Reference optical phantoms for diffuse optical spectroscopy. Part 1--Error analysis of a time resolved transmittance characterization method.
Development, production quality control and calibration of optical tissue-mimicking phantoms require a convenient and robust characterization method with known absolute accuracy. We present a solid phantom characterization technique based on time resolved transmittance measurement of light through a relatively small phantom sample. The small size of the sample enables characterization of every material batch produced in a routine phantoms production. Time resolved transmittance data are pre-processed to correct for dark noise, sample thickness and instrument response function. Pre-processed data are then compared to a forward model based on the radiative transfer equation solved through Monte Carlo simulations accurately taking into account the finite geometry of the sample. The computational burden of the Monte-Carlo technique was alleviated by building a lookup table of pre-computed results and using interpolation to obtain modeled transmittance traces at intermediate values of the optical properties. Near perfect fit residuals are obtained with a fit window using all data above 1% of the maximum value of the time resolved transmittance trace. Absolute accuracy of the method is estimated through a thorough error analysis which takes into account the following contributions: measurement noise, system repeatability, instrument response function stability, sample thickness variation refractive index inaccuracy, time correlated single photon counting system time based inaccuracy and forward model inaccuracy. Two sigma absolute error estimates of 0.01 cm(-1) (11.3%) and 0.67 cm(-1) (6.8%) are obtained for the absorption coefficient and reduced scattering coefficient respectively.


Heterologous protein expression in the methylotrophic yeast Pichia pastoris.
During the past 15 years, the methylotrophic yeast Pichia pastoris has developed into a highly successful system for the production of a variety of heterologous proteins. The increasing popularity of this particular expression system can be attributed to several factors, most importantly: (1) the simplicity of techniques needed for the molecular genetic manipulation of P. pastoris and their similarity to those of Saccharomyces cerevisiae, one of the most well-characterized experimental systems in modern biology; (2) the ability of P. pastoris to produce foreign proteins at high levels, either intracellularly or extracellularly; (3) the capability of performing many eukaryotic post-translational modifications, such as glycosylation, disulfide bond formation and proteolytic processing; and (4) the availability of the expression system as a commercially available kit. In this paper, we review the P. pastoris expression system: how it was developed, how it works, and what proteins have been produced. We also describe new promoters and auxotrophic marker/host strain combinations which extend the usefulness of the system.


Is objectively measured sitting time associated with low back pain? A cross-sectional investigation in the NOMAD study.
Studies on the association between sitting time and low back pain (LBP) have found contrasting results. This may be due to the lack of objectively measured sitting time or because socioeconomic confounders were not considered in the analysis. To investigate the association between objectively measured sitting time (daily total, and occupational and leisure-time periods) and LBP among blue-collar workers. Two-hundred-and-one blue-collar workers wore two accelerometers (GT3X+ Actigraph) for up to four consecutive working days to obtain objective measures of sitting time, estimated via Acti4 software. Workers reported their LBP intensity the past month on a scale from 0 (no pain) to 9 (worst imaginable pain) and were categorized into either low (≤ 5) or high (> 5) LBP intensity groups. In the multivariate-adjusted binary logistic regression analysis, total sitting time, and occupational and leisure-time sitting were both modeled as continuous (hours/day) and categorical variables (i.e. low, moderate and high sitting time). The multivariate logistic regression analysis showed a significant positive association between total sitting time (per hour) and high LBP intensity (odds ratio; OR = 1.43, 95%CI = 1.15-1.77, P = 0.01). Similar results were obtained for leisure-time sitting (OR = 1.45, 95%CI = 1.10-1.91, P = 0.01), and a similar but non-significant trend was obtained for occupational sitting time (OR = 1.34, 95%CI 0.99-1.82, P = 0.06). In the analysis on categorized sitting time, high sitting time was positively associated with high LBP for total (OR = 3.31, 95%CI = 1.18-9.28, P = 0.03), leisure (OR = 5.31, 95%CI = 1.57-17.90, P = 0.01), and occupational (OR = 3.26, 95%CI = 0.89-11.98, P = 0.08) periods, referencing those with low sitting time. Sitting time is positively associated with LBP intensity among blue-collar workers. Future studies using a prospective design with objective measures of sitting time are recommended.


Platinum versus non-platinum chemotherapy regimens for small cell lung cancer.
Small cell lung cancer (SCLC) is a very fast growing form of cancer and is characterised by early metastasis. As a result, chemotherapy is the mainstay of treatment. A number of different platinum-based chemotherapy regimens and non-platinum-based chemotherapy regimens have been used for the treatment of SCLC, with varying results. This review was conducted to analyse the data from these studies in order to compare their effectiveness. To determine the effectiveness of platinum chemotherapy regimens compared with non-platinum chemotherapy regimens in the treatment of SCLC with respect to survival, tumour response, toxicity and quality of life. We searched the biomedical literature databases CENTRAL (TheCochrane Library 2014, Issue 7), MEDLINE, EMBASE and CINAHL from 1966 to August 2014. In addition, we handsearched reference lists from relevant resources. All randomised controlled trials involving patients with pathologically confirmed SCLC (including both limited-stage disease and extensive-stage disease) and the use of a platinum-based chemotherapy regimen in at least one treatment arm and a non-platinum-based chemotherapy regimen in a separate arm. We used standard methodological procedures expected by the Cochrane Collaboration. Two authors independently assessed search results. We assessed included studies for methodological quality and recorded the following outcome data: survival, tumour response, toxicity and quality of life. We combined the results of the survival, tumour response and toxicity data in a meta-analysis. Quality-of-life data were analysed individually. A total of 32 studies involving 6075 patients with SCLC were included in this systematic review. The majority of studies were multi-centre randomised controlled trials conducted throughout Europe, North America and Asia with the earliest study publishing data in 1981 and the latest in 2014. The duration of studies ranged from 12 to 72 months with a median of 32 months. The median age of patients in the vast majority of studies was between 60 and 65 years of age. Eighteen studies presented data on extensive-stage disease. Nine studies presented data on limited-stage disease. Eleven studies did not present data based on the disease stage. These data were analysed separately in subgroup analyses. Sixteen (50%) studies were of good quality with a low risk of bias and the data from these studies were analysed separately in a heterogeneity analysis.There was no statistically significant difference between treatment groups in terms of survival at 6 months, 12 months and 24 months. There was also no statistically significant difference in terms of overall tumour response. However, platinum-based treatment regimens did have a significantly higher rate of complete response. Platinum-based chemotherapy regimens had significantly higher rates of nausea and vomiting and thrombocytopenia toxicity. Four trials presented quality-of-life data, but, due to the different systems used to measure quality of life this data could not be combined in a meta-analysis. Platinum-based chemotherapy regimens did not offer a statistically significant benefit in survival or overall tumour response compared with non-platinum-based regimens. However, platinum-based chemotherapy regimens did increase complete response rates, at the cost of higher adverse events including nausea and vomiting, anaemia and thrombocytopenia toxicity. These data suggest non-platinum chemotherapy regimens have a more advantageous risk-benefit profile. This systematic review highlights the lack of quality-of-life data in trials involving chemotherapy treatment for SCLC. With poor long-term survival associated with both treatment groups, the issue of the quality of the survival period takes on even more significance. It would be beneficial for future trials in this area to include a quality-of-life assessment.


A comprehensive multilocus phylogeny of the Neotropical cotingas (Cotingidae, Aves) with a comparative evolutionary analysis of breeding system and plumage dimorphism and a revised phylogenetic classification.
The Neotropical cotingas (Cotingidae: Aves) are a group of passerine birds that are characterized by extreme diversