked unconscious at about 17:40 BST on Tuesday.
He was cycling from Killay to Gowerton on the Clyne cycle path near Oakwood Drive.
The incident is being investigated by South Wales Police.
Mr Stacey said he could barely remember what happened and added: "If I didn't have a good helmet on I would have been a goner.
"The string was roughly neck or shoulder height and I came off my bike. My head hit the floor and I was knocked out completely.
"All I can remember is that it felt like hitting an invisible wall. I can just about remember going through the air and then like a firework going off inside my head and that's it."
'Sick prank'
Three men stopped and phoned the emergency services.
Mr Stacey said there was sometimes tension between walkers and cyclists on the multi-use path, with some cyclists going too fast.
He said: "Protesting against cyclists going too fast or some sick prank could have resulted in a death or brain injury.
"There's a huge dent in my bike helmet - that could have been my skull."
A police spokeswoman said: "Cyclists in the area are advised to be vigilant and to report anything suspicious."
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Mouthy Momentum nut Nadeem Ahmed, who threatened to run a deselection campaign against Jess Phillips, has been expelled from the Labour Party. Ahmed had been falsely claiming that Phillips “is racist”, demanding she apologise or he would “start deselection process” and boasting “Momentum is powerful force”. Unfortunately for him he also backed George Galloway ahead of the Labour candidate in Gorton, in obvious breach of party rules. Turns out the Labour compliance unit is also a powerful force…
| null |
minipile
|
NaturalLanguage
|
mit
| null |
If you've played around with electronic circuits, you probably know[1] the 555 timer integrated circuit, said to be the world's best-selling integrated circuit with billions sold. Designed by analog IC wizard Hans Camenzind[2] in 1970, the 555 has been called one of the greatest chips of all time with whole books devoted to 555 timer circuits.
Given the popularity of the 555 timer, I thought it would be interesting to find out what's inside the 555 timer and how it works. While the 555 timer is usually sold as a black plastic IC, it is also available in a metal can, which can be cut open with a hacksaw[3] revealing the tiny die inside.
Inside the 555 timer. The tiny die in the package is connected to the 8 pins by wires.
A brief explanation of the 555 timer
The 555 timer has hundreds of applications, operating as anything from a timer or latch to a voltage-controlled oscillator or modulator. The diagram below illustrates how the 555 timer operates as a simple oscillator. Inside the 555 chip, three resistors form a divider generating references voltages of 1/3 and 2/3 of the supply voltage. The external capacitor will charge and discharge between these limits, producing an oscillation. In more detail, the capacitor will slowly charge (A) through the external resistors until its voltage hits the 2/3 reference. At that point (B), the upper (threshold) comparator switches the flip flop off and the output off. This turns on the discharge transistor, slowly discharging the capacitor (C). When the voltage on the capacitor hits the 1/3 reference (D), the lower (trigger) comparator turns on, setting the flip flop and the output, and the cycle repeats. The values of the resistors and capacitor control the timing, from microseconds to hours. [4]
Diagram showing how the 555 timer can operate as an oscillator.
To summarize, the key components of the 555 timer are the comparators to detect the upper and lower voltage limits, the three-resistor divider to set these limits, and the flip flop to keep track of whether the circuit is charging or discharging. The 555 timer has two other pins (reset and control voltage) that I haven't covered above; they can be used for more complex circuits.
The structure of the integrated circuit
The photo below shows the silicon die of the 555 through a microscope. On top of the silicon, a thin layer of metal connects different parts of the chip. This metal is clearly visible in the photo as yellowish-white traces and regions. Under the metal, a thin, glassy silicon dioxide layer provides insulation between the metal and the silicon, except where contact holes in the silicon dioxide allow the metal to connect to the silicon. At the edge of the chip, thin wires connect the metal pads to the chip's external pins.
Die photo of the 555 timer.
The different types of silicon on the chip are harder to see. Regions of the chip are treated (doped) with impurities to change the electrical properties of the silicon. N-type silicon has an excess of electrons (negative), while P-type silicon lacks electrons (positive). In the photo, these regions show up as a slightly different color surrounded by a thin black border. These regions are the building blocks of the chip, forming transistors and resistors.
NPN transistors inside the IC
Transistors are the key components in a chip. The 555 timer uses NPN and PNP bipolar transistors. If you've studied electronics, you've probably seen a diagram of an NPN transistor like the one below, showing the collector (C), base (B), and emitter (E) of the transistor, The transistor is illustrated as a sandwich of P silicon in between two symmetric layers of N silicon; the N-P-N layers make an NPN transistor. It turns out that transistors on a chip look nothing like this, and the base often isn't even in the middle!
Schematic symbol for an NPN transistor, along with an oversimplified diagram of its internal structure.
The photo below shows one of the transistors in the 555 as it appears on the chip. The slightly different tints in the silicon indicate regions that has been doped to form N and P regions. The whitish-yellow areas are the metal layer of the chip on top of the silicon - these form the wires connecting to the collector, emitter, and base. You can spot an emitter on the chip by its "bullseye" structure, while the base rectangle surrounds the emitter.
An NPN transistor in the 555 timer chip. The collector (C), emitter (E) and base (B) are labeled, along with N and P doped silicon.
Underneath the photo is a cross-section drawing illustrating how the transistor is constructed. There's a lot more than just the N-P-N sandwich you see in books, but if you look carefully at the vertical cross section below the 'E', you can find the N-P-N that forms the transistor. The emitter (E) wire is connected to N+ silicon. Below that is a P layer connected to the base contact (B). And below that is an N+ layer connected (indirectly) to the collector (C).[5] The transistor is surrounded by a P+ ring that isolates it from neighboring components.
PNP transistors inside the IC
You might expect PNP transistors to be similar to NPN transistors, just swapping the roles of N and P silicon. But for a variety of reasons, PNP transistors have an entirely different construction. They consist of a small circular emitter (P), surrounded by a ring shaped base (N), which is surrounded by the collector (P). This forms a P-N-P sandwich horizontally (laterally), unlike the vertical structure of the NPN transistors.
The diagram below shows one of the PNP transistors in the 555, along with a cross-section showing the silicon structure. Note that although the metal contact for the base is on the edge of the transistor, it is electrically connected through the N and N+ regions to its active ring in between the collector and emitter. A metal line is routed between the collector and base, but is not part of the transistor.
A PNP transistor in the 555 timer chip. Connections for the collector (C), emitter (E) and base (B) are labeled, along with N and P doped silicon. The base forms a ring around the emitter, and the collector forms a ring around the base.
The output transistors in the 555 are much larger than the other transistors and have a different structure in order to produce the high-current output. The photo below shows one of the output transistors. Note the multiple interlocking "fingers" of the emitter and base, surrounded by the large collector.
A large, high-current NPN output transistor in the 555 timer chip. The collector (C), base (B) and emitter (E) are labeled.
How resistors are implemented in silicon
Resistors are a key component of analog chips. Unfortunately, resistors in ICs are large and inaccurate; the resistances can vary by 50% from chip to chip. Thus, analog ICs are designed so only the ratio of resistors matters, not the absolute values, since the ratios remain nearly constant.
A resistor inside the 555 timer. The resistor is a strip of P silicon between two metal contacts.
The photo above shows a 1KΩ resistor in the 555, formed from a strip of P silicon (visible as an outline). Note that the resistor connects two metal wires and another metal wire crosses it. The resistor below is an L-shaped 100KΩ pinch resistor. A layer of N silicon on top of the pinch resistor makes the conductive region much thinner (i.e. pinches it), forming a much higher but less accurate resistance.
A pinch resistor inside the 555 timer. The resistor is a strip of P silicon between two metal contacts. An N layer on top pinches the resistor and increases the resistance.
IC component: The current mirror
There are some subcircuits that are very common in analog ICs, but may seem mysterious at first. The current mirror is one of these. If you've looked at analog IC block diagrams, you may have seen the symbols below, indicating a current source, and wondered what a current source is and why you'd use one. The idea is you start with one known current and then you can "clone" multiple copies of the current with a simple transistor circuit, the current mirror.
Schematic symbols for a current source.
The following circuit shows how a current mirror is implemented with two identical transistors.[6] A reference current passes through the transistor on the left. (In this case, the current is set by the resistor.) Since both transistors have the same emitter voltage and base voltage, they source the same current, so the current on the right matches the reference current on the left.
Current mirror circuit. The current on the right copies the current on the left.
A common use of a current mirror is to replace resistors. As explained earlier, resistors inside ICs are both inconveniently large and inaccurate. It saves space to use a current mirror instead of a resistor whenever possible. Also, the currents produced by a current mirror are nearly identical, unlike the currents produced by two resistors.
Three transistors form a current mirror in the 555 timer chip. They all share the same base and two transistors share emitters.
IC component: The differential pair
The three transistors above form a current mirror with two outputs. Note the three transistors share the base connection, tied to the collector on the right, and the emitters on the right are tied together. The transistor on the left is a Widlar current source , a modified mirror that produces a smaller current. On the schematic, the two transistors on the right are drawn as a single two-collector transistor, Q19.The second important circuit to understand is the differential pair, the most common two-transistor subcircuit used in analog ICs. [7] You may have wondered how a comparator compares two voltages, or an op amp subtracts two voltages. This is the job of the differential pair.
Schematic of a simple differential pair circuit. The current sink sends a fixed current I through the differential pair. If the two inputs are equal, the current is split equally between the two branches. Otherwise, the branch with the higher input voltage gets most of the current.
The schematic above shows a simple differential pair. The current sink at the bottom provides a fixed current I, which is split between the two input transistors. If the input voltages are equal, the current will be split equally into the two branches (I1 and I2). If one of the input voltages is a bit higher than the other, the corresponding transistor will conduct more current, so one branch gets more current and the other branch gets less. A small input difference is enough to direct most of the current into the "winning" branch, flipping the comparator on or off.
In the 555, the threshold comparator uses NPN transistors, while the trigger comparator uses PNP transistors. This allows the threshold comparator to work near the supply voltage and the trigger comparator to work near ground. The 555's comparators also use two transistors on each input (Darlington pair) to buffer the inputs.
The 555 schematic interactive explorer
The 555 die photo and schematic [8] below are interactive. Click on a component in the die or schematic, and a brief explanation of the component will be displayed. (For a thorough discussion of how the 555 timer works, see 555 Principles of Operation .)
For a quick overview, the large output transistors and discharge transistor are the most obvious features on the die. The threshold comparator consists of Q1 through Q8. The trigger comparator consists of Q10 through Q13, along with current mirror Q9. Q16 and Q17 form the flip flop. The three 5KΩ resistors forming the voltage divider are in the middle of the chip.[9] Urban legend says that the 555 is named after these three 5K resistors, but according to its designer 555 is just an arbitrary number in the 500 chip series
Click the die or schematic for details...
How I photographed the 555 die
Integrated circuit usually come in a black epoxy package which require inconveniently dangerous concentrated acid to open. Instead, I bought a 555 in a metal can (below). To examine the die, I used a metallurgical microscope . Unlike a standard microscope, the metallurgical microscope shines light down through the lens allowing it to work with opaque objects (such as chips). I stitched the photos together with Hugin ( details ).
The 555 timer in an eight-pin metal can package. (Banana for scale)
The failed improved 555
Given the popularity of the 555, it's surprising that it has several rookie design flaws; unbalanced comparators, large operating currents, an asymmetric output waveform, and temperature sensitivity. [10]
In 1997, Camenzind redesigned the 555 to create a much better chip that could run at much lower voltages. The improved chip was sold by Zetex as the ZSCT1555, but unfortunately was a flop. The continuing success of the original 555 and the failure of the improved successor can be viewed as an example of the worse is better principle.
Conclusion
I hope you've found this look inside the 555 timer chip interesting. Next time you're building a 555 project , you'll know exactly what's inside the chip. If you enjoyed this article, I've also reverse-engineered the 741 op amp and 7805 voltage regulator . Thanks to Eric Schlaepfer [11] for helpful comments.
Follow me on Twitter and you won't miss an article!
Notes and references
[1] The 555 timer is iconic enough to appear on mugs caps and t-shirts
The 555 timer is popular enough to appear on t-shirts. Courtesy of EEVblog.
[2] The book Designing Analog Chips written by the 555's inventor Hans Camenzind is really interesting, and I recommend it if you want to know how analog chips work. Chapter 11 has an extensive discussion of the 555's history and operation. Page 11-3 claims the 555 has been the best-selling IC every year, although I don't know if that is still true. The free PDF is here or get the book.
[3] You can cut an IC can open with a plain hacksaw, but a jeweler's saw gives a much cleaner cut. I got a jeweler's saw on eBay for $14, and used the #2 blade. Make sure you cut near the top of the IC so you don't hit the die as I did.
[4] The brilliant part of the 555 timer is that the oscillation frequency depends only on the external resistors and capacitor and is insensitive to the supply voltage. If the supply voltage drops, the 1/3 and 2/3 references drop too, so you might expect the oscillations to be faster. But the lower voltage charges the capacitor more slowly, canceling this out and keeping the frequency constant.
This voltage insensitivity is so tricky that the chip's designer didn't figure it out until near the end of the 555's design, but it made a big difference. The original design was more complex and required nine pins, which is a terrible size for an IC since there are no packages between 8 and 14 pins. The final, simpler 555 design worked with 8 pins, making the chip's packaging much cheaper. (See page 11-3 of Designing Analog Chips for the full story.)
[5] You might have wondered why there is a distinction between the collector and emitter of a transistor, when the typical diagram of a transistor is symmetrical. As you can see from the die photo, the collector and emitter are very different in a real transistor. In addition to the very large size difference, the silicon doping is different. The result is a transistor will have poor gain if the collector and emitter are swapped.
[6] For more information about current mirrors, check wikipedia, any analog IC book, or chapter 3 of Designing Analog Chips.
[7] Differential pairs are also called long-tailed pairs. According to Analysis and Design of Analog Integrated Circuits differential pairs are "perhaps the most widely used two-transistor subcircuits in monolithic analog circuits." (p214) For more information about differential pairs, see wikipedia, any analog IC book, or chapter 4 of Designing Analog Chips.
[8] The 555 schematic used in this article is from the Philips datasheet.
[9] Note that the three resistors for the voltage divider are parallel and next to each other. This helps ensure they have the same resistance even if there are electrical variations across the silicon.
[10] I'm not criticizing the 555; Hans Camenzind points out the design flaws and attributes them to "the early period of IC design (and the inexperience of a rookie designer)"; see Designing Analog Chips, page 11-4. The design of a 555 replacement is discussed in detail in "Redesigning the old 555", IEEE Spectrum, September 1997. That article makes it clear how much much faster IC design is now than in 1970. It took months to create the layout of the 555 chip by hand and manually verify it for correctness. The new chip took two days to layout and 20 minutes to verify.
[11] Evil Mad Scientist sells a very cool discrete 555 timer kit, duplicating the 555 circuit on a larger scale with individual transistors and resistors — it actually works as a 555 replacement. Their 555 footstool is also worth a look.
Large-size 555 timer created by Evil Mad Scientist Lab.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Amisulpride versus imipramine and placebo in dysthymia and major depression. Amisulpride Study Group.
Amisulpride, a selective antagonist of D2 and D3 dopamine receptors, acts preferentially on presynaptic receptors increasing dopaminergic transmission at low doses. In a multicentre, 6 months, placebo-controlled trial, amisulpride (50 mg/daily) was compared to imipramine (100 mg/daily) in the treatment of patients with DSM-III-R criteria for primary dysthymia, dysthymia with major depression or major depression in partial remission. A total of 219 patients were included. Both analyses (intention-to-treat and "per protocol' analysis) detected significant differences between groups (active treatment vs. placebo) on all main rating scales (CGI, MADRS, ERD, and SANS). The number of patients reporting at least one adverse event was higher in the imipramine group than in the two other, mainly due to anticholinergic effects. Endocrine symptoms were more frequent in female patients treated with amisulpride. These results confirm the interest of a drug acting on dopaminergic transmission such as amisulpride in the treatment of depressed patients.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
All relevant data are within the paper and its Supporting Information files.
Introduction {#sec001}
============
Monoaminergic neurotransmitters exert their actions by interacting with diverse protein targets in their synapses. Thus, serotonin (5-HT), norepinephrine (NE) and dopamine (DA), activate either metabotropic or ionotropic receptors (e.g. β-adrenoceptors or 5-HT~3~ receptors, respectively), are catabolized by monoamine oxidase and/or catechol-*ο*-methyltransferase (in the case of NE and DA) and are pumped back into their synaptic terminals by selective transporter proteins. Furthermore, these neurotransmitters are accumulated into synaptic vesicles inside the nerve terminals by specific transporters, and even within noradrenergic neurons the presence of the enzyme DA-β-hydroxylase can be considered as an additional site for the interaction of DA \[[@pone.0200637.ref001],[@pone.0200637.ref002]\]. Moreover, several other compounds, including therapeutically useful and widely used recreational drugs which bind to more than one of these receptor proteins have been described \[[@pone.0200637.ref002],[@pone.0200637.ref003]\].
Even though this promiscuous interaction does not usually grab attention, it should be kept in mind that monoamine receptors, metabolic enzymes and transporters belong to different protein families, with highly diverse functionality, genetic origin and structure. That is the case, for instance, of the 5-HT and DA transporters (SERT and DAT, respectively) and monoamine oxidases. Although both types of proteins are involved in terminating the actions of 5-HT or DA at their synapses, their cellular localization, mechanism, structure and function are markedly different. Thus, human DAT and SERT are plasma membrane proteins which belong to the neurotransmitter/sodium symporter (NSS) family \[[@pone.0200637.ref004],[@pone.0200637.ref005]\]. The active reuptake of the corresponding monoamine into the neurons (or glial cells) against a concentration gradient is carried out by coupling the flow of neurotransmitters to that of sodium and chloride (and also to the counter-transport of potassium in the case of SERT) \[[@pone.0200637.ref006]\]. Much of the structural knowledge about human DAT and SERT transporters is based on the crystal structures of the LeuT (and homology models derived from them), a homologue Na^+^-coupled transporter from the bacterium *Aquifex aeolicus* \[[@pone.0200637.ref007]--[@pone.0200637.ref009]\]. Furthermore, the crystal structures of the DAT from *Drosophila melanogaster*, and the human SERT have been recently reported \[[@pone.0200637.ref010],[@pone.0200637.ref011]\]. In general terms, these structures revealed that these transporters contain a shot glass-shaped bundle of 12 transmembrane helices, which are connected by six extracellular and five intracellular loops. A central binding site is located approximately halfway across the membrane bilayer. At this site, both substrates and inhibitors \[[@pone.0200637.ref010]--[@pone.0200637.ref012]\], establish an ionic interaction between the ligand amino group and the carboxylate of a conserved aspartate (D46 in DAT from *Drosophila*, D98 and D79 in human SERT, and DAT, respectively). In these transporters, the majority of residues at this binding site are hydrophobic, although a few polar residues are able to form strong interactions with the substrates. All the crystal structures (as well as homology models, \[[@pone.0200637.ref013]\]) show the existence of a secondary binding pocket termed the extracellular vestibule, since it is located closer to the extracellular side of the transporter. Although in LeuT this site can accommodate selective 5-HT reuptake inhibitors or tricyclic antidepressants \[[@pone.0200637.ref014]--[@pone.0200637.ref016]\], more recent data using engineered LeuT or actual MA transporters, have unequivocally shown that these drugs inhibit DAT or SERT by acting at the central binding site \[[@pone.0200637.ref017],[@pone.0200637.ref018]\]. Nevertheless, pharmacological, mutagenesis and structural studies \[[@pone.0200637.ref017],[@pone.0200637.ref019],[@pone.0200637.ref020]\] have shown that the extracellular vestibule is an allosteric site, which can positively or negatively modulate activity at the central binding site.
On the other hand, monoamine oxidase (MAO), which in humans exists in two isoforms termed MAO-A and MAO-B, are outer mitochondrial membrane-bound flavoproteins, with the FAD cofactor covalently bound to the enzyme. 5-HT and 2-phenylethylamine are selectively oxidized by MAO-A and MAO-B respectively, while DA is a non-selective substrate of both enzyme isoforms \[[@pone.0200637.ref021],[@pone.0200637.ref022]\]. MAOs oxidize monoamines through a reaction that involves an α-C-H bond cleavage of the substrate and the concomitant reduction of the flavin cofactor, which is reoxidized by molecular oxygen producing hydrogen peroxide \[[@pone.0200637.ref021],[@pone.0200637.ref022]\]. Since 2002 a series of articles showing high-resolution structures of human or rat MAOs have been published \[[@pone.0200637.ref023]--[@pone.0200637.ref027]\], allowing a detailed comparison of the overall structures of both isoforms and their active sites \[[@pone.0200637.ref028]\]. Thus, the substrate/inhibitor binding site of both isozymes can be described as a pocket lined by the isoalloxazine ring and several aliphatic and aromatic residues. A critical role of Y444, Y407, G215 and I180 of MAO-A (Y435, Y398, G206 and L171 being the corresponding residues in MAO-B) in the orientation and stabilization of the substrate/inhibitor binding can be inferred from the X-ray diffraction data. In the case of MAO-B, the substrate/inhibitor binding site is a cavity (a flat entity of 420 Å^3^ in volume, termed the "substrate cavity") which can be distinguished, in some cases, from another hydrophobic entity (290 Å^3^ in volume, termed the "entrance cavity") located closer to the protein surface. In contrast, human and rat MAO-A's differ from human MAO-B in that they have only a single cavity, although it has been suggested that a two-cavity system could also exist in MAO-A \[[@pone.0200637.ref029]\].
The interaction of monoamines with their targets relies primarily on the shape and electronic complementarities between the ligand(s) and the receptor(s) binding site(s). Therefore, it seems reasonable to assume that all proteins targeted by a given monoamine should have certain similarities of these features at their binding sites. The availability of the crystal structures of either some of these proteins \[[@pone.0200637.ref010],[@pone.0200637.ref030]--[@pone.0200637.ref032]\] or their insect homologues \[[@pone.0200637.ref011],[@pone.0200637.ref012],[@pone.0200637.ref033],[@pone.0200637.ref034]\] as well as the development of an increasing number of algorithms aimed to evaluate the similarities between the binding sites of related and unrelated proteins \[[@pone.0200637.ref035]--[@pone.0200637.ref038]\], provide an exceptional framework to test this hypothesis.
Based on these precedents, in the present work we evaluated the likely existence of similarities among the binding sites of SERT, DAT, MAO-A and MAO-B. Beyond the mechanistic or functional clustering implications, we anticipate that the study of binding site similarities (and differences) among these proteins can be insightful for the rational design of selectively and non-selectively acting compounds.
Materials and methods {#sec002}
=====================
Molecular structures {#sec003}
--------------------
The crystallographic data of human MAO-A (\[[@pone.0200637.ref031]\]; 3.1 Å resolution), MAO-B (\[[@pone.0200637.ref024]\]; 1.7 Å resolution) and SERT (\[[@pone.0200637.ref010]\]; 3.1 Å resolution) were taken from the Protein Data Bank (PDB; PDBcodes: 2BXS, 1OJA and 5I6X respectively). A homology model of the human DAT was built as previously described \[[@pone.0200637.ref039],[@pone.0200637.ref040]\] using the crystal structure of the DAT from *Drosophila melanogaster* (\[[@pone.0200637.ref011]\]; 2.9 Å resolution, PDB code 4XPA) and the human SERT as templates.
In all cases, the corresponding transmembrane segments were embedded in a hydrated palmitoyl-oleyl-phosphatidyl-choline (POPC) bilayer membrane, solvated in a water box (type TIP3), and ions were added creating an overall neutral system in approximately 0.2M NaCl. The final systems were subjected to a molecular dynamics (MD) simulation for 5 ns using NAMD 2.6 \[[@pone.0200637.ref041]\]. The isobaric-isothermal ensemble (temperature of 310 K and 1 atm) was used to perform MD calculations. Periodic boundary conditions were applied to the system in the three coordinate directions. The simulation time was sufficient to obtain an equilibrated system (RMSD \< 2 Å; Figures A, B, C and D in [S1 File](#pone.0200637.s001){ref-type="supplementary-material"}). Stereochemical and energy quality of the homology model was evaluated using the PROSAII server \[[@pone.0200637.ref042]\] and Procheck \[[@pone.0200637.ref043]\] (Figures E and F in [S1 File](#pone.0200637.s001){ref-type="supplementary-material"}). Due to the size and complexity of the systems, in the case of SERT and DAT, MD simulations were performed applying some constraints to the backbone of the proteins.
Dummy atoms {#sec004}
-----------
An aspect that should be solved before comparing the ligand binding sites is that, because of their structure and function, both transporters and MAOs probably do not have a single ligand binding site. Indeed, both in SERT/DAT and in MAO-B (and probably in MAO-A \[[@pone.0200637.ref044]\]), a two-cavity system covered by a flexible loop has been described as the presumable path that has to be traveled by the ligand (substrates or inhibitors) in order to reach its \"final\" binding site \[[@pone.0200637.ref028],[@pone.0200637.ref045],[@pone.0200637.ref046]\]. Moreover, pharmacological, mutagenesis and structural studies \[[@pone.0200637.ref019],[@pone.0200637.ref020],[@pone.0200637.ref047],[@pone.0200637.ref048]\] have shown that the extracellular vestibule/entrance cavity (according to the nomenclature used for the secondary binding site found in transporters and MAOs, respectively), is an allosteric site which can positively or negatively modulate activity at the orthosteric binding site.
Then, the pathway traveled by the ligand in these targets might contain several binding sites, and similarities between the different proteins might appear in any of them. Therefore, in order to consider all possible ligand binding sites and to explore their similarities in detail, we decided to fill SERT, DAT, MAO-A and MAO-B cavities with \"dummy atoms\". It should be noted that the coordinates of dummy atoms, which in size correspond to a hydrogen atom, were used only as spatial references for the similarity measurements (see below), and they affect neither the structure nor the function of the protein. For MAO structures, a rectangular box of 15 Å x 15 Å x 30 Å was defined, and its center was located in the middle of the substrate/inhibitor cavity. 118 dummy atoms were located uniformly in this space ([Fig 1A](#pone.0200637.g001){ref-type="fig"}). The rectangular box defined for SERT and DAT was of 15 Å x 15 Å x 60 Å and 192 dummy atoms were located in this space with a uniform distribution ([Fig 1B](#pone.0200637.g001){ref-type="fig"}).
{#pone.0200637.g001}
Scoring of ligand binding sites similarity using dummy atoms {#sec005}
------------------------------------------------------------
To evaluate the similarity between the ligand binding sites at the proteins of interest we used the Pocketmatch algorithm \[[@pone.0200637.ref049]\]. All aspects involved in binding site comparisons followed the procedure published in the original article describing the algorithm with minor modifications \[[@pone.0200637.ref050],[@pone.0200637.ref051]\]. Briefly and as previously described \[[@pone.0200637.ref051]\], each binding site was considered as that determined by the residues for which one or more atoms surround a dummy atom (a crystallographic ligand in the original report) at a given distance (distances from 3 Å to 10 Å from the dummy atoms were considered). Each residue was classified into one of five groups (tag 1--5), taking into account its chemical properties. Then, each residue was represented as a set of three points corresponding to the coordinates of the α-C, the β-C, and the centroid coordinates of the side chain. Distances between every three points of each residue in the binding sites were measured. All computed distances were sorted in ascending order and stored in sets of distances organized by type of pairs of points and type of pairs of tags. The sorted and organized distances were then aligned and compared using a threshold of 0.5 Å, which was established considering the natural dynamics of biological systems. The similarity between sites, referred to as the PMScore, was evaluated by scoring the alignment of the pair of sites under comparison. Thus, the PMScore represents the percentage of the number of \"matches\" calculated over the maximal number of distances computed for each binding site. A PMScore of 0.5 (50%) or higher was considered as indicative of similarity between binding sites. To evaluate the similarity between the cavities of SERT and DAT where dummy atoms were inserted, each binding site surrounding the 192 dummy atoms in SERT (considering 15 distances from the atom, from 3 Å to 10 Å) were compared with the corresponding dummy atom binding sites in DAT (*i*.*e*., 192 x 192 x 15 = 552.960 measurements of PMscore were made). To compare SERT/DAT with MAO-A/MAO-B, 339.840 determinations of PMscore were made between the binding sites surrounding the 118 dummy atoms in the enzymes and those of the 192 dummy atoms in the transporters. [Fig 2](#pone.0200637.g002){ref-type="fig"} illustrates how the pairs of dummy atoms were selected in MAO-A and SERT for the comparisons. Finally, the mean of the PMScores obtained after comparing each pair of dummy atom binding sites (3--10 Å) was used to determine the similarity between the binding sites in the analyzed proteins.
{#pone.0200637.g002}
Scoring of binding site similarity in MAO-A and SERT using a promiscuous ligand {#sec006}
-------------------------------------------------------------------------------
In order to analyze the similarities found in a more realistic approach, we compared the characteristics of the binding sites of 4-methylthioamphetamine (MTA) in MAO-A and SERT. MTA is a non-selective ligand that exhibits affinity for both proteins in the low micromolar range \[[@pone.0200637.ref052],[@pone.0200637.ref053]\]. To this end, and given that MTA is a 5-HT releasing agent and apparently a SERT substrate \[[@pone.0200637.ref052]\], we used steered molecular dynamics (SMD; see below) to simulate the transport of MTA along the substrate pathway of SERT. Thus, several conformations of the SERT-MTA complex were obtained, and each one was considered as defining a putative binding site of the drug at this protein. On the other hand, as MTA is a competitive MAO-A inhibitor \[[@pone.0200637.ref054]\], the drug was docked into the active site of the enzyme as previously described \[[@pone.0200637.ref054]\]. Finally, the binding sites of MTA at SERT and MAO-A were compared using the Pocketmatch algorithm, where every similarity determination between the MTA/MAO-A complex and each MTA/SERT conformation was evaluated at 70 distances (from 3 Å to 10 Å adding 0.1 Å in all iterations).
Steered molecular dynamics simulations (SMD) {#sec007}
--------------------------------------------
Through SMD, a time-dependent external force was applied to simulate the uptake of MTA by SERT. During the simulation, we calculated the force exerted as well as the external work performed on the system. Each simulation lasted 3 ns, which was sufficient to observe almost the entire ligand uptake process (see [discussion](#sec009){ref-type="sec"}). The mean force for each step of the simulation was calculated by averaging the outcomes of 4 independent runs. Before simulations, the MTA-SERT complex was inserted into a POPC membrane and solvated with TIP3 water molecules using the VMD software \[[@pone.0200637.ref055]\]. The dimensions of the system were 100 Å x 110 Å x 120 Å. All simulations were carried out using the parallel molecular dynamics program NAMD2 \[[@pone.0200637.ref041]\] and the CHARMM27 force field. Temperature was controlled by Langevin dynamics. Periodic boundary conditions were applied to obtain consistent behavior. The initial position of MTA on the extracellular side was then relaxed for 1 ns. The final state was saved as a restart point for the initial position of SMD. The pulling velocity was 10 Å/ns and a spring constant of 2.5 kcal/mol/Å^2^ was used. During each SMD, the force was only applied along the pulling direction. The trajectories were saved every 5 ps, and the steering forces were recorded every 0.5 ps. The trajectory along SERT was repeated four times. Finally, the force profile along the MTA pathway was constructed and 2000 MTA-SERT complex states (frames) were obtained from the SMD.
Binding site alignment and common binding site generation {#sec008}
---------------------------------------------------------
Structural alignments of the similar binding sites in MAO-A and SERT proteins were performed using the MultiBind computational method \[[@pone.0200637.ref056]\]. This approach reveals the common physicochemical patterns that may be responsible for the binding of the same ligand to different protein targets. For the recognition of common patterns, MultiBind carried out a multiple alignment between the binding sites defined by all residues of the MAO-A and SERT proteins that were located up to 4 Å away from MTA. Then, multiple structural rearrangements of superimposed binding sites were made using a Geometric Hashing technique \[[@pone.0200637.ref057]\]. Briefly and as previously described \[[@pone.0200637.ref051]\], this method consists of two main processes: a) the pre-processing of the features of each binding site conformation and hashing them into a table; and b) the recognition of the similar features in the objects of the hash table. In the pre-processing, each amino acid was denoted by pseudocenters (X, Y and Z coordinates) which provided a unique physicochemical property to the binding site: hydrogen-bond donor, hydrogen-bond acceptor, mixed donor/acceptor, hydrophobic aliphatic or aromatic contacts. Finally, MultiBind performed a combination of multiple superimposed binding site conformations in order to find consensus binding patterns. The pockets that originate the consensus binding site do not necessarily must have identical residues and therefore, different residues might be matched (aligned) if the overall structural alignment score between two pockets is better with that arrange. This procedure is similar to the Needleman-Wunsch pairwise alignment algorithm implemented in BLAST \[[@pone.0200637.ref058]\], but used in a 3D perspective. Then, the highest scored consensus binding conformations at the MAO-A and SERT proteins, which are stored as independent pdb files, were manually depurated. Thus, to generate a unique and common binding site, all equivalent amino acids (same physicochemical group: polar, non-polar, positively or negatively charged) that appeared superimposed in the binding sites found in each protein (both pdb files), were merged. In contrast, all non-equivalent amino acids were preserved in the final consensus binding site \[[@pone.0200637.ref051]\].
Results and discussion {#sec009}
======================
Similarities between the dopamine and serotonin transporters {#sec010}
------------------------------------------------------------
DAT and SERT share almost 70% of their amino acids sequences and their secondary and tertiary structures are relatively similar (RMSD = 3.0 Å; Figure G in [S1 File](#pone.0200637.s001){ref-type="supplementary-material"}) Furthermore, our partial 3D comparisons yielded, in many cases, PMScore values higher than 0.5, which are indicative of similarity. As shown in [Fig 3A](#pone.0200637.g003){ref-type="fig"}, a high degree of similarity (red blocks) appeared when comparing the cavities defined by the dummy atoms located in the transmembrane regions in both proteins. It is worth pointing out that the highest PMScore values (denoted in [Fig 3A](#pone.0200637.g003){ref-type="fig"} by the brightest red blocks) were obtained when the comparison was performed considering dummy atoms located at the same relative positions in both proteins ([Fig 3B](#pone.0200637.g003){ref-type="fig"}). On the contrary, the lowest PMScores values (PMScore ≤ 0.01; blue blocks [Fig 3A](#pone.0200637.g003){ref-type="fig"}) were observed when comparing the sites defined by the dummy atoms located at the intracellular and extracellular ends of the transporters, as illustrated in [Fig 3C](#pone.0200637.g003){ref-type="fig"}.
{#pone.0200637.g003}
Overall, our results indicate that the SERT and the DAT have similar shapes and chemical features in their substrate permeation pathway, while structural differences occur in zones presumably associated with the initial recognition of selective ligands (extracellular and intracellular ends). Thus, these results yield insights regarding the structural features underlying the selectivity shown (either for uptake or reverse transport) by each protein for different substrates. Furthermore, the similarities found all along the pathway that is believed to be involved in the substrate transport process, agree with the idea that these proteins share a similar mechanism for the transport of substrates from the extracellular domain to the cytoplasm \[[@pone.0200637.ref005]\]. Interestingly, our findings might also account for the distinct transport rates that have been experimentally determined for diverse non-selective substrates \[[@pone.0200637.ref059]\].
Similarities between MAO-B versus DAT and MAO-A versus SERT using dummy atoms {#sec011}
-----------------------------------------------------------------------------
As illustrated in Figs [4](#pone.0200637.g004){ref-type="fig"} and [5](#pone.0200637.g005){ref-type="fig"}, when comparing the cavities defined by dummy atoms in DAT and MAO-B, and those in SERT and MAO-A a few pairs of sites showed similarity values greater than 0.5 (denoted by bars in red; Figures H and I in [S1 File](#pone.0200637.s001){ref-type="supplementary-material"}). Interestingly, the pockets showing similarity appeared located at places where ligands must interact to be transported or metabolized by these proteins (e.g. the extracellular vestibule in DAT or SERT, and the entrance cavity or the catalytic site in MAO-B; Figs [4](#pone.0200637.g004){ref-type="fig"} and [5](#pone.0200637.g005){ref-type="fig"}). Therefore, our results indicate that DAT and MAO-B, as well as SERT and MAO-A (whose preferential substrates are DA or 5-HT, respectively) exhibit striking structural similarities in zones presumably involved in the initial recognition of substrates. In addition, similarities were also found between the active (catalytic) site of MAOs and the extracellular vestibule in the transporters (also known as the S2 binding site; \[[@pone.0200637.ref060]\]). Indeed, additional comparisons between, SERT/MAO-B and DAT/MAO-A (as well as a reassessment of the similarities between SERT/MAO-A and DAT/MAO-B) were done using the ligand MTA docked into the S2 binding site of the transporters and into the active site of the MAOs. The results, obtained also with the PocketMatch algorithm, are shown in the Table A in [S1 File](#pone.0200637.s001){ref-type="supplementary-material"}. These data indicate that the binding sites of SERT/MAO-A and DAT/MAO-B are more similar than those in SERT/MAO-B or DAT/MAO-A, respectively. Interestingly, in these more local comparisons, all scores were higher than 0.5 (indicating more that 50% of structural similarity). This might be the reason why some ligands, *e*.*g*. amphetamine, are able to bind all of these target proteins. Thus, these results suggest the existence of a certain degree of structural convergence for proteins that have different functions, tissue distribution and genetic origin, but which share the same endogenous ligand. It is noteworthy that these similarities could not be identified using a sequence-based method, and although different algorithms and configurations were applied (local algorithms, global algorithms, low GAPs penalization, deleted GAP extension penalization, etc), no similarities were detected between MAOs and SERT/DAT (Figure J in [S1 File](#pone.0200637.s001){ref-type="supplementary-material"}). These results confirm the usefulness of the structure-based methods to find local similarities, where residues that form part of different binding sites are not located continuously in the primary sequences.
{#pone.0200637.g004}
{#pone.0200637.g005}
Steered molecular dynamics (SMD) of the ligand 4-methylthioamphetamine (MTA) in SERT {#sec012}
------------------------------------------------------------------------------------
Although our results showed significant similarities among binding sites present in all the proteins considered, these findings were obtained using dummy atoms. The use of these atoms does not consider conformational or electronic changes produced by ligands when interacting with their target structures. To address this issue, we simulated the presumable transport pathway of a substrate (in this case MTA) in SERT, and several possible binding sites (MTA-SERT complexes) were detected. As detailed in the methodology section, this was performed by forcing MTA to move from the extracellular to the intracellular domain of SERT, using an SMD simulation. Four distinct peaks of force were detected in the evaluation of the trajectory of MTA in SERT ([Fig 6A](#pone.0200637.g006){ref-type="fig"}, numbers 1--4). These force peaks indicate that more force was required to keep the velocity of MTA constant, and denote the formation of stable MTA-SERT complexes. The first peak occurred between frames 30 and 40 (number 1, [Fig 6A and 6B](#pone.0200637.g006){ref-type="fig"}) and represents the initial recognition site of MTA in the SERT. Here, a hydrogen-bond interaction between the amino group of MTA and Asp400 of SERT was identified. The second peak occurred between frames 90 and 100 (number 2, [Fig 6A and 6B](#pone.0200637.g006){ref-type="fig"}), which corresponds to the extracellular vestibule of SERT (the S2 binding site). Here, MTA is located in a position favorable to interact with residues such as Glu494, Tyr177 and Ile179. The third peak occurred between frames 120 and 130 (number 3, [Fig 6A and 6B](#pone.0200637.g006){ref-type="fig"}) and represents a putative MTA binding site that is located halfway between the S2 and the substrate binding site (also known as S1), but which still includes several residues of the extracellular vestibule of SERT. Here MTA showed a binding mode in which interactions could be established with Glu493, Ile179, Trp103, Tyr176 and Tyr177. These results are highly consistent with those recently reported for the binding and migration of 5-HT into SERT, as analyzed by computational methods \[[@pone.0200637.ref061]\].
{#pone.0200637.g006}
It is noteworthy that in the analyses performed with the dummy atoms, the zone described by peaks 2 and 3 exhibited similarity with the substrate binding site of MAO-A. The fourth peak occurred between frames 150 and 180 (number 4, [Fig 6A and 6B](#pone.0200637.g006){ref-type="fig"}), and corresponds to the substrate binding site (also known as S1) of SERT. This site was also suggested as similar to the substrate binding site of MAO-A, according to our similarity determinations done using dummy atoms. Starting in frame 185, an abrupt change in the orientation of MTA was detected (red square [Fig 6B](#pone.0200637.g006){ref-type="fig"}). This behavior, which was not observed at any of the other peaks of force, was likely caused by a steric obstruction of SERT. This appears at the moment when a major conformational change (from an outward-facing to an inward-facing conformation) must occur in SERT in order to complete the proposed transport mechanism \[[@pone.0200637.ref062]--[@pone.0200637.ref064]\]. This major motion cannot be simulated by the SMD technique and more advanced approaches must be used to confirm this idea.
Similarities between binding sites of MTA in MAO-A and several complexes of MTA-SERT from the SMD trajectory {#sec013}
------------------------------------------------------------------------------------------------------------
Several putative binding sites of MTA were detected in SERT by the SMD simulations. Three of these (peaks 2, 3 and 4) concentrate the most relevant interactions and correspond to those reported as the binding sites (S2 and S1) of substrates and inhibitors in the monoamine transporters \[[@pone.0200637.ref010]--[@pone.0200637.ref012],[@pone.0200637.ref018],[@pone.0200637.ref065]\]. Additionally, these sites were classified as similar when compared with binding sites in the MAOs. As mentioned, the dummy atom method is a robust approximation but it does not consider the natural flexibility of proteins. This issue was improved with the inclusion of ligand based similarity measurements where 200 MTA-SERT complexes were compared with the MTA binding site in MAO-A, as determined by previous experimental and docking studies \[[@pone.0200637.ref054]\]. The results of this analysis are depicted in [Fig 7](#pone.0200637.g007){ref-type="fig"}. Interestingly, PMScores indicating similarity (i.e. \> 0.5) were obtained when the binding sites detected in frames 70--130 (which include peaks 3 and 4 of [Fig 6](#pone.0200637.g006){ref-type="fig"}) were compared with the substrate binding site of MAO-A. Indeed, the highest PMScore value was detected in frame 120 (green circle in [Fig 7](#pone.0200637.g007){ref-type="fig"}). Considering that these results are in close agreement with those obtained when comparing MAO-A and SERT using dummy atoms, we propose that some shape and physicochemical features are conserved between the catalytic site of MAO-A and the extracellular vestibule of SERT. Moreover, these similarities might underlie the reasons for which a common ligand (e.g. 5-HT) is able to interact with both highly different proteins.
{#pone.0200637.g007}
Common binding site of MTA in MAO-A and SERT {#sec014}
--------------------------------------------
The binding site of MTA in MAO-A and the S2 binding site in SERT were structurally aligned using MultiBind software \[[@pone.0200637.ref056]\]. This approach revealed the common physicochemical patterns that might be responsible for the binding of the amphetamine derivative to both proteins. For the recognition of common patterns, MultiBind performed a multiple alignment between the binding sites defined by all residues of MAO-A and SERT located up to 6 Å from MTA. Several conformations were built and the most accurate alignment was identified ([Fig 8A](#pone.0200637.g008){ref-type="fig"}). Finally, and after a manual depuration, a unique common binding site was generated ([Fig 8B](#pone.0200637.g008){ref-type="fig"}).
{#pone.0200637.g008}
The consensus binding site is formed by the following residues: Tyr, Glu, Asp, Gly, Arg, Thr and Ser ([Fig 8B](#pone.0200637.g008){ref-type="fig"}). It has a well-defined shape/cavity, and some chemical features such as two polar positively charged zones, two polar negatively charged zones and four aromatic non-polar components. These properties are in agreement with both the "aromatic cage" present in the catalytic site of MAOs \[[@pone.0200637.ref028]\] and the key residues Glu, Thr and Asp that form the S2 binding site of SERT. However, it should be noted that this consensus binding site must be cautiously considered in terms of drug design, since it might not reflect some specific physicochemical features of each isolated binding site. For instance, although negatively charged residues are contained in the common binding site, there are not such type of residues at the active site of MAO-A.
Concluding remarks {#sec015}
==================
3D similarities between SERT and DAT were found all along the pathway that is presumably involved in the substrate transport process. This agrees with the idea that these proteins share a similar mechanism for the transport of substrates from the extracellular domain to the cytoplasm \[[@pone.0200637.ref007],[@pone.0200637.ref064]\]. In addition, 3D differences between SERT and DAT were found both at the extracellular and the intracellular ends of the transporters, in regions that, remarkably, are relatively distant from the S1 or S2 binding sites. These results are in agreement with recent computational and mutagenesis data showing that selective binding of substrates is not associated with the non-conserved SERT/DAT residues at S1 or S2 binding sites \[[@pone.0200637.ref066]\], but rather suggest that selectivity might be related to the initial recognition of substrates at the areas that we have found to show 3D differences. Altogether, similarities and differences detected when comparing SERT and DAT might be useful for both a better understanding of monoamine transporter function and for the design of selective and non-selective ligands.
Similarities were also found between the active (catalytic) site of MAO-A and the extracellular vestibule of SERT (the S2 binding site). These results suggest some degree of structural convergence \[[@pone.0200637.ref067]\] for these proteins which have different functions, tissue distribution and genetic origin, but which share the same endogenous ligand (5-HT). Hence, we propose the existence of a serotonergic "receptophore" in both proteins (the consensus binding site shown in [Fig 8](#pone.0200637.g008){ref-type="fig"}), which by analogy with the pharmacophore concept can be defined as a 3D ensemble, at the binding site(s) of two or more receptors, of molecular, steric and electronic features that ensure the optimal molecular interactions with a common promiscuous ligand. Further studies are necessary to determine if this 3D ensemble is also present in metabotropic and/or ionotropic 5-HT receptors, and if this concept can be extrapolated to other ligand-receptor systems.
Finally, from a methodological perspective, we want to emphasize that the use of dummy atoms instead of typical ligands to study binding site characteristics can be particularly appropriate in those cases where the ligand binding site is unknown.
Supporting information {#sec016}
======================
###### Supplementary information.
Figure A. RMSD of MAO-A. Figure B. RMSD of MAO-B. Figure C. RMSD of SERT. Figure D: RMSD of DAT. Figure E: ProsaII evaluation of DAT. Figure F: Procheck evaluation of DAT. Figure G: RMSD between SERT and DAT. Figure H: Average of Similarity between all dummy atoms in DAT and MAO-B. Figure I: Average of Similarity between all dummy atoms in SERT and MAO-A. Table A: Binding sites similarities between MAOA/SERT, MAOA/DAT, MAOB/SERT and MAOB/DAT. Figure J: Representation of a sequence-based alignment between SERT and MAO-A.
(PDF)
######
Click here for additional data file.
This project was partially supported by Fondecyt (Fondo Nacional de Desarrollo Científico y Tecnológico) Grants 1170662 (M. R-P), 1141272 (P. M), 1150615 (P. I-V), 1161375 (A. F) and the ICM MINECOM (Iniciativa Científica Milenio, Ministerio de Economía) Grants NC130011 and P09-022-F.
[^1]: **Competing Interests:**The authors have declared that no competing interests exist.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Rachel Crooks, the 35-year-old Democrat running for state legislature in Ohio who says President Trump Donald John TrumpOmar fires back at Trump over rally remarks: 'This is my country' Pelosi: Trump hurrying to fill SCOTUS seat so he can repeal ObamaCare Trump mocks Biden appearance, mask use ahead of first debate MORE forcibly kissed her in 2005, secured the Democratic nomination for her intended seat on Tuesday after running unopposed, CNN reports.
Crooks, a former receptionist who worked in Trump Tower, accused the president of forcibly kissing her in 2005 and came forward with her accusation in 2016 just before the general election.
ADVERTISEMENT
Trump denied her claims after The Washington Post covered the allegations in detail in February.
"A woman I don't know and, to the best of my knowledge, never met, is on the FRONT PAGE of the Fake News Washington Post saying I kissed her (for two minutes yet) in the lobby of Trump Tower 12 years ago. Never happened! Who would do this in a public space with live security cameras running," the president tweeted.
Crooks responded through her campaign's Twitter account at the time, challenging the president to share video footage of the alleged date of the incident.
"Please, by all means, share the footage from the hallway outside the 24th floor residential elevator bank on the morning of January 11, 2006," her campaign account tweeted. "Let's clear this up for everyone. It's liars like you in politics that have prompted me to run for office myself."
Crooks told Cosmopolitan magazine in February that friends and a liberal activist group encouraged her to run for office, and that she was inspired by a wave of Democratic activism in the face of Trump's election.
“I think like a lot of women, because we've been historically underrepresented in politics, I didn't necessarily see myself in this role," she said. "But multiple people encouraged and said, 'I think you would be great.’ … Once I sat down and mulled it over, I felt like it really was a duty that I had, that I should take on this responsibility firsthand and try to make a difference for other people.”
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Microcomputers, often referred to as PC's, have become ubiquitous. A very large number of the PC's now in use employ the Microsoft-Disk Operating System (hereinafter MS-DOS) operating system (published by Microsoft Corporation, Redmond, Wash.) or one that is virtually identical in operation to MS-DOS. The International Business Machines (hereinafter IBM) Personal Computer Model AT is one example of a PC that employs the MS-DOS operating system. Many application programs are written for MS-DOS PC's and their `clones`, which are sometimes collectively called `DOS machines`. These programs are written in reliance upon, and within the constraints of, the many standard features of DOS. Among these standard features are a utility for allocating a portion of the computer's memory space in response to a request made by the application program and a second utility for deallocating (or `freeing`) a previously allocated portion, again in response to a request from the application program.
As used herein, the following terms shall be understood as set forth below:
"memory space"--a plurality of sequentially addressed positions, each position corresponding to a basic unit of memory such as a byte or word; "segment"--a sequential portion, less than the whole, of a memory space; "memory block"--a segment which is defined by a fixed first end and second end, i.e. the lowest and highest addresses included in the block; "fragment"--a segment which can be either "allocated", i.e. assigned to an application, or "unallocated", i.e. available for assignment to an application; "size"--the number of addressed positions in a memory space or segment.
A program that is frequently encountered by designers of applications programs is memory fragmentation. FIGS. 1(a) and (b) are a schematic illustration of how memory fragmentation comes about.
It will be understood that a memory space may be viewed as a string of sequentially addressed positions, each position corresponding to a basic unit of memory, such as a byte. It will further be understood that the memory space may be considered to be occupied by a number of memory fragments, i.e. continuous blocks of sequentially addressed memory positions, and that each such fragment either has been allocated for the purpose of holding data (sometimes referred to as "in use") or is unallocated and hence available for allocation (sometimes referred to as "free" or "not in use"). In FIG. 1(a), reference numeral 10 indicates generally a box that may be considered to represent either the entire memory space of a computer, or a segment that is part of a memory space. It is assumed that memory portions, or fragments, 12, 14, 16 have been allocated, filling segment 10. In the DOS environment such an allocation can readily occur as an empty segment is allocated from beginning to end in response to a series of memory allocation requests. It will be noted that fragments 12 and 16 are approximately the same size and that fragment 14 is smaller than, and occupies the space between, fragments 12, 16. Now, if fragments 12, 16 are freed in response to deallocation requests, the status of segment 10 will be as shown in FIG. 1(b). At this point most of segment 10 is available for allocation. However, if the next requested memory allocation requires a fragment 18 that is only slightly larger than each of available fragments 12, 16, the requested fragment cannot be allocated in segment 10, even though the total available space in segment 10 greatly exceeds the size of the requested fragment.
As will be appreciated from the foregoing somewhat simplified example, memory fragmentation results in inefficient use of the memory space and also in what can be considered false indications that the memory space is exhausted. These conditions may become particularly acute for transaction-oriented or other applications in which the requested fragments vary in size over a considerable range and fragments are frequently deallocated. For these applications, a large number of relatively small unused fragments quickly builds up and it soon becomes impossible to fill requests for allocation of relatively large fragments, even though a substantial percentage of the memory space remains unused.
The usual solution to the false exhaustion of memory space is simply to run the application on a PC that has a larger memory capacity. Of course, the larger memory increases the cost of the PC, and the use of the memory remains inefficient.
Another known approach is coalescing, i.e. rearranging the allocated fragments so that unused portions of the memory space are combined. For example, and referring again to FIG. 1(b), this could take the form of moving fragment 14 to the top of segment 10 after fragments 12, 16 were freed, thereby combining fragments 12, 16. However, the software required for coalescing adds considerable complexity and may result in unacceptable overheads in terms of memory and processing time.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Shardmap
Shardmap is a directory index design by Daniel Phillips who created the HTree and PHTree tree data structures and the Tux3 file system.
A Shardmap index consists of a scalable number of index shards.
Each shard entry maps a hash key to the logical block number of a directory entry block known to contain a name that hashes to that key.
Each shard is represented as an unsorted fifo on disk and a small hash table in memory.
Shardmap scales in two ways:
Rehash a cached shard to a larger number of hash buckets
Reshard a stored shard fifo to divide it into multiple, smaller shards.
These operations are staggered to avoid latency spikes. The reshard operation imposes a modest degree of write multiplication on the Shardmap design, asymptotically approaching a factor of two.
The key ideas of Shardmap are:
The representation of directory data is not the same on media as it is in cache. On media we have fifos, but in cache we have hash tables.
Updating a fifo is cache efficient. Only the tail block of the fifo needs to be present in cache. The cache footprint of the media image of a shardmap is therefore just one disk block per shard.
A small fifo on media is easily loaded and converted to an efficient hash table shard on demand. Once in cache, index updates are performed by updating the cached hash table and appending the same entries to the final block of the shard fifo.
The shardmap implementation in the Tux3 file system uses SipHash hash function designed by Jean-Philippe Aumasson and Daniel J. Bernstein.
See also
Dirhash
External links
https://lkml.org/lkml/2013/6/18/869 on the Linux kernel mailing list (LKML)
Category:Database index techniques
| null |
minipile
|
NaturalLanguage
|
mit
| null |
How do we rise above the emotional storms that can erupt during times of change, strain, and struggle in order to get at the heart of the issues and find a constructive path forward? Whether this is applied to oneself, to relationships, or to events in a large-scale organizational initiative, this competency, emotional self-regulation, is often what makes the difference and distinguishes exemplary leaders.
Image byTsung-lin Wu
I’ll begin with an anecdote shared by Stephen Covey years ago. It portrays an emotionally charged social situation that we can use to gain insight into a powerful approach to emotional self-regulation called "mentalization." As you will see it employs a special kind of reflective function, which can be learned and leads to greater emotional freedom and relational leadership competence.
A Human Situation
Renowned leadership author Stephen Covey shared a personal experience about riding the subway in New York City and becoming annoyed with the disruptive behavior of some young children who were running, jumping, and making noise. Meanwhile, their father simply sat there saying nothing. Finally, in growing frustration, Covey turned to the man and asked: "Sir, could you please control your children?"
Many of us can immediately sympathize with Covey: We are exhausted and on our way home. All we want is to be left alone. How inconsiderate of this guy to let his kids run wild in a confined public space. What is he thinking? We are offended and resent this father's neglect of basic parenting responsibilities. It’s all we can do to contain our annoyance and moderate our tone when we finally speak up.
Then Covey throws us a curve ball: The man responds as though awakening from a deep sleep. His stunned expression conveys confusion. He struggles to orient himself to the situation at hand. Then he speaks haltingly, "Oh, I guess I was not watching. We were just at the hospital. Their mother just died. I guess they don't know what to do with themselves, and I don't either."
Wow, talk about awakenings! Suddenly Covey sees things very differently. His feelings of annoyance now seem trivial, embarrassing. They shrivel into insignificance. His mind is flooded with feelings about this poor man, his heart is softened. What Covey earlier saw as rude indifference he now recognizes as shock and trauma. Covey calls this sudden shift in perspective a paradigm shift.
Call it what you wish, the disclosure is jarring and its effects are transformative. Even as second-hand experience for the reader, the power and impact of this story is stunning. We so easily sympathize with Covey's feelings of annoyance and his resentment of the father's inaction. We so readily accepted his attributions of inconsiderate behavior to this man—"how could this man be so rude?"
Covey's initial attitude was governed by norms of propriety and considerations of what was due him, Stephen Covey, as a fellow passenger. In that moment he does not wonder what might be going on with the man that would explain his actions. The father is objectified. He's merely a fellow passenger, and he and his obnoxious kids are being "bad" passengers, a source of annoyance.
Then suddenly all these assumptions are shattered. The emotional meaning of the interpersonal situation is transformed. A new set of values and norms now apply. It is no longer a matter of common courtesy among subway passengers. Offense at the violation of such perfunctory rules evaporates as Covey is drawn into this person's raw and early moments of bereavement and loss.
Covey finds himself sharing the bereaved man's confusion, caring less about how his children might be "misbehaving" and more about how he might comfort or help the man. His emotional attunement to this man's inner world activates norms of compassion, caring, and yes, patience. Time is suspended. This has become a moment to restart engagement, realign priorities, and connect with another human being if only to the next station stop.
The Reflective Function
First, I must say that I admire Covey's candor and willingness to confess to what some may regard as petty annoyance. Such disconnects and misunderstandings happen. We know from studies in human development (attachment) that even in a well-bonded infant-mother relationship there are many moments when the pair is out of synch. What differentiates a secure attachment is its capacity and commitment to repair ruptures, to restore connection.[ii]
Now, let's go to the heart of this example of human interaction, for it offers us some important insights that are equally relevant at home, at work, and in the community. And for those who seek to lead and lead well, I believe these insights should be of particular relevance and importance to you. After all, not only do leaders succeed by establishing and maintaining alignment with stakeholders, but when it comes to leading change, attunement to issues of the heart becomes especially crucial.
A colleague from whom I have learned a great deal, David Wallin[iii], has distinguished three levels of consciousness available to us in waking life: 1) embeddedness, 2) reflection, and 3) mindfulness. In the anecdote Covey shares with us, his initial social-emotional reactions arise from a state of embeddedness. He is in the grip of his own intensifying emotions and projects onto the father a role (rude passenger) and attitudinal characteristics (indifference), which justify his own reactions.
It's important to observe that we all do this regularly. That is, we evaluate and respond to others and social situations from an embedded level of consciousness. In most cases, it is not problematic, our reactions are more or less appropriate and proportionate to the external situation. However, as we see in Covey's story, our assumptions and attributions about others are not always accurate. In his case, Covey is shaken from his embeddedness by a rather dramatic disclosure from the man. This prompts what we might call "implicit" reflection and re-evaluation.
This reflective function places our social-emotional feelings and the associated assumptions and attributions that underlie them before us, questions them, making them problematic: "Wait a minute, this situation is very different in meaning than I thought. I was way off the mark! Oh my God, this poor man." In this reappraisal of the situation Covey is implicitly recognizing that the man is acting from his own unique subjective life experience, which is very different from Covey's. The man’s behavior is mediated by his state of mind, i.e. trauma, shock, confusion, disorientation.
This mode of reflection could also be more deliberately invoked ("explicit" reflection) by recognizing beforehand that a situation, e.g. a discussion about change with organizational stakeholders, is likely to evoke strong emotions from others. Anticipating this, we might expect that others may react from a state of embedded consciousness. Their reactions may be defensive, i.e., intended to protect them from what they perceive to be adverse effects of change. We might also anticipate that the tension of the situation could arouse our own anxiety and excite our own defenses.
In the embedded state, we believe that whatever we feel fully and accurately represents the objective state of affairs; it is the full story. In the reflective mode, we act from an awareness that each person experiences a situation from their own subjective point of view. We also recognize that each person's viewpoint is energized by feelings (desires, fears, worries, aspirations) and by the values that they believe are at stake (dignity, respect, fairness). A reflective attitude thereby opens a space for addressing these differences, giving them their due. This reflective function is central to an adaptive capacity of the person known as mentalization.
Mentalization, a concept coined by Peter Fonagy[iv] and his colleagues, has been defined as "keeping one's own [mental] state, desires, and goals in mind as one addresses one's own experience; and keeping another's [mental] state, desires, and goals in mind as one interprets his or her behavior."
An even simpler way of thinking about it is as the capacity to see oneself from the outside and to see others from the inside. It is particularly helpful when seeking to understand feelings. Mentalized affect provides us with a full and accurate grasp of the meaning and the importance of feelings, ours and those of others.
Conclusion
On the one hand, life would be a tedious affair if we had to deliberate or reflect on every action we took or each feeling we had in the course of a business day. Therefore, I want to reinforce that operating from an embedded state of mind is normal and healthy. Moreover, when we do mentalize, it need not always be explicit or deliberately initiated. The key to judging the quality of our emotional self-management is to appraise it from a pragmatic point of view: Is it working for us and for others?
On the other hand, the capacity to explicitly mentalize one's own and others' feelings, aspiration, values, and goals can go a long way toward promoting constructive problem solving, collaborative stakeholder relations, and resilience at the individual, team, and organizational levels. It is through explicit practice that one's implicit ("natural") mentalizing skills grow—mentalizing is action[v]; it’s something we do. And it can be incorporated into developmental interventions such as coaching, team development workshops, or change leadership programs.
I haven’t said much about the third of level of consciousness, mindfulness. Suffice it to say that it provides two vital functions: 1) a restorative function in meditation, which helps moderate our baseline emotional intensity; and, 2) an attentional function, invoked as an attitude in a helping relationship. Jon Kabat-Zinn defines this second function as, “the awareness that emerges through paying attention on purpose, in the present, and nonjudgmentally to the unfolding of experience moment to moment.”[vi]
Contact Information:
As always, we're happy to discuss any questions you may have about how the topic in this blog might be relevant to you, others in your organization, and your ways of being helpful to them. Contact me by phone at 401.885.1631 or by email at [email protected].
Endnotes:
[i] This article draws upon research and practice in clinical and developmental psychology, which I have adaptively applied to developmental coaching and leader development in the workplace. As such, its use may imply needs for further training for those who approach the practice of coaching from outside professional psychology.
[ii] Indeed, it is by working through and repairing ruptures that relational competence is gained. E.g., see Safran J. & Kraus J. (2014). Alliance ruptures, impasses, and enactments: A relational perspective. Psychotherapy, 51 (3) 381-387.
Our Threefold Mission
Design, develop, and deliver assessment-based development solutions for early-career leaders that ensure a diverse and sustainable lership talent pipeline. Provide guidance to management on their role in adopting and promoting such an approach to organizational sustainability. Support efficient and effective use of solutions with certification training and ongoing research on best development strategies.
About the Founder
William P. Macaux, the principal and founder of Generativity LLC, is a management psychologist with more than 20 years of experience in executive development. His research has contributed to innovations in executive assessment, including the Bates ExPI, the first research-based model and assessment of executive presence. Throughout his career, Bill has held leadership roles within organizations such as RHR International, a global management psychology consultancy; Right Management, and IBM. He has extensive experience consulting to individuals and organizations in the US, Western Europe, and South Africa. Bill is a licensed psychologist (Ph.D., Indiana State University) with a strong background and education (MBA, Indiana Wesleyan University) in management. He has presented and written extensively on adaptive adult development and organizational sustainability, and has spoken internationally and written on the subject of responsible leadership in an age of sustainability.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Caltrans offers tips for keeping safe on roads through winter
Related Media
Severe weather can be alarming and hazardous for drivers. The best defense is not to venture out on the roads during stormy weather, but if you must drive, use caution and common sense, and always be prepared.
The California Department of Transportation (Caltrans) advises motorists to prepare for the storm season. Harsh weather can bring high winds, heavy rains and snow and ice in higher elevations. Winter weather and road conditions can change rapidly. Drivers should have their vehicle winterized. Important items to check on your vehicle are: brakes, coolant, tires, windshield wipers, defroster, heater and exhaust systems. If possible have your vehicle checked by a professional mechanic.
In California’s Central Valley dense fog can blanket the area’s highways, especially November through January. This fog can catch you by surprise, as it hangs in the low-lying valley bottoms and can cause dramatic changes in visibility. When encountering fog, follow these tips:
• Reduce speed to allow for safe stopping distance
• Drive with headlights on low beam, never drive with just parking or fog lights.
• Use extreme caution when crossing traffic or busy intersections.
• Lower your window and listen for traffic you cannot see.
• Use windshield wipers and the defroster to improve visibility.
• Be patient. Do not pass lines of traffic.
• If visibility diminishes to the point that you no longer feel safe driving, do not stop in the traffic lanes.
• Attempt to utilize the closest off-ramp so you can stop at a safe location and wait for the fog to clear.
Carry chains
All vehicles, including those with four-wheel drive or snow tires, should carry correctly sized chains when traveling during snowy weather. Highway signs will indicate if chains are required. If motorists do not have chains in their possession, they may not be allowed to proceed and risk being cited or fined.
Motorists should check road conditions frequently. For state-operated highways this can be done in a number of ways. Visit the Caltrans website at www.dot.ca.gov to get road conditions, weekly road reports and press releases by district; check information through the automated California Highway Information Network (CHIN) by telephoning (800) 427-7623 (800) GAS-ROAD) and following the prompts; motorists can also tune to the Caltrans Highway Advisory Radio, which broadcasts road conditions on low frequency radio transmitters located along some mountain highways.
During winter storm conditions, motorists should anticipate unexpected delays and closures. Caltrans strives to reduce the frequency and the length of unplanned closures on state highways. During major storms when traffic flow is heavy, Caltrans may meter traffic to ease congestion.
The following tips will assist you in making your winter driving experience safe and pleasant:
| null |
minipile
|
NaturalLanguage
|
mit
| null |
# $Id: synflood.bro 4054 2007-03-05 21:45:58Z vern $
@load notice
redef enum Notice += {
SynFloodStart, # start of syn-flood against a certain victim
SynFloodEnd, # end of syn-flood against a certain victim
SynFloodStatus, # report of ongoing syn-flood
};
# We report a syn-flood if more than SYNFLOOD_THRESHOLD new connections
# have been reported within the last SYNFLOOD_INTERVAL for a certain IP.
# (We sample the conns by one out of SYNFLOOD_SAMPLE_RATE, so the attempt
# counter is an estimated value.). If a victim is identified, we install a
# filter via install_dst_filter and sample the packets targeting it by
# SYNFLOOD_VICTIM_SAMPLE_RATE.
#
# Ongoing syn-floods are reported every SYNFLOOD_REPORT_INTERVAL.
global SYNFLOOD_THRESHOLD = 15000 &redef;
global SYNFLOOD_INTERVAL = 60 secs &redef;
global SYNFLOOD_REPORT_INTERVAL = 1 mins &redef;
# Sample connections by one out of x.
global SYNFLOOD_SAMPLE_RATE = 100 &redef;
# Sample packets to known victims with probability x.
global SYNFLOOD_VICTIM_SAMPLE_RATE = 0.01 &redef;
global conn_attempts: table[addr] of count &default = 0;
global victim_attempts: table[addr,addr] of count
&default = 0 &read_expire = 5mins;
# We remember up to this many number of sources per victim.
global max_sources = 100;
global current_victims: table[addr] of set[addr] &read_expire = 60mins;
global accumulated_conn_attempts: table[addr] of count &default = 0;
global sample_count = 0;
global interval_start: time = 0;
# Using new_connection() can be quite expensive but connection_attempt() has
# a rather large lag that may lead to detecting flood too late. Additionally,
# it does not cover UDP/ICMP traffic.
event new_connection(c: connection)
{
if ( c$id$resp_h in current_victims )
{
++conn_attempts[c$id$resp_h];
local srcs = current_victims[c$id$resp_h];
if ( length(srcs) < max_sources )
add srcs[c$id$orig_h];
return;
}
if ( ++sample_count % SYNFLOOD_SAMPLE_RATE == 0 )
{
local ip = c$id$resp_h;
if ( ++conn_attempts[ip] * SYNFLOOD_SAMPLE_RATE >
SYNFLOOD_THRESHOLD )
{
NOTICE([$note=SynFloodStart, $src=ip,
$msg=fmt("start of syn-flood against %s; sampling packets now", ip)]);
add current_victims[ip][c$id$orig_h];
# Drop most packets to victim.
install_dst_addr_filter(ip, 0,
1 - SYNFLOOD_VICTIM_SAMPLE_RATE);
# Drop all packets from victim.
install_src_addr_filter(ip, 0, 1.0);
}
}
}
event check_synflood()
{
for ( ip in current_victims )
{
accumulated_conn_attempts[ip] =
accumulated_conn_attempts[ip] + conn_attempts[ip];
if ( conn_attempts[ip] * (1 / SYNFLOOD_VICTIM_SAMPLE_RATE) <
SYNFLOOD_THRESHOLD )
{
NOTICE([$note=SynFloodEnd, $src=ip, $n=length(current_victims[ip]),
$msg=fmt("end of syn-flood against %s; stopping sampling",
ip)]);
delete current_victims[ip];
uninstall_dst_addr_filter(ip);
uninstall_src_addr_filter(ip);
}
}
clear_table(conn_attempts);
schedule SYNFLOOD_INTERVAL { check_synflood() };
}
event report_synflood()
{
for ( ip in current_victims )
{
local est_num_conn = accumulated_conn_attempts[ip] *
(1 / SYNFLOOD_VICTIM_SAMPLE_RATE);
local interv: interval;
if ( interval_start != 0 )
interv = network_time() - interval_start;
else
interv = SYNFLOOD_INTERVAL;
NOTICE([$note=SynFloodStatus, $src=ip, $n=length(current_victims[ip]),
$msg=fmt("syn-flood against %s; estimated %.0f connections in last %s",
ip, est_num_conn, interv)]);
}
clear_table(accumulated_conn_attempts);
schedule SYNFLOOD_REPORT_INTERVAL { report_synflood() };
interval_start = network_time();
}
event bro_init()
{
schedule SYNFLOOD_INTERVAL { check_synflood() };
schedule SYNFLOOD_REPORT_INTERVAL { report_synflood() };
}
| null |
minipile
|
NaturalLanguage
|
mit
| null |
This invention relates generally to packaging assemblies, and more particularly to strong, protective but at least partially transparent appliance packaging assemblies and methods for producing such assemblies.
Presently, many appliances such as refrigerators, ranges, dishwashers and laundry machines, including washers and dryers, are packaged in full corrugated boxes after manufacture for shipping and handling. A discussion of such boxes is provided, for example, in U.S. Pat. No. 6,578,346, granted Jun. 17, 2003.
Fully corrugated packages have many advantages including relatively good protection of the appliance, durability and high reliability. Many of these packages may also be lifted and handled by a “Basiloid” spade or blade mounted on a lift truck. The Basiloid blade is a generally u-shaped member that is hooked under interlocking folded flaps of a top cap on a side portion of the package or container, and permits handling of the container without clamping or fork lifting. The Basiloid blade is used widely in the United States.
Although fully corrugated packages have many advantages these packages prevent viewing or inspection of the contents of the package without opening the closed package. Visual inspection is highly desirable for assessing shipping damage, for identifying product and for ultimate display in a retail or warehouse environment. Fully corrugated packages are also sometimes difficult to assemble, result in a significant amount of material to be recycled and are relatively costly.
As an alternative, transparent film type packaging has been developed for appliances in an effort to reduce materials, labor and costs. U.S. Pat. No. 4,881,840 entitled “Appliance Shipping Container with Integral Corner Post”, for example, discloses a corrugated container wrapped with a transparent film. That type container includes corrugated side panels with cutout windows on opposing sides of the container. The side panels also have overlapping folded portions that are retained over the upper portion of the appliance by a horizontal strap.
Transparent appliance packaging allows the contents to be inspected visually. However, transparent appliance packaging has not been accepted widely because of an inability to be applied for heavier packaging applications.
The present invention is directed to improvements in packaging assemblies, and more particularly to transparent packaging assemblies in which at least a portion of the assembly could be could be used to support the appliance on the assembly line and, as the appliance itself is assembled, the packaging assembly can be completed around the appliance in a simple, effective and low cost manner.
An advantage of the invention is that it provides novel, desirable packaging assemblies for appliances or the like which can be lifted and handled by a Basiloid blade.
A further advantage of the invention is that it provides novel packaging assemblies and methods useable for appliances comprising generally a reinforced base pad disposed beneath an appliance to be packaged and a plurality of posts disposed alongside the appliance and extending between the base pad and a top cover. The base pad is configured so as to be adhered to the corner posts as they are added to the package. To achieve this desired end, the base pad is provided with extended flanges that fold upwards, preferably flush with the edges of the corner posts. The flanges and posts can be sealed inline, with traditional gluing equipment or by hand labor such as staples or glue guns. A transparent film may be disposed about the posts and the appliance. The top cover includes a lifting flange member and is disposed over the plurality of posts.
Another advantage of the invention is to provide novel packaging assemblies and methods for appliances comprising a corrugated paperboard cover having folded side portions, and a lifting flange disposed across one of the cover, side or rear portions. The lifting flange member may have a reinforcing member extending from an inner portion of the cover.
These and other features and advantages of the present invention will become apparent from a consideration of the following detailed description in conjunction with the accompanying Drawings, wherein corresponding structures are referenced by corresponding reference numbers.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
A US military court has convicted an army squad commander of leading a "kill team" in Afghanistan that murdered unarmed civilians and collected body parts as war trophies.
But Staff Sergeant Calvin Gibbs, 26, could be freed in less than 10 years after receiving a life sentence with the possibility of early parole for murder, assault and conspiracy over the killings of three Afghans in separate incidents staged to look as if the victims were combatants.
In one of the most serious accusations of war crimes to emerge from the Afghan conflict, Gibbs recruited other soldiers to murder civilians he called "savages" after he took over command of a US army squad in Afghanistan's Kandahar province in November 2009. Prosecutors described Gibbs as hunting innocent Afghans "for sport", a view reinforced by the staff sergeant's statement likening the amputation of body parts as trophies to collecting antlers from a deer.
The military prosecutor, Major Rob Stelle, told the court: "Sergeant Gibbs had a charisma, he had a 'follow me' personality. But it was all a bunch of crap, he had his own mission: murder and depravity. No one died before Sergeant Gibbs showed up."
Gibbs was convicted of murder for inciting two soldiers to kill 15-year-old Gul Mudin as he worked in a field. The platoon commander gave a grenade to one of the soldiers, Jeremy Morlock, who threw it at Mudin. A second soldier, Andrew Holmes, then shot the boy. Gibbs played with the corpse of the teenager "as if it was a puppet", Morlock told the trial.
The staff sergeant was also convicted of shooting dead Marach Agha, a man sleeping by a roadside, and then planting a Kalashnikov next to the corpse to make it look as if he was a fighter. He kept part of the victim's skull as a trophy.
Gibbs was convicted on a third count of murder for killing a Muslim cleric, Mullah Adahdad, with a grenade and then shooting him. Two other soldiers, Morlock and Adam Winfield, have already pleaded guilty over their roles in the killing.
Gibbs and other soldiers collected fingers, teeth and other body parts as trophies. They also took photographs of themselves posing next to their dead victims. In one of the pictures Morlock is seen lifting Mudin's head by its hair for the camera and smiling. The soldiers also took ghoulish pictures of themselves with dead combatants.
The jury of five soldiers was shown pages of Facebook messages sent by Winfield to his parents in which he described how Gibbs led the killings. In one exchange with his father Winfield recounted Mudin's killing.
"An innocent dude. They planned and went through with it. I knew about it. Didn't believe they were going to do it. Then it happened. Pretty much the whole platoon knows about it. It's OK with all of them pretty much. Except me. I want to do something about it. The only problem is I don't feel safe here telling anyone. The guy who did it is the golden boy in the company who can never do anything wrong and it's my word against theirs," Winfield wrote.
Winfield later told investigators: "[Gibbs] likes to kill things. He is pretty much evil incarnate. I mean, I have never met a man who can go from one minute joking around, then mindless killings."
The court martial was told that Gibbs had six skull tattoos on his leg to mark up each of his "kills" from tours in Iraq and Afghanistan.
In his testimony Gibbs denied responsibility for the killings, saying the victims all died in legitimate combat. But he did admit slicing off body parts from Afghans, including the fingers of a man, and keeping them or giving them to other soldiers as trophies.
"In my mind I was there to take the antlers off the deer. You have to come to terms with what you're doing. Shooting people is not an easy thing to do," said Gibbs.
The prosecution witnesses against Gibbs included members of his army unit who were also involved in the atrocities. Morlock and Holmes have pleaded guilty to murder and received prison sentences of 24 years and seven years respectively. Winfield pleaded guilty to involuntary manslaughter for failing to prevent other soldiers from attacking Afghan civilians. He was jailed for three years.
Another soldier, Michael Wagnon, is awaiting trial over the killings and collecting human body parts.
The killings came to light in May after the army began investigating an assault on a soldier, Justin Stoner, after he reported to superiors that members of his unit were smoking hashish. Gibbs, Morlock and other members of the platoon are alleged to have beaten Stoner and told him to keep his mouth shut. Stoner reported the beating and told investigators what he knew of the "kill team".
Prosecutors called Gibbs "monstrous" and "savage" and told the military jury he should never be released from prison. But the jurors acceded to the convicted soldier's plea to have the hope of being reunited with his son and sentenced him to life with the possibility of parole after less than 10 years.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Q:
Prove that $f(c)=\frac12(c-a)(c-b)f''(\xi)$
A function $f:[a,b] \rightarrow \mathbb R$ is continuous on $[a,b]$ and $f''(x)$ exists $\forall x\in (a,b)$. If $a<c<b$ and $f(a)=f(b)=0$, prove that there exists a point $\xi$ in $(a,b)$ such that $f(c)=\frac12(c-a)(c-b)f''(\xi)$
My attempt: using Lagrange's Mean Value Theorem on $f$ in $[a,c]$ and $[c,b]$, $\exists \xi_1 \in (a,c)$ and $\exists \xi_2 \in (c,b)$ such that $f'(\xi_1)=\frac{f(c)-f(a)}{c-a}=\frac{f(c)}{c-a}$ and $f'(\xi_2)=\frac{f(b)-f(c)}{b-c}=\frac{-f(c)}{b-c}$
This is where I'm stuck. I tried applying MVT again, but it didn't lead me anywhere. I tried using Rolle's Theorem or Darboux Theorem but it only gave me a $f''(\xi_n)=0$. Can someone please tell me what to do next?
A:
Consider the function: $\displaystyle g(t) = f(t) - \frac{(t-a)(t-b)}{(c-a)(c-b)}f(c)$, we have $g(a) = g(b) = g(c) = 0$.
So, Apply Rolle's Theorem on $g$ in the intervals $[a,c]$ and $[c,b]$, to conclude there are $\xi_1 \in (a,c)$ and $\xi_2 \in (c,b)$, such that $g'(\xi_1) = g'(\xi_2) = 0$.
Since, $\xi_1 \neq \xi_2$, we can again apply Rolle's Theorem on $g'$ in $[\xi_1 ,\xi_2]$, to conclude there is $\xi \in (\xi_1 ,\xi_2)$, such that $\displaystyle g''(\xi) = f''(\xi) - 2\frac{f(c)}{(c-a)(c-b)} = 0$.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
This invention relates generally to a printing system and, more particularly, to a system for automatically positioning a second image on a to second special stock page based, at least in part, on stored information regarding the position of a first image previously positioned on a first special stock page.
Electronic printing systems typically include an input section, sometimes referred to as an input image terminal ("IIT"), a controller, sometimes referred to as an electronic subsystem ("ESS") and an output section or print engine, sometimes referred to as an image output terminal ("IOT"). In one type of electronic printing system, manufactured by Xerox.RTM. Corporation, known as the DocuTech.RTM. electronic printing system, a job can be inputted to the printing system from, among other sources, a network. An example of a printing system with a network input is found in the following patent:
| null |
minipile
|
NaturalLanguage
|
mit
| null |
<package>
<description brief="pipeline">
pipeline
</description>
<author>Stanford Driving</author>
<license>BSD</license>
<review status="unreviewed" notes=""/>
<url>http://ros.org/wiki/pipeline</url>
<depend package="eigen"/>
<export>
<cpp cflags="-I${prefix}/include `rosboost-cfg --cflags`" lflags="-lpthread -L${prefix}/lib -Wl,-rpath ${prefix}/lib -lpipeline"/>
</export>
</package>
| null |
minipile
|
NaturalLanguage
|
mit
| null |
His Holiness Hui Neng, who became the great Sixth Patriarch of Ch'an (Japanese Zen) was a poor illiterate peasant boy from Hsin Chou of Kwangtung. One day, after he had delivered firewood to a shop, he overheard a man reciting the following line from the "Diamond Sutra" - "Depending upon no-thing, you must find your own mind." Instantly, Hui Neng became Enlightened. The full verse said: "All Bodhisattvas (Compassionate Ones) should develop a pure mind which clings to no-thing whatsoever; and so he should establish it."
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Result awaiting candidates may apply but their admission will be confirmed only after providing of the final grade sheet.
MBA (2 Year):
Those who have completed M.Com/B.Com(Hons)/BBA(Hons) with minimum CGPA 2.5 are eligible to apply for admission. However, admission will be granted on the basis of merit, determined on the basis of admission test and academic record.
The degree is awarded after completion of 36 credit hours with minimum CGPA of 2.5. The degree requirements are normally completed in 2 year spreading over 4 semesters.
MBA:
Those who have completed B.A/B.Sc/B.COM (14 Years) with minimum second division are eligible to apply for admission. However, admission will be granted on the basis of merit, determined on the basis of admission test and academic record.
The degree is awarded after completion of 96 credit hours with minimum CGPA of 2.5. The degree requirements are normally completed in 3.5 year spreading over 7 semesters.
M.Com:
B.A/B.Sc/B.Com or equivalent with minimum 2nd division.
Result awaiting candidates may apply but their admission will be confirmed only after provision of the final grade sheet.
Applicants will have to clear entry test as well as interview to get admission in M.Com.
Students with underlined combinations in graduation are eligible to apply for M.Com. admission.
Degree
Combinations
Bachelor of Science (B.Sc.)
Mathematics, Statistics, Economics
Double Mathematics, Statistics
Double Mathematics, Physics
Double Mathematics, Computers
Double Computers, Mathematics
Bachelor of Arts (B. A.)
Mathematics, Economics
Statistics, Economics
General Mathematics, Statistics
Computers, Economics
Computers, Statistics
Students who have taken a minimum of two out of the four subjects (Statistics, Mathematics, Economics and Computers) in their bachelor programme are also eligible for M.Com programme.
The student is required to complete the degree requirements in 4-semesters with at least 2.00 CGPA.
BBA/BS. Commerce:
Students with FA/F.Sc/I.Com/A-Level or equivalent (with minimum second division) are eligible to apply for admission. However, admission will be granted considering the score of admission test and academic record.
The degree is awarded after completion of 126 credit hours with a minimum CGPA of 2.0 and an internship of 6 to 8 weeks with any organization. The degree requirements are normally completed within 4 years spreading over 8 semesters.
BSCS:
Intermediate or equivalent with minimum 2nd division. The students awaiting result may also apply for admission on provisional basis.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
New Delhi: The nine-member Lok Sabha panel probing the Parliament video of AAP MP Bhagwant Mann on Wednesday said there were contradictions in his stand on the issue.
File image of Bhagwant Mann. IBNlive
"The committee gave four opportunities to Mann to explain his stand. But there are contradictions. We are certainly taking a serious view of it," panel chairman Kirit Somaiya told reporters.
"We also want to consult a few experts to suggest measures so that such incidents do not occur in the future," he said.
On Somaiya's request, Lok Sabha Speaker Sumitra Mahajan has granted two more weeks to the panel, which was to submit its report on 3 August.
The Speaker set up the panel on 25 July to probe the alleged breach of Parliament security by the Aam Aadmi Party leader, who on 21 July posted on Facebook a video footage of his journey from home to Parliament.
Asked what action can be taken against Mann, Somaiya said the panel will now "start the exercise of what could be done".
He also hoped that the report may be submitted by 12 August, the last day of the ongoing monsoon session of Parliament.
According to the report, Mann remained defiant when he appeared before the panel and insisted he did not breach Parliament's security.
However, on 25 July he told Speaker Mahajan that he was ready to tender an unconditional apology.
Informed sources said while no decision had been taken by the probe panel, there was unanimity that Mann was politicising the issue by dragging Prime Minister Narendra Modi into the controversy.
The panel has also taken cognisance of the letter written by three Lok Sabha members – Mahesh Girri of BJP, Prem Singh Chandumajra of the Akali Dal and suspended AAP lawmaker Harinder Singh Khalsa – demanding that Mann be sent to a rehabilitation centre for de-addiction.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Community integration and associated factors among older adults with schizophrenia.
Community integration has been increasingly recognized as an important element in recovery. There is a paucity of data on community integration for older adults with schizophrenia. This study compared community integration for older persons with schizophrenia with their age peers in the community and examined factors associated with community integration in the schizophrenia group. The schizophrenia group consisted of 198 community-dwelling persons aged 55 and older who developed schizophrenia before age 45. A community comparison group (N=113) was recruited by randomly selected block groups. Wong and Solomon's 2002 conceptual framework was used to develop a 12-item community integration scale with four components: independence, psychological integration, physical integration, and social integration. Moos' ecosystem model was used to examine 15 personal and environmental factors associated with community integration. Compared with the general community group, the schizophrenia group had significantly lower total community integration scale scores and lower scores on each of the four components. Within the schizophrenia group, regression analysis showed that seven variables were significantly associated with community integration: being female, higher personal income, lower depressive symptoms, lower positive symptoms, lower Abnormal Involuntary Movement Scale score, higher CAGE lifetime scores, and greater control of one's life. The model was significant and explained 49% of the variance. The data confirmed that older persons with schizophrenia had a lower level of community integration than their age peers in the community and that the model for community integration can identify potentially ameliorable clinical and social variables that may be targets for intervention research.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Abalonetti Bar & Grill
One of Monterey’s Original Restaurants!
Abalonetti is the given name to the squid when it is prepared just like abalone. Even the connoisseur cannot tell the difference to make the squid Abalonetti. Remove the skin, split the squid and pound it until tender … then bread the squid. Now you have Abalonetti ready for any type of cooking.
We specialize in Monterey Bay Calamari and offer almost a dozen varieties of these squid dishes — many found only at Abalonetti Bar & Grill – Try our Exclusive Buffalo Calamari! We also offer Gluten Free options.
Located on Monterey’s Fisherman’s Wharf
LOCATION
HOURS
Open 7 days a Week
Lunch & Dinner: 11:30 am to 9 pm,
Closed Christmas Day
CONTACT US
Phone 831.373.1851Fax 831.373.2058
NEWS AND OFFERS
Register for a Complimentary Appetizer and special occasion promotions,
Email *
First Name
Example: Yes, I would like to receive emails from Abalonetti Bar and Grill. (You can unsubscribe anytime)
Constant Contact Use.
By submitting this form, you are consenting to receive marketing emails from: Monterey Restaurants, 620 Ocean View Boulevard, Pacific Grove, CA, 93950. You can revoke your consent to receive emails at any time by using the SafeUnsubscribe® link, found at the bottom of every email. Emails are serviced by Constant Contact
Sign up for our newsletter
Email *
First Name
Example: Yes, I would like to receive emails from Abalonetti Bar and Grill. (You can unsubscribe anytime)
Constant Contact Use.
By submitting this form, you are consenting to receive marketing emails from: Monterey Restaurants, 620 Ocean View Boulevard, Pacific Grove, CA, 93950. You can revoke your consent to receive emails at any time by using the SafeUnsubscribe® link, found at the bottom of every email. Emails are serviced by Constant Contact
| null |
minipile
|
NaturalLanguage
|
mit
| null |
An article on Planet5D talking about Panasonic potentially dropping the Micro 4/3 system (except for the GH4) also mentions the possibility of Canon acquiring Panasonic’s camera division. We’ve heard various things in the past about Canon acquiring camera technologies and companies, but nothing has ever come of it. It’s usually been focused around medium format companies or print technology companies such as Kodak.
From Planet5D
dalubo 1:15PM
I heard from some very reliable sources that Canon is about to take over the Panasonic camera division. And that Olympus retreats from MFT too.
I have no idea what Panasonic has that Canon would want, perhaps there’s some video technology or patents that are of interest. I am reminded of a few articles I’ve read about the camera industry needing a giant shakeup. One of the suggested shakeups is less camera manufacturers. Panasonic, while making some very good products in the industry, seems to relegated to a niche market of budget conscience videographers and photographers.
Whether or not this is true doesn’t matter, it’s a telling reminder of the state of the industry. Some companies are going to be leaving the camera marketplace in the coming years, there just isn’t enough growth to keep companies profitable. Canon and Nikon are safe, though the latter isn’t exactly a profit machine. Sony seems content of giving it their all to find a place in the photography world and Fuji is making some cool niche products and are profitable. Leica has become a lifestyle brand, and the Louis Vuitton customer will continue to purchase the high margin German cameras. The rest? I’m not sure how much longer we’ll see Olympus, Panasonic, Samsung and Ricoh/Pentax in the game, I expect at least 2 of those names will be moving onto other things.
While it might make sense for Canon to acquire Panasonic's camera division to buy themselves back into current sensor technology the idea of Panasonic and Olympus dropping Micro 4/3? I think this one falls under a bad joke.
While it might make sense for Canon to acquire Panasonic's camera division to buy themselves back into current sensor technology the idea of Panasonic and Olympus dropping Micro 4/3? I think one falls under a bad joke.
"Panasonic's CEO seems dead set on sticking by his "5% profitability" line in the sand. He's already begun closing down businesses that don't meet that goal and have no possibility of doing so any time soon. It seems clear that more businesses will be shut down at Panasonic if they can't get to that 5% number within the next 12-18 months. More so than any other camera company, I worry about Panasonic's ability to come out of the camera sales slump intact...
Bottom line is this: Panasonic is the company to watch carefully, as they're the canary in the coal mine. They're the only one of the Japanese camera companies that currently appears to be trying to fully address years of slothful organizational bloat and are actively closing down businesses that underperform. If they keep their still camera group going, all the Japanese companies will, I think. If Panasonic takes an ax to that group (or even just the compact camera part), others may follow."
We have a limited vision (pun intended) of the camera manufacturers. But given the financial climate, Sony seems better suited to sell its department of photographic cameras and sensors. Panasonic is deficient, but not as hopeless as Sony.
"Panasonic's CEO seems dead set on sticking by his "5% profitability" line in the sand. He's already begun closing down businesses that don't meet that goal and have no possibility of doing so any time soon. It seems clear that more businesses will be shut down at Panasonic if they can't get to that 5% number within the next 12-18 months. More so than any other camera company, I worry about Panasonic's ability to come out of the camera sales slump intact...
Bottom line is this: Panasonic is the company to watch carefully, as they're the canary in the coal mine. They're the only one of the Japanese camera companies that currently appears to be trying to fully address years of slothful organizational bloat and are actively closing down businesses that underperform. If they keep their still camera group going, all the Japanese companies will, I think. If Panasonic takes an ax to that group (or even just the compact camera part), others may follow."
Look at what Olympus did to 4/3 cameras (NOT micro 4/3). The whole line died. No more semi-pro cameras... gone with no warning leaving it's customer base in the dust....
yeah.....I think this is just hoax upon hoax..(as in April Fools)..the hoax on the MFT sites is that Panasonic is getting out pf MFT and going to make a FF camera only...This is all from a (supposed) Clandestine Asian-Language audio tape translation of higher ups in a private conversation...now someone has just added Canon buying Panasonic out....It all looks like an April Fools Day hoax....
It makes little sense to buy into a business that is selling compact cameras. Canon is also rumored to be getting out of the low end point and shoot business, that makes more sense.
Panasonic does make some very good video equipment and lenses, that might be what interests Canon. The factory with its skilled workers might also be worth a ton of money. They might buy it to keep Sigma or Tamron from buying it.
"Panasonic's CEO seems dead set on sticking by his "5% profitability" line in the sand. He's already begun closing down businesses that don't meet that goal and have no possibility of doing so any time soon. It seems clear that more businesses will be shut down at Panasonic if they can't get to that 5% number within the next 12-18 months. More so than any other camera company, I worry about Panasonic's ability to come out of the camera sales slump intact...
Bottom line is this: Panasonic is the company to watch carefully, as they're the canary in the coal mine. They're the only one of the Japanese camera companies that currently appears to be trying to fully address years of slothful organizational bloat and are actively closing down businesses that underperform. If they keep their still camera group going, all the Japanese companies will, I think. If Panasonic takes an ax to that group (or even just the compact camera part), others may follow."
Look at what Olympus did to 4/3 cameras (NOT micro 4/3). The whole line died. No more semi-pro cameras... gone with no warning leaving it's customer base in the dust....
Not totally true...the new M1 plus new adaptor finally takes up the slack there....4/3 lenses work well with the M1.I think this is a hoax though for April Fools Day.
Gotta be a joke. Not that they couldn't make use of some sensor patents perhaps, as Canon is the odd man out at this point when it comes to lower ISO DR. But surely they could get those for less than the whole company and it really doesn't seem to make any sense other than April Fools.
Probably an April Fools, but I still find it more credible than the rumors about Canon purchasing a MF manufacturer.
APS-C & EOS-M made sense because (a) those are big markets, and (b) Canon's FF lenses could be mounted on those cameras.
What would be the benefit of making MF cameras? Selling a small amount of cameras with another manufacturer's mount? Making a whole new line of lenses, rather than investing resources into some other line which benefit it more, e.g. EOS-M?
Panasonic recently hived off its CMOS sensor fab plants to TowerJazz the Israeli company, it retains a small shareholding but that tells you they were not a profit centre like Sony fab plants (Sony bought a Renesas fab plant to increase its production for cell phones). Panasonic have a tie-in with Leica making their low end models (but not the sensor for the Leica M 240 which was designed by CMOSIS) and they license Leica lens designs much like Sony does with Zeiss.
Sony own a shareholding in Olympus after the Olympus scandal left them vunerable and Olympus switched its sensor supply from Panasonic to Sony. Olympus has improved its performance in its camera division although its still loss making, Sony bought in for the medical division an area it was not in.
Canon purchasing Panasonic is plausable for two reasons:-
1. Canon use back side illuminated sensors & Panasonic have good IP on front side. 2. Panasonic & Fuji are co-developing organic CMOS sensors which may produce results more like film
| null |
minipile
|
NaturalLanguage
|
mit
| null |
The Argus (Fremont)
The Argus was a newspaper in the town of Fremont, California. Floyd L. Sparks was the longtime owner of The Argus, along with the Daily Review and the Tri-Valley Herald. It was last owned by Bay Area News Group-East Bay (BANG-EB), a subsidiary of MediaNews Group, who purchased the papers from Sparks in 1985.
The newspaper was scheduled to be closed down, with the last issue of the paper published on November 1, 2011. The Oakland Tribune, Alameda Times-Star, Hayward Daily Review, Fremont Argus and West County Times all published their last editions the same day. On November 2, subscribers will get copies of the new East Bay Tribune, a localized edition of The Mercury News. The plans were later reversed. In 2016, the paper was one of four that was merged into the East Bay Times.
References
External links
Official site
Archive at Newspapers.com
Category:Media in Alameda County, California
Category:Fremont, California
Category:Newspapers published in the San Francisco Bay Area
Category:Defunct newspapers of California
Category:MediaNews Group publications
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Q:
OpenCV Multi Core Support
I was wondering if there is multi core support for the OpenCV library. I am experimenting with Haar cascading and it's pretty slow on my Raspberry 2 which would have four cores, but my application is currently running only on a single one.
Any ideas?
A:
CascadedDetect has multi core support.
Recompile OpenCV with the WITH_TBB or WITH_OPENMP (or any other threading framework supported by OpenCV) flag on to enable it.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Journal of Immigrant and Minority Health
The Journal of Immigrant and Minority Health is a bimonthly peer-reviewed medical journal covering research on immigrant health and the health of minority groups. It was established in 1999 as the Journal of Immigrant Health, obtaining its current name in 2006. It is published by Springer Science+Business Media and the editor-in-chief is Sana Loue (Case Western Reserve University School of Medicine). According to the Journal Citation Reports, the journal has a 2016 impact factor of 1.314.
References
External links
Category:Public health journals
Category:Publications established in 1999
Category:Bimonthly journals
Category:Springer Science+Business Media academic journals
Category:English-language journals
Category:General medical journals
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Escherichia coli recA protein protects single-stranded DNA or gapped duplex DNA from degradation by RecBC DNase.
RecA- mutants of Escherichia coli extensively degrade their DNA following UV irradiation. Most of this degradation is due to the recBC DNase, which suggests that the recA gene is involved in the control of recBC DNase in vivo. We have shown that purified recA protein inhibits the endonuclease and exonuclease activities of recBC DNase on single-stranded DNA. The extent of inhibition is dependent on the relative concentration of recA protein, recBC DNase, and the DNA substrate; inhibition is greatest when the concentrations of DNA and recBC DNase are low and the concentrations of recA protein is high. At fixed concentrations of recA protein and recBC DNase, inhibition is eliminated at high concentrations of DNA. In the presence of adenosine 5'-O-(3-thiotriphosphate), an ATP analog which stabilizes the binding of recA protein to both single- and double-stranded DNA, recA protein is a more potent inhibitor of the nuclease activities on single-stranded DNA and is a weak inhibitor of the exonuclease activity on double-stranded DNA. Inhibition of the latter is enhanced by oligodeoxynucleotides, which stimulate the binding of recA protein to double-stranded DNA. In the presence of adenosine 5'-O-(3-thiotriphosphate), recA protein also inhibits the action of exonuclease I on single-stranded DNA and of lambda exonuclease on double-stranded DNA. These observations are most consistent with the idea that recA protein protects DNA from recBC DNase by binding to DNA. RecA protein also blocks the endonucleolytic cleavage of gapped circular DNA by recBC DNase. Since both recA protein and recBC DNase have the ability under certain conditions to unwind duplex DNA and to displace strands, we looked for evidence that their combined action would enlarge gaps but found no extensive enlargement. D-loops, a putative intermediate in genetic recombination, are effectively protected against the action of recBC DNase by the E. coli single strand binding protein and by recA protein in the presence of adenosine 5'-O-(3-thiotriphosphate).
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Poca buddhist single women
Someone you can love is nearby browse profiles & photos of single buddhist women in ponca, ne join matchcom, the leader in online dating with more dates, more relationships and more marriages than any other dating site. Poca's best 100% free online dating site meet loads of available single women in poca with mingle2's poca dating services find a girlfriend or lover in poca, or just have fun flirting online with poca single girls. Poca west virginia, country girl if u not looking for a steady relationship don't bother me looking for a prince to take me away. Buddhist singles in fact, millions have already made the leap to online dating as a way to find a relationship online dating professionals birth order relationships long distance love advice if you are like most people these days, your time is limited as work, family and other commitments take up much of your schedule.
Buddhism and women a female child may prove even to be a better offspring than a male women's position in buddhism is unique the buddha gave women full freedom to participate in a religious life the buddha was the first religious teacher who gave this religious freedom to women before the buddha, women's duties had been restricted to the. Meet buddhist thai singles there are 1000's of profiles to view for free at thaicupidcom - join today. Free buddhist chat rooms can provide you with the option to create friendships, to create love and form powerful spiritual connections with a woman you intend to develop a lasting relationship with.
Edit article how to have a buddhist girlfriend, but be of another religion yourself you're an ignorant male completely unaware of your potential to make your super devout buddhist girlfriend miserable through your complete ignorance. Meet buddhist indonesian singles interested in dating there are 1000s of profiles to view for free at indonesiancupidcom - join today. Poca's best 100% free buddhist dating site meet thousands of single buddhists in poca with mingle2's free buddhist personal ads and chat rooms our network of buddhist men and women in poca is the perfect place to make buddhist friends or find a buddhist boyfriend or girlfriend in poca. Single women looking for love older men looking for younger men buddhist dating site you can develop a long term relationship with that special someone on the internet home dating questions on first date.
Buddhist dating site is part of the online connections dating network, which includes many other general and buddhist dating sites as a member of buddhist dating site, your profile will automatically be shown on related buddhist dating sites or to related users in the online connections network at no additional charge. Meet buddhist mexican singles interested in dating there are 1000s of profiles to view for free at mexicancupidcom - join today. Welcome to the simplest online dating site to date, flirt, or just chat with buddhist women in kandersteg it's free to register, view photos, and send messages to single buddhist men and women in the kandersteg area. Today, when the role of women in society is an issue of worldwide interest it is opportune that we should pause to look at it from a buddhist perspective in the recent past, a number of books have been written on the changing status of women in hindu and islamic societies, but with regard to women.
Poca buddhist single women
The very existence of a “women and buddhism” entry but no “men in buddhism” entry implies a set of methodological lacunae in buddhist studies on the one hand, buddhist studies have often proceeded as if the history of men in buddhism stands in for buddhist history, with little effort made. Maybe you’re tired of dating the same types of people over and over again well, if that’s the case, i’d like to suggest something you may not have thought about: a buddhist buddhists are down to earth, real, and strong. That women participate equally is probably the single biggest change with buddhism being established in the west 10 tibetan buddhist women you need to know female buddhist leaders. Find winfield single buddhist women to meet on zoosk online dating lets you meet great people out there who we just haven't bumped into yet take the plunge into online dating and start meeting possible people to date in winfield date smarter try zoosk online dating.
Meetville is an interracial dating site, which will help you to meet the local single buddhist women and men, searching in thousands of single people looking for each other online to build successful, long-lasting and happy relationship in norway total users: 18,684,430 online: 16,543. The book completely embodies buddhism in my opinion, every single piece of advice is consistent with buddhist teachings, i haven't found a single thing in the book that is un-buddhist in any way women, sex, and addiction: a search for love and power charlotte s kasl 44 out of 5 stars 48 paperback 71 offers from $200 next pages. Women in buddhism is a topic that can be approached from varied perspectives including those of theology, history, anthropology and feminismtopical interests include the theological status of women, the treatment of women in buddhist societies at home and in public, the history of women in buddhism, and a comparison of the experiences of women across different forms of buddhism.
Buddhist personals is part of the online connections dating network, which includes many other general and buddhist dating sites as a member of buddhist personals, your profile will automatically be shown on related buddhist dating sites or to related users in the online connections network at no additional charge. Dharmamatch, a dating/matchmaking site for spiritual singles browse in-depth photo profiles/personals meet local singles who share your beliefs & values free to join. Buddhist dating online is a sure-shot way of finding the person that can really complete you there are no trials and errors when it comes to buddhist chat rooms online in all, if you’re buddhist single and are ready to mingle on a personal and spiritual level, nothing can beat online buddhist chat rooms.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Some considerations on the ion transport properties of the rod disc membrane.
The ion transport properties of the disc membranes in rod outer segments are discussed on the basis of available data. The properties of an air-water interface film of spectroscopically intact and chemically regenerable rhodopsin are presented, and results of studies of ion binding to these films are reported.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Developing 152Eu into a standard for detector efficiency calibration.
A gamma-gamma coincidence experiment was performed to check the 152Eu 13-year decay scheme and the placement of the observed gamma-ray transitions. The multi-detector array for residual activity measurement of the Linear Accelerator Laboratory was used. The source activity was 1 MBq, and about 10(9) coincidence events were observed. About 30 gamma's were placed in the decay scheme and four 152Sm levels were added to the previously known set of levels fed in 152Eu 13-year decay.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Q:
Find combinations of rows grouped by a column by picking 1 row from each group in dataframe
I have a dataframe which can be grouped by column. Each row in a particular group has a unique id. By picking 1 row from each group, I want to form all possible combinations possible.
I have tried to solve it by combn() and expand.grid(). But was not able to get the desired solution.
I have following type of data
Col1 id Unique id
A 1 A_1
A 2 A_2
B 1 B_1
C 1 C_1
C 2 C_2
C 3 C_3
I want something like this:
Groups or dataframes for following type:
(A_1,B_1,C_1)
(A_1,B_1,C_2)
(A_1,B_1,C_3)
(A_2,B_1,C_1)
(A_2,B_1,C_2)
(A_2,B_1,C_3)
Here I have shown only 3 groups that are A,B,C.
I real dataset I can have any number of groups and each row can have any number of ids.
Please help me for this with code or logic whatever possible.
A:
You can split unique_id by Col1 then use expand.grid().
expand.grid(split(df$Unique_id, f = df$Col1))
A B C
1 A_1 B_1 C_1
2 A_2 B_1 C_1
3 A_1 B_1 C_2
4 A_2 B_1 C_2
5 A_1 B_1 C_3
6 A_2 B_1 C_3
| null |
minipile
|
NaturalLanguage
|
mit
| null |
You are here
When Factories Fall, Transparency Matters
Just before the fourth anniversary of the collapse of Rana Plaza, the most fatal tragedy in the history of manufacturing, a coalition of human rights advocates are calling for greater transparency in the global apparel industry. The report, Follow the Thread: the Need for Supply Chain Transparency in the Garment and Footwear Industry, is the base document for a new drive by the global trade unions and labor rights advocacy organizations to demand greater transparency from apparel brands. The report is based on letters sent to 72 brands, asking them to publish the names, addresses, and other important information about factories manufacturing their products. Of those brands, 17 agreed to align with the pledge, a powerful tool for promoting corporate accountability that allows garment workers, unions, and nongovernmental organizations to call on these apparel companies to help ensure that abuses stop.
The collapse of Rana Plaza, which killed 1,134 workers in Bangladesh and injured more than 2,000, came months after a string of factory fires in Pakistan and Bangladesh that led to the deaths of more than 370 primarily women workers. Each tragedy triggered a multi-year struggle to secure compensation for the injured workers and the families of the deceased, including global demonstrations and campaigns. Uncountable hours were wasted as workers, unions and NGOs struggled to establish connections between the factories and the brands whose clothes they produced – and then convince those brands to support the worker compensation fund. Bangladeshi law does not provide any guarantee of compensation following injury or death, which is crippling for families who have lost their primary breadwinner. In the end, Rana Plaza victims waited more than two years for compensation, while the victims of less high profile cases waited longer or never received anything because the brands quietly walked away.
Shamefully, these delays prolonged the victims’ suffering and plunged them even further into poverty as debts mounted, medicines ran out, and children’s educations were disrupted. The amount of time spent on the cat–and-mouse game of having to figure out which brands were buying from which factories was incredibly wasteful. And some brands, like Walmart, contributed much less than their fair share. The majority of the clothes found after the 2012 fire at Tazreen Fashions, which killed 112 workers, was Walmart labeled product. Yet Walmart initially claimed that because the factory was no longer on their approved list, they had no reason to contribute to the worker compensation fund. Notably, while Walmart acknowledged receipt of correspondence about the Transparency Pledge, they did not indicate any commitment to publish their supplier factories, and they are one of five companies targeted by the Follow the Threadcampaign launched in conjunction with this report.
To be sure, supply chain transparency will not address the root causes of labor rights violations: the brands’ perpetual search to reduce production costs. Without strong, independent unions to lift up worker voices and brands’ making commitments to ensure factories address problems that workers’ identify, no amount of information can prevent a future tragedy.
On the morning that Rana Plaza collapsed, workers could see cracks in the building and knew it was unsafe. Still, the factory managers forced them inside, to keep on pace with the brands’ orders. In a future where brands are transparent about where they produce, and when workers have a trade union, the union could call brand representatives directly and tell them about the cracks. Would The Children’s Place or Benetton refuse to adjust their order expectations in order to save lives? We certainly hope so! Combining the Transparency Pledge with ongoing dialogue and contractual commitments between brands and unions is a way to keep workers safe and help brands regain credibility.
Gone are the days where brands could claim that to publish their supplier lists would somehow harm their competitiveness. Not only do the growing number of brands already disclosing those lists disprove this, but in a post Rana world, transparency must become the norm.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Signatures of the immune response.
A compendium of global gene expression measurements from DNA microarray analysis of immune cells identifies gene expression signatures defining various lineages, differentiation stages, and signaling pathways. Germinal center (GC) B cells represent a discrete stage of differentiation with a unique gene expression signature. This includes genes involved in proliferation, as evidenced by high expression of G2/M phase regulators and low expression of ribosomal and metabolic genes that are transcriptional targets of c-myc. GC B cells also lack expression of the NF-kappaB signature genes, which may favor apoptosis. Finally, the transcriptional repression signature of BCL-6 reveals how this factor can prevent terminal differentiation of B cells and cause B cell lymphomas.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
If you would like to see more articles like this please support our coverage of the space program by becoming a Spaceflight Now Member . If everyone who enjoys our website helps fund it, we can expand and improve our coverage further.
A Russian communications satellite lifted off from a snow-covered launch pad in Kazakhstan on Monday, marking the 400th flight of a Proton rocket and the launcher’s first commercial mission in 10 months.
The Yamal 401 communications satellite launched at 0016 GMT Monday (7:16 p.m. EST Sunday) from the Baikonur Cosmodrome, riding a Proton booster away from the historic rocket base just before dawn local time.
Temperatures hovered near 10 degrees Fahrenheit at the frigid launch facility, but clear skies offered unobstructed views of the Proton rocket’s ascent east from Baikonur.
The three-stage Proton booster accelerated the Yamal 401 satellite and its Breeze M upper stage to nearly orbital velocity, then the hydrazine-fueled Breeze M main engine fired four times to raise its orbit more than 22,000 miles above Earth for deployment of Yamal 401 at 0917 GMT (4:17 a.m. EST) Monday.
International Launch Services, which arranged Yamal 401’s launch on a Proton rocket, confirmed a successful mission early Monday.
The 6,560-pound satellite’s relative low mass allowed the Proton/Breeze M to place it directly into geostationary orbit over the equator, minimizing the amount of fuel the spacecraft must expend to reach its operating position. The Breeze M stage drops heavier satellites in lower orbits inclined at an angle to the equator, requiring the spacecraft to fire its own engine to move into its final orbit.
Yamal 401 will enter service in early 2015 at 90 degrees east longitude, where it will hover over a fixed location on Earth to beam communications services across Russia and neighboring countries for Moscow-based Gazprom Space Systems.
Thales Alenia Space of France and Italy provided the Yamal 401 satellite’s communications systems.
Launches of Russian communications satellites are usually managed by the Russian government as part of the country’s federal space program, but Gazprom has elected to negotiate with ILS for commercial launch services for three payloads — Yamal 402 launched in 2012, Yamal 401 sent to space Monday, and the Yamal 601 spacecraft scheduled for liftoff in 2016.
The Proton rocket’s recent reliability woes — five launch failures in four years — have primarily affected the booster’s launches for the Russian government. Commercial Proton flights managed by ILS have mostly occurred without incident.
Two other Proton/Breeze M launches in December 2012 and October 2014 deposited their satellite passengers in off-target orbits, but the payloads were able to recover from the orbit shortfall and continue their missions.
Built by ISS Reshetnev, a Russian satellite manufacturer, Yamal 401 is designed for a 15-year service life. The craft carries 53 transponders and will generate more than 10 kilowatts of power from its solar arrays.
“We thank Gazprom for the opportunity to launch this important satellite and to help expand their business with the launch of Yamal 401, the second launch for Gazprom by ILS,” said Phil Slack, president of ILS. “We are grateful for the mission teams of Gazprom, ILS, Khrunichev, ISS Reshetnev and Thales Alenia Space for their dedication to mission success throughout the entire campaign.”
Monday’s successful flight was the first Proton launch conducted under the ILS umbrella since February. Based in Reston, Va., the U.S.-based company manages commercial Proton missions carrying large telecommunications satellites to orbit.
The Proton rocket was grounded after a May 15 launch failure with the Russian-owned Express AM4R communications spacecraft. When the Proton returned to flight in September, Russian authorities prioritized two government satellites before ILS could launch a satellite for a commercial customer.
The Astra 2G communications satellite, owned by SES of Luxembourg, was supposed to take off Nov. 27. Engineers discovered a problem with a gyro unit on the rocket’s Breeze M upper stage requiring the booster to be removed from the launch pad.
The launch of Astra 2G has been reset for Dec. 28, and the Proton rocket’s next mission with Yamal 401 jumped to next in line for Monday’s launch.
ILS plans a busy schedule of commercial Proton launches in 2015 to catch after delays in 2014.
First up in January is the launch of Inmarsat 5 F2, the second of four satellites owned by London-based Inmarsat designed to help roll out the company’s Global Xpress mobile communications service, an initiative in the works for four years that aims to boost connectivity speeds for users on-the-move in airplanes, on boats and on land.
The launch of Inmarsat 5 F2 was expected in mid-2014 before the Proton rocket’s grounding. The third satellite in Inmarsat’s Global Xpress mobile broadband fleet is expected to launch near the end of the first half of 2015. Both satellites are in storage at a Boeing manufacturing plant in California.
Satellites owned by the Mexican government and Turkey’s national satellite telecom operator are also on the Proton’s manifest in early 2015.
Despite the busy short-term launch schedule, ILS expects a slower launch rate in its long-term business forecast. The company announced a 25 percent staff reduction in August to prepare for the slowdown. Instead of seven or eight commercial Proton launches per year, ILS officials said they now predict three or four flights per year.
Follow Stephen Clark on Twitter: @StephenClark1.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Application Form
Once you have completed and submitted the membership form to the ISPA Secretariat, the application will be subjected to a cursory inspection to ensure that the basic requirements are met.
Thereafter you will be billed an application fee equivalent to a three-month membership fee. Once the payment has been received you will be placed in a provisional category and requested to do the following:
Step 1 of 5
20%
Full or Formal Name of Organisation*
Public Display Name of Organisation*
Blurb / About Organisation
Company Registration Number*
Public Web Address*
Public Email Address*
Enter EmailConfirm Email
Public Telephone Number*
Public Fax Number*
Postal Address*
Please use a maximum of 5 lines.
Street Address*
We hereby apply to join the Internet Service Providers Association as a*
Primary Contact
Title, Name and Surname*
Email Address*
Enter EmailConfirm Email
Direct Telephone
Mobile
Regulatory Contact
Title, Name and Surname*
Email Address*
Enter EmailConfirm Email
Direct Telephone
Mobile
Technical Contact
Title, Name and Surname*
Email Address*
Enter EmailConfirm Email
Direct Telephone
Mobile
Billing Contact
Title, Name and Surname*
Email Address*
Enter EmailConfirm Email
Direct Telephone
Mobile
Help Desk Contact
Title, Name and Surname*
Email Address*
Enter EmailConfirm Email
Direct Telephone
Mobile
Security Information
This is the email address / number who should be contacted in the event ISPA becomes aware of a compromise your network.
Security Role Email Address*
Enter EmailConfirm Email
Security Role Telephone
Security Role Operational Hours
Preferred Contact Method
Email
Telephone
Services Offered
The types of services offered by ISPA's members have been grouped into major categories below. Please indicate all of the services which your company offers in each category by selecting the relevant checkbox.
Each section has space for you to fill in other services you provide which fall in that category, but which aren't already listed. Please include any additional services you'd like us to include here.
The appropriate services will be listed next to your company's name on the ISPA website.
Internet Access Services
Leased Line Access (dedicated 64k+)
DSL Access
Wireless Access
Mobile Access
Dial-up or ISDN access
Other Internet Access Services
Hosting Services
Web Site Hosting (site hosted on ISP server)
Server hosting (Hosting of clients' server on ISP's network)
Managed server hosting (client has access to an ISP managed server)
Other Hosting Services
Miscellaneous Services
VoIP services
Domain name services
Virtual private network (VPN) services
Virtual ISP services
Network management
Content design and development
Other Miscellaneous Services
Hardware Provision
Routers (rental)
Routers (sale)
Servers (rental)
Servers (sale)
Wireless Equipment
PCs and other consumer electronics
Other Hardware Provision
Security Services
Software Firewalls (installation, configuration, maintenance)
Hardware Firewalls (installation, configuration, maintenance)
Security Audits
Other Security Services
Training
Internet literacy
Network maintenance and operation
Advanced Networking
Other training
Domain Name Registrations
A page on ISPA's website will list all ISPA members who always register domains in their clients' names, and not in their own name.
Both ISPA and UniForum SA are able to use this page as a reference when queries are submitted by consumers for information on ISPs whose policy it is to register domains in their clients' names. We believe that this will alleviate some of the Code of Conduct complaints that ISPA receives.
Domain Name Registrations
We always register our customers' domains in the name of that customer (field 2a on the co.za registration form), and we would like to be listed accordingly on the ISPA web site.
We do not always register domains in the name of the clients, or we do not register domain names on behalf of clients at all, and therefore do not qualify to be listed.
When would you like your membership to start?*
As soon as the membership is approved.
At a future date.
If you want your membership to start at a future date, please enter the date here*
Settlement Options*
When, and how regularly would you like to be billed?
VAT Vendor?*
Yes
No
VAT Number
Where did you hear about ISPA?
What are your primary reasons for wanting to join the association?
If you have any IECNS/IECS licenses, please enter the details here (one license number per line)
If there are any other comments you would like listed about your company, or your company's products and services, please include them below
Agreements
I understand that on submission of this form I will be billed an application fee equivalent to a three-month membership fee.
I have read and understand the membership application guidelines.
I have read the ISPA's Code of Conduct and I accept that as a member of ISPA, my organisation will be bound by this Code.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
non-x86 blade servers Tag Index
When it comes to blade servers, x86 is the most frequent architecture of choice. Bladed or not, however, x86 servers are not the perfect tool for every task. Non-x86 blade server options, while limited, fill many of the gaps that their x86 siblings leave.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
STOPDVTs: Development and testing of a clinical assessment tool to guide nursing assessment of postoperative patients for Deep Vein Thrombosis.
To develop and test a clinical tool to guide nurses' assessment of postoperative patients for Deep Vein Thrombosis. Preventing venous thromboembolism in hospitalised patients is an international patient safety priority. Despite high-level evidence for optimal venous thromboembolism prophylaxis, implementation is inconsistent and the incidence of Deep Vein Thrombosis remains high. A two-stage sequential multi-method design was used. In stage 1, the STOPDVTs tool was developed using a review of the literature and focus groups with local clinical experts. Stage 2 involved pilot testing the tool with 38 surgical nurses who conducted repeated assessments on a prospective sample of 50 postoperative orthopaedic patients. Stage 1: The focus group members who were members of the nursing leadership team agreed on eight local and systemic signs and symptoms that should be included in a nursing patient assessment tool for early Deep Vein Thrombosis. Local symptoms were pain in the limbs, calf swelling and tightness, changes in the affected limb's skin temperature. Systemic signs included in the tool were as follows: increased shortness of breath, increased respiratory and heart rates, and decreased oxygen saturation. Stage 2: The STOPDVTs tool had acceptable face and content validity, the agreement between the expert nurse and surgical nurses on assessments of individual signs and symptoms varied between 44%-94%. Surgical nurses were less likely than the expert nurse to identify signs indicative of Deep Vein Thrombosis. Despite finding the STOPDVTs clinical assessment tool was a useful guide for nursing assessment, surgical nurses often underestimated the potential importance of clinical signs. The findings reveal a gap in nursing knowledge and skill in assessing for Deep Vein Thrombosis in postoperative orthopaedic patients. This study identified a possible risk to patient safety related to under-recognition of the signs and symptoms of possible Deep Vein Thrombosis (DVT) in postoperative orthopaedic patients. The findings demonstrate the feasibility of developing and implementing a protocol for consistent screening by nurses for possible DVT in the postoperative period.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
1. Introduction {#sec0005}
===============
Anisakiasis is the zoonotic disease caused by the third larval stage of anisakid nematodes, most frequently belonging to the Anisakis, Pseudoterranova genera and species of the genus Contracaecum \[[@bib0005]\]. This zoonotic infection is acquired through the consumption of raw or undercooked squid, mackerel and cod \[[@bib0010]\]. This is a relatively common diagnosis in East Asia due to the predominant food culture. However, with the increasing popularity of Japanese cuisine, the incidence of anisakiasis has become more frequent around the world due to the increased consumption of raw fish and mackerel \[[@bib0015], [@bib0020], [@bib0025]\]. More than 99% of anisakiasis cases occur in the gastrointestinal tract, specifically in the stomach and small intestine, however the larvae can penetrate the gastrointestinal mucosa or other organs with clinical consequences and potentially allergic reactions \[[@bib0030]\].
There are two types of allergic reaction, including relaxation type with primary infection and fulminant type with reinfection. At the time of primary infection, the allergic reaction is weak and there are few symptoms. In extragastrointestinal anisakiasis, anisakis larvae from the primary infection penetrate the wall of the gastrointestinal tract asymptomatically, and sometimes granulomatous tissues are formed in the intraperitoneal organs including the omentum, mesentery, peritoneum, abdominal wall, lymph nodes, liver, pancreas, and ovaries.
Hepatic anisakiasis is said to be about 0.2% of all cases \[[@bib0035], [@bib0040], [@bib0045]\]. To our knowledge, there have been no reports of hepatic anisakiasis outside of Japan, and there is not yet a clear description of the imaging characteristics of the disease. Since the possibility that hepatic anisakiasis will occur in other countries is high, it is important to describe any diagnostic factors. We provide details of our case of hepatic anisakiasis which developed as a tumour at the border of the liver, and summarize the presentations of previously reported cases.
The work has been reported in line with the SCARE criteria \[[@bib0050]\].
2. Presentation of case {#sec0010}
=======================
The patient was a 60-year-old man who had been diagnosed with rectal cancer. He underwent laparoscopic radical low anterior rectal resection and construction of a covering ileostomy. Pathological examination revealed that the rectal cancer was pT3 (A), pN1b (2/17), cM0, pStage IIIB. To prevent recurrence, he received postoperative adjuvant chemotherapy of modified FOLFOX (fluorouracil, [l]{.smallcaps}-leucovorin and oxaliplatin) for 6 months after surgery. Follow-up computed tomography (CT) performed at 7 months after surgery detected a new low density area of 10 mm in diameter in the surface of liver segment 4/8, and a deformation in which the liver surface in the vicinity was recessed. The patient showed no symptoms such as abdominal pain during follow-up period after surgery. Gadoxetic acid magnetic resonance imaging (EOB-MRI) revealed nodules of about 8 mm on the surface of liver segment 4/8 and a surrounding area of abnormal EOB uptake. Positron emission tomography (PET)-CT was performed to confirm the presence of a malignant liver tumour and to search for other metastasis. The liver lesion had localized light fluorodeoxyglucose (FDG) uptake in the delayed phase (standardized uptake value (SUV) max: 2.8) and other distant metastasis was not detected ([Fig. 1](#fig0005){ref-type="fig"}). Serum tumour markers including CEA and CA19-9 were not elevated, and were similar to the levels before initial chemotherapy. These findings were compatible with a metastatic tumour from rectal cancer. Because the mass was judged to be resectable, laparoscopic partial hepatectomy and ileostomy closure was planned with a diagnosis of liver metastasis from rectal cancer. Intraoperative findings revealed a slight white, crude tumour on the liver segment 8 surface with no other lesions recognized, so partial hepatectomy of segment 8 was performed. The patient recovered postoperatively and was discharged on postoperative day 7. A nodule of approximately 8 mm in diameter was macroscopically identified in the resected specimen ([Fig. 2](#fig0010){ref-type="fig"}). Necrotic granulation tissue of approximately 5 mm was found in the centre of the nodule, accompanied by a few polygonal giant cells at the margin on the microscopic examination. A parasitic worm body was recognized with Elastica van Gieson staining in a structure suspected to be a vein. Grocott staining did not reveal any fungus or protozoon infection, and the worm body was finally proved to be anisakis simplex by anisakis antibody staining ([Fig. 3](#fig0015){ref-type="fig"}). It was thought that the anisakis larvae broke through the intestinal wall and invaded the vein from the liver surface. Detailed inquiry after surgery revealed that the patient had a history of eating raw fish. Thereafter, no new lesions have appeared in the liver and there has been no recurrence of rectal cancer.Fig. 1Images of the liver. A: A 10 mm area of low density is observed on the surface in segment 8 of the liver in contrast CT. B: EOB-MRI shows a decrease in uptake of EOB. C: Abnormal FDG accumulation of SUV max 2.8 is seen on PET examination. CT: computer tomography. EOB MRI: gadoxetic acid magnetic resonance imaging. FDG: fluoro-deoxyglucose. SUV: standardized uptake value. PET: positron emission tomography.Fig. 1Fig. 2Intraoperative findings and resected specimen. A: Intraoperative findings show a white fleck in segment 8 of the liver. B: An 8 mm nodule of white necrosisis found in the resected specimen right under the serous membrane.Fig. 2Fig. 3A: A nodule with surrounding necrosis and inflammatory cell infiltration is observed in the vicinity of the serosa. B: Structures considered to be worm bodies are seen in the nodule. C: The worm body is shown intravenously by EVG staining. D: The worm body shows positive immunostaining against anisakis antigen. EVG: elastic-van Giesen.Fig. 3
3. Discussion {#sec0015}
=============
Two important facts were derived from this case: firstly the existence of hepatic anisakiasis, and secondly, the possibility of hepatic anisakiasis should be considered with low density liver margin tumours of less than 20 mm by contrast CT if the patient has a history of eating raw fish.
The first zoonotic case attributed to the anisakis species was described in the Netherlands by Van Thiel et al. in 1960, and anisakiasis is divided into three types; gastric, intestinal, and extragastrointestinal anisakiasis \[[@bib0055]\]. Ishikura et al reported that gastric anisakiasis accounts for 95.7% of all cases, intestinal anisakiasis 3.8%, and extragastrointestinal anisakiasis just 0.5% of all cases. Among extragastrointestinal anisakiasis, hepatic anisakiasis is extremely rare. Only 12 cases of hepatic anisakiasis have been reported previously ([Table 1](#tbl0005){ref-type="table"}). To the best of our knowledge, our case was the 13th case in the world. As in this case, most of extra-gastrointestinal anisakiasis including hepatic anisakiasis are asymptomatic and detected incidentally by imaging studies. In primary infection, anisakis larvae penetrate the wall of the gastrointestinal tract with no symptoms and form abscesses and granulomas in intraperitoneal organs \[[@bib0040]\].Table 1Reported cases of hepatic anisakiasis.Table 1AuthorAge (Years)SexLocalizationSize (mm)CT findingsUeki62MRight lobe surface2NoneKagei51Munknown15NoneKawakami58MS8 surface20LDAKunitomi34FS4 surface20LDAIdeguchi68FS4/514LDAMorita59FS2 surface20LDAIshida64MS8 surface20LDAHayashi70MS8 surface8LDAIrieunknownunknownunknown22LDANogami44FS4 surface15LDASekoguchi63MS6 surface4NoneMurata28MS7 surface12LDAOur case60MS8 surface8LDA[^1]
Hepatic anisakiasis may occur as anisakis larvae migrating from the digestive tract wall into the peritoneal cavity invade the liver surface and form a tumour at the liver margin. It is also speculated that larvae from the gastrointestinal tract might reach the liver via the portal vein, but there are no reports of hepatic anisakiasis invasion routes from any other path than the liver surface.
In our case, anisakis larvae were recognized in the hepatic vein. Although pathological findings could not show clear evidence of invasion from the liver surface, we judged that anisakis larvae penetrated the liver surface from intraoperative findings which confirmed liver surface contractions at the tumour site and pathological findings in which necrotic tissue and granulation tissue spread around the liver surface.
In general, hepatic anisakiasis is difficult to make clinical diagnosis simply by using imaging modalities. In all presented cases including our case, precise diagnosis based on imaging studies was not achieved before pathological examination. Even after pathological examination, to make a definitive diagnosis is also difficult because larva body has often collapsed. The infection in human body is transient and the parasite will die within 14 days, leaving a persistent inflammation forming granuloma. Various immunologic assays like complement fixation test, immunofluorescent-antibody test, immunodiffusion test, immunoelectrophoretic assays, enzyme-linked immunosorbent assay, and radio-allergosorbent test is reliable for obtaining final diagnosis even when the larvae body collapses with time. Use of monoclonal antibodies specific to anisakis antigens also help the definite diagnosis.
Hepatic anisakiasis tumours present as a small low density area of the liver margin on CT. In previously reported cases where there was a description of localization, all tumours were at the liver margin, with an average size of 13.8 mm, and almost all tumour less than 20 mm. Low density areas in contrast CT are thought to reflect granulomas and necrotic tissue. Incidental detection of this lesion is difficult to distinguish from carcinoma recurrence in patients with a history of malignancy, and can lead to unnecessary surgery, chemotherapy, and radiotherapy. Follow-up observation or biopsy can be options for a small low density tumour at the liver margin, unless we positively suspect malignant disease.
In some cases the collapsing worm body may make the final diagnosis difficult, even after resection. Therefore, the exact frequency of hepatic anisakiasis may be higher than suspected. In our case, the dietary history of the patient and the pathological findings, including significant infiltration of inflammatory cells, oedema, formation of granulation tissue, and cuticular structures characteristic of nematodes such as anisakis and gnathostoma, were consistent with a diagnosis of anisakiasis \[[@bib0060]\].
4. Conclusion {#sec0020}
=============
Changing food cultures, including consumption of raw fish, will likely lead to an increase in anisakiasis cases in the Western countries. Hepatic anisakiasis is rare but should be a consideration if a low density small tumour of the liver margin is detected on contrast CT. The dietary history for the patient should be thoroughly evaluated. When clinical findings do not support positive suspicion of malignant tumours, close observation or biopsy may prevent excessive surgical invasion.
Declaration of Competing Interest {#sec0025}
=================================
The authors have no conflict of interest.
Sources of funding {#sec0030}
==================
This study has not received any funding.
Ethical approval {#sec0035}
================
This case report was approved by the committee of our institute.
Consent {#sec0040}
=======
Written informed consent was obtained from the patient.
Author contribution {#sec0045}
===================
Ryosuke Kita -- Author, Editing of manuscript.
Hiroki Hashida -- contributor.
Kenji Uryuhara -- contributor.
Satoshi Kaihara -- contributor.
Registration of research studies {#sec0050}
================================
None.
Guarantor {#sec0055}
=========
The Guarantor is Ryosuke Kita.
Provenance and peer review {#sec0060}
==========================
Not commissioned, externally peer-reviewed.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
[^1]: CT: computed tomography. LDA: low density area.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
106 Adams Street, Houston, TX 77011
3 Bed, 2 Bath Single Family Home For Sale
This listing is courtesy of Ignacio Osorio from Champions Real Estate Group.
Property Description for 106 Adams Street, Houston, TX 77011
Quaint Bungalow in EDO District just 2 blocks from Metro Rail, minutes from University of Houston DT and Minute Maid Park. Main house has 2 bedrooms and 2 baths, all tile floor, ceiling fans with remote control in all rooms. This 1930's home has the solid walls of its time but has been renovated in the last 2 years from top to bottom including HVAC system. Property includes a 20 ft steel container for storage and a fully functional efficiency tiny apartment, perfect for a caregiver or as guest unit. Large yard with 6 foot wood fence on sides and back gives you privacy and plenty of room to entertain out back, back door has built in pet access door and a ramp. The front is secured by an iron fence with automatic gate and lockable pedestrian door.
Other Details
Request more information or Schedule an Appointment
We are dedicated to meeting all your needs in a prompt manner. In most cases, we will call you back the same day or at the most 24 hours. You can also reach us at (832) 308-8111 or email us at [email protected].
Listings Similar to 106 Adams Street, Houston, TX 77011
Winning location! Downtown, EaDo, Midtown/Montrose and Medical Center all close by! Sleek contemporary design with first floor living and bedrooms up. Urban style freestanding homes with features that you wouldn't expect such as 8' doors, tall ceilings, modern plumbing fixtures and clean lined cabinets. Design palettes include mixes of ebony, gray and white tones in the tiles, woods and walls. ...
2 LOTS SIDE-BY-SIDE (90' x 100' WHEN COMBINED; 45' x 100' if separated; Seller willing to subdivide) THAT CAN BE USED TO BUILD SEVERAL TOWNHOMES ON!!! INVESTORS CAN BUY AND REHAB TO FUNCTIONAL TO RENT UNTIL READY TO BUILD NEW! SURROUNDED BY NEW HOMES ON SURROUNDING STREETS! NEAR NEW METRO RAIL LINE AND TSU AND U OF H...CLOSE TO ALL MAJOR FREEWAYS, AS WELL AS DOWNTOWN AND MED CENTER! THIS ONE...
Avenue Place is quality, green, in-town living at its best. Located near downtown Houston. New construction inside the Loop. Beautiful one-story with spacious living room and formal dining. Easy access to kitchen from garage. Plenty of storage throughout.
My Notes
Mortgage Calculator
Home PriceDown Payment (20%)
Monthly Mortgage Payments
30 year fixed$1,04015 year fixed$1,449
Town Description
Houston is the largest city in the state of Texas, and the fourth-largest city in the United States. According to the 2010 U.S. Census, the city had a population of 2.1 million people within an area...
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Novel genetic techniques and approaches in the microbial genomics era: identification and/or validation of targets for the discovery of new antibacterial agents.
The availability of microbial genome sequences has ushered in the genomics era and has led to numerous technical advancements over the past decade. These advances have been both in the bioinformatics field that has integrated computer-based approaches with biology and in research methods in the laboratory. The advances have assisted scientists in their study of bacterial gene complements and the roles of their gene products in the bacterial life cycle. Assignment of genes as essential to the bacterial cell nominated them as potential targets for antibacterial drugs and spurred attempts to exploit this information and convert it into drugs. At present, these efforts have met with minimal success. There are several possible reasons for these disappointing results including choice of targets and screen designs, compound libraries chosen for screens, and decreased commitment to antibacterial drug discovery by many large pharmaceutical companies. Structure-based approaches could become very effective in the future as methodologies continue to improve.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Monday, February 7, 2011
They are most aggressive when I eat spaghetti, anything creamy or chips. They will form a circle around us and wait. Then Shelley, the most forward one, will attempt to dip her paw on to my plate when I am not looking, especially if I am eating spaghetti--her favourite. Ack.
Oh, and thanks so much for the super nice messages in regards to the upcoming book. You are all so sweet. And yes, CvsH will be updated as usual.
Lol! Lupe is not really obsessed with food but she is with any liquid! if she sees you carrying a mug, a glass or a cup, she will follow you arround and eventually manage to drink out of it when you are distracted!
Bella Mae is my 'old lady' kitty, and she has gotten to where smells of some people food make her act like she's possessed by a human-food-eating creature. She'll come over and stretch her neck out as far as she can....mew *stretch* mew *streeeetch* I'll move her gently, but she keeps coming over until finally she realizes I will not relent.Ironically anything she wants to eat off my plate is not kitty-diet friendly (loaded up with garlic, onion, meat that wouldn't digest well, etc.)Cordelia Joy thinks it is fun to partake in the stalking of mommy also. She'll come at me from the coffee table, but is much more quick to acknowledge I will not bend.
Mostly my cats land in my food plates while running and jumping around the house. Plate on the table? Landed in. Plate on my lap on the couch? Jumped onto the couch, ran through and jumped back off of the couch again.
I swear my little buggers never love me more than they do at dinner time. No matter what I eat, they purr at it and try to look saccharine sweet in the (vain) hope something might fall off my plate by mere accident. Self- serving liars, the lot of them!
My grumpy old man cat can always tell when we have some sort of frozen fudgcicle or our new favorite snack, frozen lemon pops. He comes the second he realizes what we have and leans in to lick the pop with his eyes closed (I think the citrus is too fragrant for him). Hes the same way with cups of any type of liquid. Also, Aislin I'm very sorry to hear about your kitty, I'm sure she had a great life with you.
My kitties looooove macaroni and cheese. I had it for dinner tonight and they went crazy. Lily(the bold one) kept trying to swat some off my plate. Her brother and sister were more patient and they were all rewarded with a few noodles to "kill" when I was done eating. I love the way they shake the noodles to kill them before they eat them. :-)
I am going to buy your book! I love your comics. I printed one out, and stuck it on my work binder, the one where the kitty wont go in the carrier. HILARIOUS! I show it to my customers and tell them about your blog all the time. If you start making t-shirts or mugs or framed comics, I will so get some of that. You need to keep making these, because you are my favorite cartoonist!
My kitties love corn on the cob. They will eat every bit of it then play with the cob. I'm glad I looked at these comments, I had no idea garlic and onions are bad for kitties!! I have to fight them for the roasted garlic.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Q:
Do Scala files need to be released before deleting?
In the code below, if I uncomment the for loop the file no longer gets deleted
val file = "myfile.csv"
//for (line <- Source.fromFile(file).getLines()) { }
new File(file).delete()
If so is there some type of close function that I should be calling?
A:
There is some sort of close that you should be calling:
val file = "myfile.csv"
val source = Source.fromFile(file)
for (line <- source.getLines()) { }
source.close
new File(file).delete
but this is a bit tedious. If you rewrite the for loop as
source.getLines().foreach{ line => }
you can then
class CloseAfter[A <: { def close(): Unit }](a: A) {
def closed[B](f: A => B) = try { f(a) } finally { a.close }
}
implicit def close_things[A <: { def close(): Unit }](a: A) = new CloseAfter(a)
and now your code would become
val file = "myfile.csv"
Source.fromFile(file).closed(_.foreach{ line => })
new File(file).delete
(which would be a benefit if you're doing it many times in your code, or if you already maintain your own library of helpful functions and it would be easy to add the closing implicit just once there so you could use it everywhere).
A:
As others have said, yes, you need to close the Source when you're done with it. Another good solution is to use scala-arm to automagically close the file for you.
import resource._
val file = "myfile.csv"
for {
source <- managed(Source.fromFile(file))
line <- source.getLines()
} {
}
new File(file).delete
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Director Jason Reitman Finds His Feet 'Up In The Air'Director Jason Reitman may be young, but he comes from Hollywood stock — his dad is Ghostbusters creator Ivan Reitman — and he has already directed two well-received feature films, Juno and Thank You For Smoking. His latest is Up in the Air, starring George Clooney. Reitman says it's his first really mature work as a moviemaker.
Jason Reitman began writing Up in the Air six years ago but put it aside to write and direct his first major feature, Thank You For Smoking.
Dale Robinette/Paramount Pictures
hide caption
toggle caption
Dale Robinette/Paramount Pictures
Jason Reitman began writing Up in the Air six years ago but put it aside to write and direct his first major feature, Thank You For Smoking.
Dale Robinette/Paramount Pictures
Watch Clips
'Order Five Meals'
'Club Cards'
'Something Real'
Accusations of nepotism were only to be expected for director Jason Reitman: His father, Ivan Reitman, was the director-producer behind the Ghostbusters films, a boldface Hollywood name for decades.
But Reitman, who directed the 2007 hit Juno and the new George Clooney film Up in the Air, notes that his famous father wasn't in a hurry to do him any favors. Financial backing for the younger Reitman's first feature film, Thank You For Smoking, didn't come from Dad, but from David Sacks, a San Francisco financier and founder of PayPal.
Reitman's latest film is based on the novel by Walter Kirn; Clooney plays Ryan Bingham, a strident cynic who makes a living by firing downsized employees. He lives his entire life alone on the road, Reitman explains, moving from airplane to airplane, hotel to hotel, religiously collecting air miles along the way.
"That's kind of his primary philosophy," says Reitman. "He wants to live without anyone or anything. And that's something that I really locked into."
Reitman created two new characters, a traveling executive played by Vera Farmiga and an arrogant young assistant played by Anna Kendrick, to challenge Bingham's philosophy and way of life.
The addition of two main characters is one of many differences between the film and Kirn's novel, but Reitman says every decision was made with the author's blessing.
"I've always wanted to have a good relationship with my authors," Reitman says. "I've heard the stories of Stanley Kubrick and Stephen King going at each other's throats, so the first time I got hired to write [on Thank You For Smoking], I called Christopher Buckley up and said, 'Hi, this is Jason Reitman, the guy they hired to expletive your book.' And he knew immediately that it was going to be a good relationship."
Reitman (right) says that upon reading Walter Kirn's novel, he felt an immediate connection to the cynical drifter Ryan Bingham (played by George Clooney, left).
Dale Robinette/Paramount Pictures
Reitman began writing the script for Up in the Air six years ago, and he says that the biggest challenge was adapting the script to reflect a society in transition.
"When I started writing this screenplay," says Reitman, "we were in the midst of an economic boom, and by the time I was finished we were in one of the worst recessions on record. And as I approached the shooting of this film, there was no way I could use the original scenes I had written, which approached firing in a very satirical manner."
Searching for ways to inject the film with the realities he was seeing as he scouted locations across the country, he decided that rather than using only actors to portray fired employees, he would use real people who had lost their jobs.
The film's crew placed ads in local papers saying that they were making a documentary about job loss and were looking to interview individuals who had recently been fired. At the end of the interview, Reitman would ask to them to re-create the experience of being fired — on camera.
"When they heard those words, you'd see them change" he says. "One girl just literally broke into hives across her neck. ... They said the kinds of things that I would have never thought to write."
Among those things: what's really worst about getting fired.
"If you'd asked me before I did this movie, 'What's the worst thing about losing your job in this type of economy?' I would've probably said the loss of income," Reitman explains. "But as I talked to these people, that rarely came up. What people said, time and time again, was: 'I don't know what I'm supposed to do.' ... It was really about a lack of purpose. They would say, you know, 'After I finish this interview, I'm going to go get in my car, and I have nowhere to be.' And I can't imagine thinking that every day."
'A More Articulated Film'
Up in the Air marks a kind of coming of age for Reitman, who sees the film as a more mature counterpart to his earlier work.
"Over the six years that I wrote this film, I went from being a single guy in my 20s living in my apartment to a guy who was married, a father, a guy with a mortgage. I grew up. And if you look at the difference between Thank You For Smoking and Up in the Air, there is a difference in pure life experience."
And life experience, Reitman explains, inevitably informs the countless decisions — "mostly binary decisions, yes or no, this one or that one, the red one or the blue one, faster or slower" — that together define the tone of a film and determine whether it moves an audience.
"The only way you become a better director is by watching the result of those decisions, and understanding how they worked — and if they didn't work, how to make them better," Reitman says. "And over the course of the past six years, as I've directed more features and commercials, I've become better at articulating exactly how I want the audience to feel."
Reitman thinks Up in the Air deals with a range of complicated human issues in way that his other films did not.
"It's a more articulated film," he says, "and because of that, I am most proud of it."
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Will You Marry Me Online
ALL LINKS REMOVED, IN COMPLIANCE WITH DMCA.
Will You Marry Me Preview
Why is it that when there is a successful Hollywood movie, at least 10 Bollywood flicks need to follow the treaded territory. From what we have managed to collect about ‘Will You Marry Me’ starring Shreyas Talpade, Rajeev Khandelwal and Muzamil Ibrahim, we could not help but notice the where the inspirations are drawn from.
We have a group of three young men played by the three hunks or not so handsome hunks, who pledge to bachelorhood until Nikhil (Muzamil Ibrahim) decides to tie the knot. The wedding is set to take place on a beach in Dubai (weird?), wait for the rest, before the wedding can take place, the bride is kidnapped by a local don played by Paresh Rawal (Hangover anyone?). Meanwhile, the other two hunks of the film, Rajeev Khandelwal and Shreyas Talpade fall for the same sexy woman, Mugdha Godse and it is not sure who she would finally select as a groom. (Did Mugdha come in to the movie to select a groom?).
Pardon my idiosyncrasies but I cannot help but try and make fun of the nature of stories that Bollywood is producing. However, I would tend to draw a line across before judging the movie prior to its release and I would talk more when it eventually rolls out its reels.
It would be interesting to note how a movie which basically has got all its premises dismally wrong, try to live up to the audience expectation, if at all there is any.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
A magnitude 7.8 earthquake hit Nepal early this morning, striking an area between Kathmandu and the city of Pokhara, with damage extending to India, Bangladesh, and Tibet. At the time of publication, nearly 1,000 people have died and more than 1,700 have been injured as a result of the earthquake, the BBC reports. In an attempt to aid rescue efforts, Google has once again opened up its Person Finder tool — a simple crowd-sourced missing persons database.
Google first launched the application in 2010, following the devastating earthquake in Haiti, and has since deployed the tool several times after natural disasters. Person Finder gathers information from emergency responders and individual users who can enter information for a missing person or someone who has been found. At this time, around 1,300 records have been collected and that number will likely continue to grow throughout the day.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
I love Perl because of its expressiveness. You can write incredible code and it feels just so natural compared to other languages. Here are 8 secret Perl operators that I often use. Only one of them is a real operator (first one). The others are syntactic tricks that make them look like operators but they are not.
The Eskimo greeting operator can be most frequently met in Perl one-liners.
For example, this one-liner uses the Eskimo greeting to emulate wc -l command and prints the number of lines in a file:
perl -lne '}{ print $.' file
Here the Eskimo greets the print function. To understand what happens here, you have to know what the -n command line option does. It causes Perl to assume the following loop around your program:
while (<>) {
...
}
Where ... contains the code specified by the -e command line option. If the code specified is }{ ... then it causes the while loop to be closed with no actions to be done and only the ... part gets executed.
Therefore the one-liner above is equivalent to:
while (<>) {
}
{
print $.
}
This just prints the special variable $. which is the number of input lines processed.
This can be extended further and we can have Eskimo greet code on both sides:
This program prints 3 - the number of digits in $str. How does it do it? Let's deparse the 2nd line:
(my $count = (() = ($str =~ /\d/g)));
What happens here is that the expression ($str =~ /\d/g) gets assigned to the empty list (). Assigning to a list forces the list context. The whole (() = ($str =~ /\d/g)) thing gets evaluated in list context, but then it gets assigned to a scalar which causes it to get evaluated again in scalar context. So what we have is a list assignment in scalar context. The key thing to remember is that a list assignment in scalar context returns the number of elements on the right-hand side of the list assignment. In this example the right-hand side of the list assignment is ($str =~ /\d/g). This matches globally (/g flag) and finds 3 digits in $str. Therefore the result is 3.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Skills in minimally invasive and open surgery show limited transferability to robotic surgery: results from a prospective study.
There is limited evidence on the transferability of conventional laparoscopic and open surgical skills to robotic-assisted surgery. The primary aim of this study was to evaluate the transferability of expertise in conventional laparoscopy and open surgery to robotic-assisted surgery using the da Vinci Skills Simulator (dVSS). Secondary aims included evaluating the influence of individual participants' characteristics. Participants performed four tasks on the dVSS: Peg Board 1 (PB), Pick and Place (PP), Thread the Rings (TR), and Suture Sponge 1 (SS). Participants were classified into three groups (Novice, Intermediate, Experts) according to experience in laparoscopic and open surgery. All tasks were performed twice except for SS. Performance was assessed using the built-in scoring system. 37 medical students and 25 surgeons participated. Experts did not perform significantly better than less experienced participants on the dVSS. Specifically, with regard to laparoscopic experience, total simulator scores were: Novices 68.2 ± 28.8; Intermediates 65.1 ± 31.2; Experts 65.1 ± 30.0; p = 0.611. Regarding open surgical experience, scores were: Novices 68.6 ± 28.7; Intermediates 68.2 ± 30.8; Experts 63.2 ± 30.3; p = 0.305. Although there were some significant differences among groups for single parameters in specific tasks, there was no constant superiority of one group. Laparoscopic and open surgical Novices improved significantly in overall score and time for all three tasks (p < 0.05). Laparoscopic intermediates improved only in PP time (4.64 ± 3.42; p = 0.006), open Intermediates in PB score (11.98 ± 13.01; p = 0.025), and open Experts in PP score (6.69 ± 11.48; p = 0.048). Laparoscopic experts showed no improvement. Participants with gaming experience had better overall scores than non-gamers when comparing all second attempts (Gamer 83.62 ± 7.57; Non-Gamer 76.31 ± 12.78; p = 0.008) as well as first and second attempts together (Gamer 72.08 ± 8.86; Non-Gamer 65.45 ± 11.68; p = 0.039). Musical and sports experience showed no correlation with robotic performance. Robotic-assisted surgery requires skills distinct from conventional laparoscopy or open surgery. Basic robotic skills training prior to patient contact should be required.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
These are the text only pages from A Story To Share.Com, true stories of heartache and love. If you have been referred here by a search engine then click at the very bottom of the page to read hundreds of true stories of heartache and love.
Untitled
I really don't know where to begin,life sometimes is so hard and you wonder why your here and what your purpose really is.You know how people say everything happens for a reason,i really use to believe that until now. Back in Aug 2006 i met this guy,he seemed great at first,he loved me and adored me but he turned out to be a total jerk,so i told him i couldn't see him anymore,then in Nov i met this other guy,i thought that it was going somewhere but it turned out that he just wanted someone to 'fool' around with,so i told him that if he didn't want a relationship with me it was over,so that ended. I started going on line ,and joined many dating sites,i met a few guys but nothing ever did work out. I was just about ready to give up,until i met this guy in March of 2007,i thought nothing of him at first,just consider him a friend,until he asked if he could meet me,so i said yes,then we stared going out,i feel totally and completely in love with him,and he said he felt the same,we spent so much time together,i never wanted to be apart from him. One day just after i left his house,i came home,got on line and started talking to him,i remember the exact words i said " do you love me tonight?" and he said " i will love you always" but then it all changed,he said that he didn't think he could deal with a relationship right now because there was just so much going on in his family,i thought that he was using it as an excuse,but he said he loved me and he wanted to be with me,he just needed some time to be alone,so i gave him what he wanted,eventho it was tearing me apart.I cried for days,i couldn't eat,sleep,didn't even want to be alive anymore.He said that we would still be friends,but how can you really be friends with someone who you are so inlove with,and everytime you see the person you'll be wondering what would have happened if you too were together now..You can never really explain the feeling you get when you lose someone that close to you,you feel helpless,short of breath like someone punched you in the stomach,an unbelievable amount of sadness and rage because you want to be with them,you feel as if your whole world as just caved in around you,you think that you will never get over what your feeling ,and that you will never be able to move on,but eventually you will,you'll find someone new,maybe someone better,or maybe if your lucky he will realize that he misses you and come back..but you know what the sad part about this story is??? I'm still waiting !!!
| null |
minipile
|
NaturalLanguage
|
mit
| null |
564 P.2d 443 (1977)
Cynthia M. KAU, Plaintiff-Appellee,
v.
STATE FARM MUTUAL AUTOMOBILE INSURANCE COMPANY, an Illinois Corporation, Defendant-Appellant.
No. 5829.
Supreme Court of Hawaii.
May 19, 1977.
James Kawashima, Honolulu, for defendant-appellant.
Steven H. Levinson, Honolulu, for plaintiff-appellee.
Before RICHARDSON, C.J., OGATA, MENOR and KIDWELL, JJ., and Circuit Judge LUM in place of KOBAYASHI, J., disqualified.
PER CURIAM.
This is an appeal from an order granting the plaintiff's motion for partial summary judgment.
Plaintiff-appellee Cynthia M. Kau was involved in a motor vehicle accident in the City and County of Honolulu on January 28, 1973. She was then residing with her parents, Harry K.F. Kau and Leimomi C. Kau. She was driving a 1966 Volkswagen, owned by and registered in the name of her mother, Leimomi C. Kau. The driver of the other vehicle was one Roger A. Sundby, whose negligence was the proximate cause of the collision and the resulting injuries to Miss Kau. Neither he nor the vehicle he was operating was insured.
At the time of the accident, Harry K.F. Kau owned a 1971 Dodge Dart automobile which was registered in his name. He had in effect at the time an insurance policy issued to him by defendant-appellant State Farm Mutual Automobile Insurance Company. The declarations page of the policy listed Mr. Kau as the "named insured" and the Dodge automobile as a "described motor vehicle." The insurance policy did not list the Volkswagen, which was involved in the collision, as a "described motor vehicle."
It is conceded by State Farm that Miss Kau was an "insured," with respect to uninsured *444 motorist coverage, under the terms of her father's insurance policy. It denies liability to Miss Kau, however, on the strength of the following exclusionary clause in the policy:
"This [uninsured motorist] insurance does not apply: ... (b) To bodily injury to an insured while occupying ... a land motor vehicle owned by the named insured or any resident of the same household, if such vehicle is not an owned motor vehicle ..."
An "owned motor vehicle" is defined in the policy as "the motor vehicle or trailer described in the declarations, and includes a temporary substitute automobile, a newly acquired automobile...." The Volkswagen automobile did not come within this definition.
The basic issue for determination, therefore, is whether the foregoing exclusionary clause is violative of the provisions of the uninsured motorist statute (HRS § 431-448), which provides as follows:
"No automobile liability or motor vehicle liability policy insuring against loss resulting from liability imposed by law for bodily injury or death suffered by any person arising out of the ownership, maintenance, or use of a motor vehicle, shall be [issued], with respect to any motor vehicle registered ... in this State, unless coverage is provided therein or supplemental thereto, in limits for bodily injury or death set forth in section 287-7, ... for the protection of persons insured thereunder who are legally entitled to recover damages from owners or operators of uninsured motor vehicles because of bodily injury, sickness, or disease, including death, resulting therefrom... ."
The statute must be liberally construed to accomplish its remedial purposes and to give effect to the legislative intent. Palisbo v. Hawaiian Ins. & Guaranty Co., 57 Haw. 10, 547 P.2d 1350 (1976). A literal reading of the statute leaves no room for the exclusion which appellant attempted to write into its policy. This is consistent with the intent evidenced by the legislative history:
"An insurance company offering uninsured motorist protection engages to pay to the insured, spouse or minor children of either, resident in the named insured's household, sums not to exceed the stated limits, for any uncollectible valid claim or unsatisfied judgment for damages resulting from bodily injury or death, resulting from the ownership, maintenance or use of an automobile. The claim becomes payable when the innocent victim shows that his claim is valid, that is, that there is legal liability on the person alleged to be responsible and that claim cannot be collected because of the financial irresponsibility of that person or because of the inability to identify the person or persons responsible." Stand.Com.Rep. No. 194, 1965 House Journal, at 582.
The effect of the exclusionary clause is to deny Miss Kau the full protection of the statute. Stephens v. State Farm Mutual Automobile Ins. Co., 508 F.2d 1363 (5th Cir.1975); State Farm Automobile Ins. Co. v. Reaves, 292 Ala. 218, 292 So.2d 95 (1974); Bell v. State Farm Mutual Automobile Ins. Co., 207 S.E.2d 147 (W. Va. 1974); Nygaard v. State Farm Mutual Automobile Ins. Co., 301 Minn. 10, 221 N.W.2d 151 (1974); cf. Walton v. State Farm Auto. Ins., 55 Haw. 326, 518 P.2d 1399 (1974). Accordingly, we hold that the clause limiting the insurance company's liability is repugnant to the statute and is therefore void. HRS § 431-448.
Affirmed.[1]
NOTES
[1] Had the plaintiff-appellee been a passenger in an uninsured or underinsured motor vehicle owned by a party not a member of the Kau household, she would have been covered by her father's uninsured motorist policy. See Palisbo v. Hawaiian Ins. and Guaranty Co., supra. Or had she been driving an automobile not owned by a member of the Kau household, she would still have been covered by her father's policy. See State Farm Automobile Ins. Co. v. Reaves, supra. It would be anomalous, and certainly inconsistent with the legislative intent, to hold that in those situations the statute would allow recovery but in the present situation it would not.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Current weather
Letters to the Editor
This letter comes to you from the newly established and recently dedicated and blessed St. Yakov Center for Orthodox Christian Learning in Soldotna.
This is a God-given dream which began to take shape for Alaska and the Kenai Peninsula especially, when a small house on 1.44 acres of wooded land became available in Soldotna. It will serve as a resource center and will be available to all who wish to become better acquainted with the Orthodox faith, as well as those Orthodox Christians who would like to come to a better understanding of the faith of their forefathers.
Since your office was notified regarding the special open house when an explanation for its purpose was explained, we wish you had utilized our available resources on church history prior to publishing the article, "300 years -- and counting, Russian Old Believers hang on in Oregon," by Andrew Kramer in Friday's Peninsula Clarion. Mr. Kramer, obviously, is unclear about the main issues which transpired and caused a group in Russia to break away from the Holy Catholic and Apostolic Church and to form the sect: the Old Believers.
This is apparent when Mr. Kramer says that "the schism concerned such seemingly trivial issues as how many fingers should be extended while making the sign of the cross: The Old Believers use two, modern Russian Orthodox three."
First of all, "the Old Believers" are in reality the "modern Russian Orthodox," being in existence for only, according to the author, "300 years." The One, Holy Catholic and Apostolic Orthodox Church from which this group broke away to form a sect had its birth from Pentecost and continues to the present. Secondly, there is a deep meaning for Orthodox Christians when we make the sign of the Cross. Orthodox Christians pray in the name of the Triune God, (Holy Trinity). When we make the sign of the Cross we say: "In the name of the Father and of the Son and of the Holy Spirit." The two index fingers and the thumb of the right hand are joined together at the tips to show that we believe in God the Father Who loves us, God the Son Who saves us, God the Holy Spirit Who lives in us. The three fingers are joined together to show that we believe not in three gods but in one.
The remaining fingers stand for the two natures of God. These two fingers are brought down into the palm of the hand to show that Jesus came down from heaven for our salvation. Orthodox Christians, when making the sign of the Cross are praying with our whole body; with our whole person, body, mind and heart. This act reminds us of the price Jesus our Savior paid to save us. When we touch our forehead, we are saying "In the name of the Father," that we love Him, our Lord God, with all of our mind, heart, soul and strength. When we touch our chest, we reconfirm our love to God, the Son, with heart and soul. When we touch our shoulders, in the name of the Holy Spirit, we are telling Him that we love Him with all of our strength.
"God so loved the world that He gave His one and only Son, that whoever believes in Him shall not perish but have everlasting life." (John 3:16)
Today, more than a thousand years later, the Orthodox Apostolic Faith of the inspired New Testament record, remains intact and in full communion.
We who live in Alaska are the recipients of those who have come before us: Saint Herman, Saint Innocent, Saint Yuvenaly, Saint Peter the Aleut and Saint Yakov -- selfless servants of God and of His Church. We are on Holy Ground.
Sincerely, a servant in Christ,
Varvara (Barbara Sediakina-Larson)
Soldotna
Puppies' tragic deaths point to need for responsible humans
I have lived on the Kenai Peninsula since 1983 during which time I have made precious friendships and met some very caring, responsible people. Unfortunately, I have also observed and read about the opposite side of the human condition, in varying degrees and situations.
I was infuriated and horrified to read of the cruelty case of puppies recently thrown into an Anchor Point Dumpster on a sub-zero night, all but one suffering a painful and unnecessary death. The one lucky female "Holly Beary" nearly died as well before being saved by a kind teen-ager who heard her cries and went for help.
My first reaction to "whoever you are" was to tell you that you are despicable! How dare you treat lives who have as much right to live and be cared for as you do this way! My second thought is to realize that you are in dire need of help for this and your apparent other social and behavioral problems that go hand-in-hand with this sort of thing.
I can find compassion for you only in the hope that you will realize what you have done and vow to never ever harm an innocent creature again. Take a moment to stand alone outdoors on a clear winter night in our magnificent wilderness and think about the misery and suffering you unnecessarily caused these innocent puppies, ask for forgiveness, and most importantly get yourself some help!
To the families who inquired about "Holly" and to the family who adopted her as soon as they were allowed to, it's people like you who give our world hope and make it a better place. To anyone who knows the individual(s) responsible for this heartless act, it is your moral obligation to notify the Alaska State Troopers so that this sort of thing is not allowed to happen again. Our world is different now, and each and every one of us needs to work one day at a time to make our world both safe and loving "for all creatures." I am confident that the majority of the residents on this peninsula share my opinion.
I appreciate the vast coverage that the Peninsula Clarion gave to this situation, and its continued work toward educating the community as to the correct and humane treatment of animals. To the offender, there were so many other solutions to your problem of not wanting these puppies. They would have been better off having been taken to the local animal shelter where they would have at least been warm and fed and had a chance or an animal rescue group been contacted.
And what about these puppies' mother? I think we are all worried about her well-being, too. Please consider bringing her to a spay clinic so that she does not suffer this trauma again.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Feds hit PFG's Wasendorf with 31 charges
Russell Wasendort, Sr., founder and former CEO of PFG, is charged with fraudulently overstating the value of his firm.
Federal prosecutors in Iowa have charged Russell Wasendorf, Sr., founder and former CEO of Peregrine Financial Group, with 31 counts of fraudulently overstating the financial soundness of his commodities brokerage.
Wasendorf, who police say attempted suicide near his company's Iowa headquarters in July, was indicted Monday for allegedly submitting fraudulent financial statements to the U.S. Commodity Futures Trading Commission. There were 31 monthly statements, spanning from October 2010 to May 2012, according to documents submitted by federal prosecutors at the U.S. District Court for the Northern District of Iowa.
The documents also said Wasendorf's financial statements overstated the value of PFG's customer funds "by at least tens of millions of dollars."
Wasendorf, 64, was found in his parked car near the firm's Cedar Falls office by a sheriff's deputy in early July. Officials say the deputy was responding to a 911 call and found the engine running with a hose going into the car. He found a suicide note, but Wasendorf was still alive.
Wasendorf's fraud might have actually exceeded $200 million, according to a criminal complaint filed by the U.S. Attorney's Office on July 13, when he was arrested. In that complaint, FBI agents from Omaha, Neb., used his own suicide note against him.
"I have committed fraud," read the note, which was written to his wife, according to the criminal complaint. "Through a scheme of using false bank statements I have been able to embezzle millions of dollars from customer accounts at Peregrine Financial Group, Inc. The forgeries started nearly twenty years ago and have gone undetected until now."
In the note, Wasendorf allegedly bragged about his forgery skills.
His son, Russell Wasendorf, Jr., is the chief operating officer of PFG. He filed to liquidate the firm last month.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Tuesday, November 10, 2015
I learned a few things with the last carousel I had built. I had done a few smart and few not so smart things. The best thing I had done was cut out multiple disks for future carousels when I had my jig set up. When I went to make the next one, all I had to do was reach on the shelf and half my cutting was already done. I had also swapped out the camel from the plans in John R. Nelson Jr's amazing "American Folk Toys" and had replaced him (her?) with a zebra. That was the transition to saying "Hey, I can put any sorts of critters on this that I want!"
I had made a series of rookie mistake in cutting out the giraffe and in how I glued the animals in place. I simply didn't allow for how the grain ran in the wood for the giraffe. Specifically in its legs. If the grain had run vertically the legs would have been much stronger, however it ran horizontally which made them far too brittle. I know... Woodworking 101, Day 1. Now, in fairness to me, that's the way the grain is shown on the plans and maybe that makes it less likely to have his snout break off but because I don't run a pole through the animals bodies to make it look like a Merry-Go-Round animal, it means the legs are pretty easy to snap along the grain. Which is exactly what happened... twice.
So I briefly discussed "putting him down" and replacing him with another animal since no way would a giraffe make it the wild with one, let alone two, broken legs. However, the owner's mom made it clear that the patient had to live. I try to keep my toys as close to 100% wood as I can so I went with very carefully drilling 1/8" holes through the legs and then inserting dowels to complete the surgery. It was touch and go there but the patient never said a word and the procedure was a success.
Now for the second mistake. Initially several of the animals had come off of the spinning base and I think it was because I had used spray acrylic on the base BEFORE I glued the animals in place. (As a certain Crawfish reminded me.. it is called wood glue for a reason.) Okay. So I left the surgical implants in a bit long so that they could become pegs to insert in the base. Then I made a little template out of some scrap clementine box wood and drilled 1/8" holes so I could line up the pegs with the holes.
I made sure that I wasn't going to drill too deeply into the base by using a flag/tag of masking tape that is just a little bit longer than the pegs.
Then I drilled one hole in the base and pegged it in place so that the next hole would be the correct distance. This worked surprisingly well... almost too well... if that was a possibility. Which it isn't.
Last step was to trim the pegs up a bit so they would fit in nice and smooth. I also scrapped the acrylic off where the feet and pegs will be glued down to be sure there would be good adhesion. All fixed and truly "better than ever."
Ultimately, this ended up improving the toy for me. On the next one I built, I pegged all the animals to the base using the same method and it was very easy and resulted in a stronger toy.
Necessity is the mother of invention but I guess failure is the father of improvement.
Thursday, September 17, 2015
As I've said on numerous occasions...I'm a sucker for $1 Store wooden toy kits, especially airplanes. It's fun to try and turn them into something that that is immediately recognizable as a particular plane and give them some fun historical detailing.
While you come to expect the sub $5 arc welder, 20' band saw or 3,000 ton industrial press from Harbor Freight, you might be surprised to know that they also sell little wooden airplane kits for under $2. The line is called "Legends of the Air." They are made in Taiwan and the pieces are punched from 1/8"sheets of plywood not balsa wood and they are not puzzles as the HF site says.
There are six kits in the line. Four are WW1 aircraft. Two of those are Allied - a SPAD and a Nieuport, and two are German - a Fokker Triplane and an Albatros. The other two kits in the series are interwar biplanes - the Bristol Bulldog and this model, the Curtiss Goshawk.
So this is actually the Curtiss F11C Goshawk that was made for the US Navy in the 1930s. The Navy only had a few dozen of them in service. There was another more widely produced version of the actual aircraft and it had retractable landing gear, not the fixed "spatted" gear on this model. A little bit of an odd choice as a "Legend of the Air" but still reasonably cool.
So I started on this model over a year ago. I had finished the Fokker Triplane from this series and was ready to tackle this one. Over the course of a weekend little one and I painted parts and glued parts up following the "directions" included. The instructions consist of an exploded view of the numbered parts. It is an exercise in patience and clairvoyance to put them together.
I covered a bunch of this when I wrote up the Fokker build but these kits really aren't for unsupervised construction by the "Age 6+" crowd. Besides the issues with the instructions, the wood is fairly stiff and you are going to need to use rubber bands and or clamps to hold the pieces in place while it is gluing up. I even boiled some pieces to make them bendable. Speaking of glue... not for one minute did I think about using the white glue that came with the kit. I went right to my wood glue.
So after some initial work, it all went into a clementine box with the intention of being pulled out the next weekend for completion. Well, something, or a lot of things, must have come up. Quite a few weekends went by and the box sort of bounced around in different places throughout the house for a year before making its way to my work bench a couple of weeks ago.
Only one piece was missing; a vertical strut. I was able to trace out a pattern on a scrap piece of the 1/8" plywood all the pieces were punched out of. That trick is something that I learned to do when I built my first balsa wood and tissue airplane from way back in the day. (A Guillow's Hawker Hurricane, thank you very much.) You certainly can't do that with plastic models if you break or lose a piece.
In my book a toy airplane has to have a spinning propeller. Unfortunately, these kits are not designed with that in mind but where there's a will, there's a way. This one took a little figuring to get to a way. Basically I assembled the cowling and then drilled a 3/16" hole through the center. I assembled the prop but drilled a shallow 1/8" hole in the back of the spacer so I could put a piece of 1/8" dowel to use as the shaft. I also made a small nut with a 1/8" hole in it to place at the end of the opposite end of the shaft.
I then used a forstner bit around the back of the cowling to make a hole deep and wide enough that I could put a disk on the end of the shaft that would allow the shaft to spin freely once the assembled engine was glued to the fuselage.
Hole deep enough to allow
nut to spin freely.
Wood nut cut from scrap
and glued to shaft.
The wing roots needed to be trimmed up a bit to fit into their slots on the fuselage. Again, this is one of those things that will be a little tough on the 11 year olds who work on the kit but dad can lend a hand. Just remember the woodworking truism... You can always remove more wood but you can't add any back on. Take off a little at a time and keep checking the fit.
I paint as much as I can before I assemble things because sometimes it is awfully hard to get the paint in there with parts in the way. I made a mistake in initially painting the struts black so I repainted them silver and then took my time and glued them up carefully. Take your time. No rush. Make sure everything lines up. With the outside struts in place, I fit the small ones on the fuselage. They needed to be trimmed up to fit in their slots the same way the wings did.
US planes from this era are often called "Yellow Wings" because... well... THEY HAD YELLOW WINGS! They also tended to have red and white tail stripes and brightly colored cowlings and markings. It's a very classy look and a big part of the reason for this was to make them highly visible for search and rescue efforts. It was also a bit of a bold confident statement but the idea was never to go into combat like this. I went with the blue stripes and cowling on this so that it would look like a Goshawk that was assigned to the USS Saratoga. Blue painter's tape gave me great lines for what I needed. After I glued the top wing in place and let it dry, I put the single rear struts in place on each side.
I probably glued the landing gear a bit higher into the fuselage than the plans called for but it seemed to match the scale better that the picture on the box. I also think it will make the landing gear less fragile. I had temporary shims wedged in while the gear dried. I made sure the wheels were level and the angle was the same on each side. After they dried, I added the external fuel tank... which had two different size teardrop sides... weird.
Last thing was I printed out some US 1930's roundels with a color printer on regular paper. I carefully cut out and glued the roundels in place and then sprayed the whole toy with several coats of clear gloss acrylic. (We stopped using those roundels early in WW2 because the red dots could be confused in the heat of battle with the markings on Japanese aircraft.)
There you go. I like how it came out and it makes me want to make more "Yellow Wings" era themed toys.
Again... these Legends of the Air kits have poor instructions and some questionable fits but are really fun to turn into a neat looking little toy. Now to make a toy aircraft carrier for it to land on...
Sunday, September 6, 2015
Somewhere inside a box full of other boxes full of photos is a picture of my younger brother and I on a trip from way back in the day to Luray Caverns. I remember being a grumpy pill on the trip because I had to wear shorts. (In retrospect, I probably didn't have too much to complain about in my childhood.) Even though I had to wear shorts, I still had fond memories of the trip and always wanted to go back for another visit.
Anyway, with summer winding down I decided that little one and I could do a father/daughter day trip and revisit the amazing caverns. In looking up the cost and directions, I saw that your ticket also gets you admission to two museums on the premises, namely The Luray Valley Museum and a collection of antique vehicles in The Car and Carriage Caravan. Okay, sounded good...but what's this? An onsite toy collection to visit for free - Toy Town Junction! Not a minute to lose - To the Toy Making Dad Mobile!
Okay - We drove out and took the tour of the caverns. In a word - Spectacular. I'd share more pictures but this isn't a travel site, it is a toy making site (well, at least theoretically.) I do want to share a thought though, but I'll wait to the end to hop on my soap box.
So after a mile and a half of caverns and a quick stop at the gift shop, it was time for Toy Town Junction! The building that houses Town Town is right next to the Luray Caverns entrance and it has its own cafe and gift shop attached to the display area. Don't expect some giant warehouse though. It is more a very large room - several hundred square feet and hundreds (mmm maybe thousands) of toys displayed in themed areas around the walls with the center taken up by large working train sets.
It is a very eclectic collection and it all belongs to Richard Worden, a retired Methodist minister from Kentucky. There is a lot to see and you'd be hard pressed to not spot at least one toy from your childhood if not dozens. The collection covers a wide spread of American history. Unfortunately, most of the toys are not labeled and there isn't a guide or description for them. There is the large train collection, a lot of Playmobil and Playskool Little People as well as dolls, but seeing as I am basically still a 12 year old boy... my attention was drawn to to the airplanes and tanks.
So this guy is hanging from the ceiling and a couple of things stood out - It's metal and my guess is that it is pre-war or very early WW2 since the US Army Air Corps/Air Force roundels on the plane are the ones where there is a red dot in the center of the star. (We stopped using the red dot early in WW2 because it was too easy to confuse with the markings on Japanese aircraft.) I found pictures of similar toys on the web when I got home and these were made by Marx Toys. They were windup toys that would roll across the floor and many had spots for sparks to come out where the machine guns were on the aircraft.
One bummer for me though is that while this plane is super cool... it really isn't intended to evoke a particular aircraft. It just has a sleek bomber look, but nothing the US was flying at the time really looked like this. There were some twin tailed typed out there but not like this. It still has an amazing 30's vibe to it though.
This plane sort of has the opposite issue for me. You can tell it was post war because of the markings (and metal was so precious during the war, they weren't using it to make toys.) These were made by a company called Hubley in the 60's and it looks like they made gazillions of them is all sorts of different forms and colors. Here's the deal though - they sold this as a "P-47." It does have the general shape of the immortal Thunderbolt/Jug but it has folding wings. Folding wings are for Navy aircraft so that they will fit on the elevators and take up less room below deck on an aircraft carrier. I know... relax! Lighten up Francis, It's a toy! I still think it is neat and would love to have one. I just think that's it a little odd to go through the trouble of matching the general shape of one aircraft and then have it do something else. Couldn't they have made it a Corsair? Just saying...
So, to wrap up the airplane part for me is this gem. WOW. It is a toy, not a detailed model and it is clearly made to look like a massive flying boat from the 1920's called the Dornier Do X. At the time the plane was second in size but first in weight in the world. Only three were ever built but it was really out there in the public conscious. The toy is really big as well, at least 18" or 24" long and made from wood. I wonder if it was a one off toy made by some 1930's toy making dad?
Source -Bundesarchiv, Bild 102-12963CC-BY-SA 3.0
I really like that you can tell at a glance that this is the plane it is supposed to be. However there wasn't someone counting rivets to make it super accurate and probably more expensive and fragile for no added playability. It really struck me that you can capture the general sense of the subject without having to make a "model." It is something I struggle with at times while making historically themed toys.
This is a Marx windup tin tank. As it runs along the floor, sparks come flying out from the main gun and the soldier pops out of the back and then goes back into the hull. Super cool and super classy. One thing I noticed about this toy and some of the other similar Marx toys is that the pattern on the side representing the tracks is made to look the same if it is used on either the right or left hand side of the toy. It saves having to make different left and right hand pieces. Pretty clever.
Marx also made a ton of these "Turn Over Tanks" (mmmmm turnovers....) They are wind up and they roll across the floor and then a bar extends from beneath the tank and flips it on its back. The shape of the tank and its momentum cause it to do a full flip.It then goes a few inches and flips again. There was one version that had a little Superman instead of the bar flip out from under the tank so it looked like Superman was actually flipping the tank.
Not sure what the tanks are doing at that circus. Maybe they are guarding the blue port-a-potties in the background?
I also spotted these tanks in with the train sets. Well, one tank, one armored car, a truck and what I think is a truck with a searchlight mounted on it. The train is the real toy and the vehicles are just accessories but it is interesting that the tank is sort of M4 Sherman in shape but a bit generic. The armored car looks to be closer to the sorts of armored cars that the British used during WW2, some of which were actually built by the US.
I also enjoyed the fantastic amazing cool toys... that would probably be illegal to sell now.
Here is "The Boys Favorite Tool Chest." Now besides that fact the folks over at "Overly Sensitive Parenting Quarterly" would flip their lids at the lack of "inclusiveness" in the name, the box is full of real tools! Sharp metal stuff... that is all a little rusty now. Throw in a box of strike anywhere matches and you might have the ultimate toy for young boys (in their minds at least.)
Erector sets were the Legos of their day. Make anything you want and make it out of metal. I remember my brothers making a rubber band powered catapult that came down with such force that I'm sure it could have been used as a deli meat slicer. Anyway, what I like about this kit is that you can launch a rocket. From the cover art I thought the rocket was metal and even I was like... maybe not such a great idea. Upon further review of other internet resources, the launcher was metal. The rocket was plastic.
I had heard about this toy but never seen one. This is Marx's famous "Shop King." It is an all in one shop toy for future toy making moms and dads. You use Styrofoam as the raw material and the toy has a lathe, jig saw, table saw, sabre saw, grinder, sander, polisher, borer, and router built in. GIMME, GIMME, GIMME!!! (The blades are plastic.)
So all in all a fun little side stop on our visit to the caverns. Little one was tired but pretty patient with me and I'd say we were though the collection in maybe 20 or 30 minutes. I don't honestly know that it would warrant a cross country trip to go and just see the collection, but it is definitely fun. If you are ever in the area, its worth stopping by for sure. Remember, if you don't have time for the caverns, Toy Town Junction is free .There is a lot of love and lot of fun on display. I enjoyed soaking some of it up.
And now my two cents - Thank God the caverns were discovered 140 years ago.
If they were discovered now, I can only assume they would be sealed off so that the public couldn't go into them. They would have to be preserved in their untouched state. While I appreciate that sentiment, I can't get past the fact that around 500,000 people a year visit the caverns and get to enjoy it in ways that no website or magazine spread could ever hope to. The picture at left doesn't begin to give justice to "Dream Lake." Shallow still water creates a perfect mirror image of what is above and it is the closest I've ever felt to looking at an alien landscape. Amazing. How many people have been inspired by the site over the years? How many future geologists and scientists got started there? If you ask me, the trade-off of lighting the place and creating the walkways was worth it.
Friday, July 3, 2015
I really like toys that have a "trick" to them. Something simple that makes it work but almost seems magical when you watch it in action. Tumble Down the Ladder toys really fit that bill for me.
If you are not familiar with them, it is basically a 90 degree vertical ladder with evenly spaced rungs. A peg or character with specially cut holes and grooves on it is placed on the top rung and then allowed to fall down the ladder one rung at a time.
It is a really pleasing motion and it is fun to watch the peg fall back and forth as it tumbles down the ladder and never falls off until it hits the bottom. The trick is that the peg (or monkey, or clown, or whatever) can't fall to the next rung until it is perpendicular and can't fall out of line once it is lined up. It is a pretty ingenious idea.
Anyway, a few months ago a friend told me a story about how one of her friends had given her and her daughters a wooden tumble down the ladder toy about 35 years ago. The toy had gotten plenty of use over the years and was now a little rough for wear. In short, it was broken. She also mentioned that her grandson has tried to play with it when he visits, but because of missing and damaged rungs, it simply doesn't work.
Since there is nothing sadder than a broken toy except for a broken toy that a kid is trying to play with and can't... I offered to take a look and see if I could fix it.
Somehow I failed to measure the height of the pegs, but my guess is that they were about 3" tall. Long enough so that when they fall to the next rung, they will just clear the rung above before they start to tumble to the next rung after that.The pivot holes are 7/16" in diameter.
So first impression when I started looking over the toy was that it was really solid and really well made. One rung was missing and two were damaged. The rungs are plywood but everything else is solid wood. I wish I could tell you what it was made from, but that would just be a wild guess.
I noticed a bit of a "ghost" on the bottom of the toy. It looks like it may have been the name of the original maker or some sort of brand name. It appears to be adhesive residue. Needless to say, I am curious as to what this says or means. It is hard to make out but if you know what it is, or have a guess, drop me a line.
JOAR? JOAN?
JEOC? JEOG?
As I said, the top rung was missing and needed to be replaced. I noticed another one was broken enough that it would prevent the peg from falling properly and that one other was starting to break. I figured it made sense to just replace all three.
Broken
Soon to be broken
There were a couple of challenges with replacing the rungs. First off the holes (mortises) in the uprights had to be cleaned out of glue and wood without disassembling/breaking the rungs that were fine. The toy was still very solid and I didn't want to break it apart and replace all the rungs. The next issue is that once the mortises were clean, the new rungs would have to be short enough to be slipped into the ladder without breaking anything but long enough that they would still sit firmly in their holes. Thirdly (that may be the first time I ever typed that word... it looks weird) there is only about 2 1/2" of space to work in so it is hard to get at to clean everything out since the other vertical piece is in the way.
No worries. The secret ended up just being patient and remembering the woodworking truism that you can always remove more material but you can't ever add it back on. I got to live the dream sitting at my workbench, listening to the Washington Nationals' game on the radio and drinking a Mexican Coke. Brothers and sisters... it don't get no better than that.
It was great to use my workbench as... gasp... a workbench! Not just a horizontal surface, but a bench designed to help facilitate actual work. It has an end vice and I used some soft dollar store shelf liner to cushion the toy. I mainly used a rotary tool with a very small bit it clean out the holes a little at a time. An Xacto knife and some rather evil looking dental type tools also came in handy.
I cut a little mini rung to check fit. Here is the basic process for us visual learners...
Wood and glue
All clean
Test fit
I did that for all six of the holes. After I was finished I went to test fit an 1/8" plywood rung I made out of the onion of the frugal woodworker world... Clementine Box Wood! As I was test fitting it, I wasn't happy with how sturdy it seemed. More specifically, I wasn't happy with how flimsy it seemed. It didn't make sense to spend the time to fix the toy to only have it break again, so I acquired some 1/8" maple and cut it to size.
I had to experiment quite a bit to get a close match on the finish for the wood. I seem to have the worst luck trying to match finishes. The way it looks on the can is NEVER the way it comes out for me. Anyway, the rungs were eventually finished with Danish Oil and a touch up pen. The match wasn't perfect but it was close enough and I was sorta, kinda, happy about it.
Last step was putting glue in the mortises and slipping in the new rungs. They were a tight fit but all went in without too much trouble. One of the secrets of getting this sort of toy to work is to be sure that the rungs are parallel and equally spaced. I made a little spacer out of.. .Clementine Box Wood! Note the exotic wooden spring clamps I was able to employ. Right tool for the right job.
After it dried all I had to do was test it.
And I tested it a lot :)
Here is the completed toy in action -
It worked fine and hopefully it will hang in there and last for my friend and her grand kids for another 35 years.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Search form
Researchers find evidence for the origin of cosmic rays
Researchers find evidence for the origin of cosmic rays
Studies of supernova remnant RCW 86 have revealed the origin of cosmic rays. (Image courtesy of ESO/E. Helder and NASA/Chandra.)
An international team of researchers has discovered strong evidence that extremely energetic cosmic rays are born in supernova remnants.
"Cosmic rays constantly bombard the earth's atmosphere but, until now, we didn't have proof of where in our galaxy they originated," said co-author Stefan Funk of the Kavli Institute for Particle Astrophysics and Cosmology at SLAC National Accelerator Laboratory. "That's because cosmic rays are almost entirely made of protons, which as charged particles are bent by magnetic forces as they travel to Earth. So we can't just trace a straight line back to know where they originated, like we can with light."
Instead, the researchers traced the sources of cosmic rays by indirect means.
In a paper published last week in Science Express, the researchers describe measurements made with the European Southern Observatory's Very Large Telescope and NASA's Chandra X-ray Observatory. These measurements, of a star that exploded in the year A.D. 185, compare the temperature of the gas immediately behind the shockwave created by the stellar explosion with the speed of the shockwave itself. If the energy of the stellar explosion was converted solely into heat and motion, these two measurements should have been directly related by a very well-known and well-tested equation. Yet when the researchers plugged their measurements into the equation, it didn't balance. Something else was being energized by the explosion.
"When a star explodes in what we call a supernova, a large part of the explosion energy is used for accelerating some particles up to extremely high energies," said co-author Eveline Helder of the Astronomical Institute Utrecht in the Netherlands. "The energy that is used for particle acceleration is at the expense of heating the gas, which is therefore much colder than theory predicts."
The researchers concluded that the missing energy goes into accelerating protons to nearly the speed of light-creating the cosmic rays that continually pummel our solar system, creating flashes of light behind the eyelids of astronauts and causing glitches in electronic components on Earth.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Q:
Run Chromium inside container: libGl error
I'm trying to run Chromium inside docker container.
Here's the output I get:
Created new window in existing browser session.
libGL error: failed to open drm device: No such file or directory
libGL error: failed to load driver: vmwgfx
I've searched a lot on the internet about this issue but cannot find anything clear. Do you have any suggestions on how can I solve this problem ?
Thank you in advance.
A:
As Mark Wragg wrote in a comment; this guide from wiki.ros.org is pretty good
It seems like you're missing the vmwgfx GL drivers, at mesa3d.org you can see how to install them.
Myself ran into this issue after all drivers was installed, but then I found out that I also need to mount the graphic card to the docker container. For Intel cards that's made with
docker run --device=/dev/dri:/dev/dri ...
For other graphic cards I recommend the guide from wiki.ros.org
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Updated 22:45
DESPITE FACING TWO public offence charges, Tony Rochford has deemed his protest against Irish Water yesterday a success.
The Trim resident, who became well-known last year for holding a hunger strike outside the Dáil, was arrested for obstructing traffic with his vehicle.
But achieved his goal of delaying the installation of a water meter at his house.
It is understood to be the first arrest associated with growing protests against the Irish Water across the country.
Authorities had previously warned protesters that their actions could lead to arrests.
Rochford had parked his blue Isuzu crew-cab jeep across a road in the Steeple Manor estate. According to gardaí, he was blocking access for some residents and obstructing Irish Water staff as they installed meters.
However, Rochford confirmed that only one resident required access during the time and her car was allowed through immediately.
“I’m 100% happy my meter is still not in,” he told TheJournal.ie today.
Videos of the arrest have emerged, showing Rochford discussing the problems the homeowners in the estate have had with their heating and water systems with gardaí.
He says he has tried to have the problems fixed through contacting the local authorities, TDs and the Department of the Environment.
He blames the lack of regulation in the plumbing sector for the fault and believes he should not be charged for water.
Gardaí confirmed the charges were made under the Criminal Justice (Public Order Act) 1994. Rochford was charged and bailed. He is due before Trim District Court on 5 June.
Rochford believes he will be fined, refuse to pay and be jailed.
He is also not optimistic about keeping his home water meter-free.
“I’ll try and block them,” he explained. “But they’ll just come in and do it – there’s not a lot I can do if I’m not here.”
But he will try anyway, and he has plans to attend another strike in Trim tomorrow.
Originally published 12:08
| null |
minipile
|
NaturalLanguage
|
mit
| null |
The private-equity owners of Toys “R” Us Inc. are putting together a $20 million fund to make payments to thousands of former employees left jobless by the retailer’s liquidation, according to people familiar with the matter.
The fund’s creation by Bain Capital and KKR & Co. is an unusual move by private-equity owners of a bankrupt company. It isn’t required under bankruptcy law and has no ties to the bankruptcy process, the people said. The funding will be provided by the buyout firms’ general partners, they added.
The...
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Q:
Building a csv file from multiple files
I have on a folder multiple txt file containing one or several lines. Each file name is an email address containing different email(s) address(es) inside.
For example, I have 3 files on my folder :
[email protected]
[email protected]
[email protected]
Content of each files:
cat [email protected]
[email protected]
[email protected]
cat [email protected]
[email protected]
cat [email protected]
[email protected]
[email protected]
[email protected]
I would like to build only one file containing those data:
[email protected];[email protected]
[email protected];[email protected]
[email protected];[email protected]
[email protected];[email protected]
[email protected];[email protected]
[email protected];[email protected]
A:
lists_merge.sh
#!/usr/bin/env bash
shopt -s nullglob;
for fname in *.txt;
do
while read line;
do
printf "%s;%s\n" "$fname" "$line";
done <"$fname";
done;
output
$ ./lists_merge.sh
[email protected];[email protected]
[email protected];[email protected]
[email protected];[email protected]
[email protected];[email protected]
[email protected];[email protected]
[email protected];[email protected]
note: script assumed to be in same directory as distribution list text
files. assumed no other text files are in this directory
reference
nullglob info
| null |
minipile
|
NaturalLanguage
|
mit
| null |
AslpFileQueryVersionString is called from the AslpFileMakeStringVersionAttributes function. As you can see on the
code provided above the "crashloc" label is executed in a loop. Where the ESI register is the counter incremented
every cycle (address 0x000208B9) and the EDI register is the maximum number of allowed loop cycles (address 0x000208C3).
As you can see there is another condition that can end the loop (0x000208A7) which tests whether the wanted value was
found by the AslpFileVerQueryValue however it is always passed since ebx=STATUSNOT_FOUND (assuming forged PE file is used).
The value of EDI is taken from the PE file (resource section, Var->wValueLength [1] field) through the AslpFileVerQueryValue
function where the wanted sub-block argument is "\VarFileInfo\Translation" (Var identifiers are often used by applications to
access a language-specific StringTable structure in the version-information resource). Just like presented below:
Obtained maximum loops cycles value is later divided by 4 and supplied as an argument to the AslpFileQueryVersionString function
and later used as the loop limit. When attacker forges this value it is possible to cause access violation exception because
unavailable memory will be accessed (address 0x00020856). This happens because there are no boundary checks testing whether the
obtained data from the resource section is big enough to cover extra size provided by Var->wValueLength. This causes whole system to
crash and can be triggered remotely.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
lemon ricotta and raspberry crepes
This morning I woke up in full pancake mode. The little man and I crept into the kitchen with big plans of making a warm batch of banana pancakes for the very overworked and very sleepy daddy.
As my go-to pancake recipe makes at least 20 pancakes and knowing there was no way we could eat that many, I divided the recipe by 1/3 – thinking that I would have about 8 pancakes for the three of us.
Well, as the little man mixed the ingredients together I realized that the thick pancake batter that I was used to seeing was now a very thin batter and something was definitely amiss. But being intrigued by the new mixture I slowly ladled a bit into a hot skillet and swirled it around and ended up with a crepe instead of a pancake.
So, it was a cinnamon and raspberry crepe kind of morning and the sleeping hubby was overjoyed to be woken up to something so special that was made by those who love him.
Happy accidents = delicious breakfast. Gotta love it!
lemon ricotta and raspberry crepes
makes about 8 -10 large crepes
for the crepes:
1 cup spelt flour
1 pinch of salt
1 teaspoon baking soda
1 teaspoon baking powder
1 teaspoon cinnamon
2 tablespoons coconut sugar
2 tablespoons melted butter
1 cup almond milk
1 egg
non-stick cooking spray
In a medium sized bowl, mix all of the dry ingredients together. In a small bowl, mix all of the wet ingredients together. Slowly add the wet ingredients to the dry and whisk to combine.
Heat a non-stick pan over high heat. Once the pan is hot, turn the heat down to medium and spray the pan with a good dose of cooking spray. Pour about 1/4 cup of crepe batter into the heated pan and immediately pick up the pan and swirl the batter around the bottom of the pan, covering the entire bottom with the batter. Place the pan back on the heat and let the crepe cook through. You will see small bubbles forming in the crepe and once the bubbles stop forming, it’s time to flip the crepe over. Carefully slide a rubber spatula completely under the crepe and in one fluid motion, flip the crepe over to the uncooked side. Cook for about one minute and then remove the crepe to a large flat plate to cool.
Repeat with the remaining batter – stacking the crepes on top of each other as you go.
Serve warm or chill crepes, covered with plastic, until you are ready to use them.
for the ricotta filling:
1 1/2 cups of part-skim ricotta cheese
1/4 cup of coconut milk
zest of one lemon
juice of half of a lemon
2 tablespoons coconut sugar
In a medium sized bowl, mix all ingredients together and set aside until ready to use.
for the topping/fruit filling:
1 1/4 cup of coconut milk
1 teaspoon vanilla extract
2 cups raspberries (or fruit of your choice)
1 tablespoon coconut sugar
1 teaspoon lemon juice
1/2 cup slivered almonds, optional
fresh mint leaves, optional
powdered sugar, optional
In a stand mixer fitted with the whisk attachment, whip the coconut milk and vanilla extract on high until the mixture becomes light and frothy, about 5 minutes.
In a medium sized bowl, carefully toss the raspberries with the agave nectar and lemon juice.
to assemble:
Lay one crepe on a large plate. Place 2-3 tablespoons of the ricotta mixture in the center of the crepe and top with a small bit of the marinated raspberries. Roll the crepe from one side to the other, carefully tucking the filling inside the crepe. Place it on a serving plate or platter.
Continue in the same pattern with the remaining crepes until all the crepes have been filled.
Dollop the whipped coconut cream over the top of the crepes. Add the marinated raspberries to the top of the cream, finishing with the almonds, mint, and powdered sugar, if using.
my notes: I used spelt flour for the crepes, but you can certainly use all purpose flour. Any fruit can be used in place of the raspberries – other berries, stone fruit or even cooked apples or pears – or a combination of your favorites. Any unused crepes will keep, tightly wrapped, in the refrigerator for up to five days. You can freeze crepes – just place a piece of parchment paper between each crepe and place the whole bunch in a large zippered freezer bag.
Related
Your email address will not be published. Required fields are marked *
Comment
Name *
Email *
Website
Notify me of follow-up comments by email.
Notify me of new posts by email.
Search
Oh, hi there!
Welcome to girl on the range! I'm Jennifer, a professional chef, recipe developer, self-taught photographer and food blogger. Please pull up a chair and join me at the table ~ I'm so happy you are here!
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Mass spectrometry measures the mass-to-charge ratio (m/z) of ions formed from analyte molecules. As shown in FIG. 1, mass spectrometers have three principal components: an ion source, a mass analyzer and an ion detector. The function of the ionization source is to convert analyte molecules into gas phase ions. Electrospray ionization (ESI) is a technique used in mass spectrometry to produce ions. It is especially useful in producing ions from macromolecules because it overcomes the propensity of these molecules to fragment when ionized. The ions are accelerated under vacuum in an electric filed and separated by mass analyzers according to their m/z ratios. Exemplary mass analyzers include triple-quadrupole, time-of-flight (TOF), ion trap, quadrupole-TOF, and Fourier transform ion cyclotron resonance (FTICR) analyzers. As individual ions reach the detector, they are counted. During the last several years, technological developments in mass spectrometers have greatly improved the mass accuracy, resolution and sensitivity. However, there still remain great opportunities and challenges in mass spectrometry.
Proteomics and metabolomics as are generating new knowledge-bases for hypothesis-driven biochemical and bioimaging studies. Mass spectrometry has been the enabling technology for much of this research. Yet, the sensitivity and dynamic range have not been sufficient for all analyses. Thus far, Fourier transform ion cyclotron resonance mass spectrometry has achieved some of the best results—a detection limit of 10 zmole (i.e., 6000 molecules) for tryptic peptides of bovine albumin and a dynamic range of at least 6 orders of magnitude. This sensitivity suffices for the detection of the most abundant proteins in a single mammalian cell. However, due to the huge dynamic range (106-109) of proteins in the cell, it still remains a challenge to detect many of the less abundant proteins, even those that are present in large amounts. Revolutionary innovations can help to achieve proteomics and metabolomics of single cells. Mass spectrometry analysis that uses a very small sample size and has excellent ionization efficiency and extremely high resolution, accuracy, and dynamic range would be useful for performing such analyses.
One dominant soft-ionization method that can ionize large biomolecules such as peptides and proteins without significant fragmentation is electrospray ionization (ESI). In ESI, a volatile liquid containing an analyte moves through a very thin, charged capillary. The liquid is dispersed into a mist of small charged droplets by applying a high electric potential between the capillary and a counter electrode. As the liquid evaporates, highly charged analyte molecules explode out from the droplets. The smaller the droplets, the larger the explosion. In general, for conventional electrospray, the smallest capillaries have an inner diameter of approximately 1 μm and generate droplet diameters in the range of 1-2 μm with a flow rate of 20-40 nanoliters per minute (nL/min).
At sufficiently low flow rate and concentration, there is on average less than one analyte molecule per droplet. Ionization efficiencies can approach 100% as the analyte is dispersed in very small, easily desolvated, charged droplets. This limit is reached only if the concentration is low enough. The abundance of sample ions created by ESI can reach a plateau at certain concentrations and does not increase beyond the plateau even with increased sample concentration. Thus there is a limited dynamic range, which can be a serious drawback. In a complex mixture this problem can be especially severe. This ion suppression effect, which seems to occur at flow rates in the range of 50 nL/min and higher and is effectively absent at flow rates below approximately 20 nL/min, can render less abundant ions undetectable. Further reduction in the droplet size can alleviate this problem, increasing both the dynamic range and sensitivity of mass spectrometry.
In order to achieve lower flow rates, in the range of picoliters per minute (pL/min) or less, much smaller capillaries with sub-micron inner-diameters are needed. But there are difficulties associated with fabrication of such small capillaries, and there can be problems with increased back pressures from such extremely small channels. In addition, very small capillaries can lead to low throughput because of the need for careful and tedious alignment in the mass spectrometer.
There have been efforts to fabricate ESI emitters using polymeric materials, such as parylene (Licklider, L.; Wang, X. Q.; Desai, A.; Tai, Y. C.; Lee, T. D. Anal. Chem. 2000, 72, 367-375; Yang, Y. N.; Kameoka, J.; Wachs, T.; Henion, J. D.; Craighead, H. G. Anal. Chem. 2004, 76, 2568-2574), poly(dimethylsiloxane) (PDMS) (Kim, J. S.; Knapp, D. R. J. Am. Soc. Mass Spectrom. 2001, 12, 463-469), poly(methyl methacrylate) (PMMA) (Schilling, M.; Nigge, W.; Rudzinski, A.; Neyer, A.; Hergenroder, R. Lab Chip 2004, 4, 220-224), and negative photoresist SU-8 (Le Gac, S.; Arscott, S.; Rolando, C. Electrophoresis 2003, 24, 3640-3647; Nordstrom, M.; Marie, R.; Calleja, M.; Boisen, A. J. Micromech. Microeng. 2004, 14, 1614-1617). However, inherent properties of these hydrophobic polymers, such as strong binding affinity to proteins and incompatibility with organic solvents, have limited their usefulness for electrospray applications.
There have also been efforts to fabricate ESI emitters using silicon-based materials, such as silicon nitride (Desai, A.; Tai, Y.; Davis, M. T.; Lee, T. D. International Conference on Solid State Sensors and Actuators (Transducers '97), Piscataway, N.J., 1997, 927-930) and silicon/silica (Schultz, G. A.; Corso, T. N.; Prosser, S. J.; Zhang, S. Anal. Chem. 2000, 72, 4058-4063; Griss, P.; Melin, J.; Sjodahl, J.; Roeraade, J.; Stemme, G. J. Micromech. Microeng. 2002, 12, 682-687). In-plane silicon nitride emitter fabrication has failed due to intrinsic clogging problems arising from the etching of phosphosilicate glass between silicon nitride layers. Out-of-plane fabrication of silicon/silica has been limited critically because of the additional assembly steps needed to attach emitters to the end of a microfluidic channel. More recent efforts to make nanoelectrospray emitters from nanofluidic capillary slot and micromachined ultrasonic ejector arrays have faced similar challenges (Arscott, S.; Troadec, D. Appl. Phys. Lett. 2005, 87, 134101). None of these emitters has achieved desired flow rates of pL/min or less. In addition, no monolithic multinozzle emitter for nanoelectrospray mass spectrometry has ever been fabricated.
To increase the sensitivity of ESI further and to interface the emitters with lab-on-a-chip, breakthroughs in the design and fabrication of ultra-narrow emitters are clearly needed.
| null |
minipile
|
NaturalLanguage
|
mit
| null |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.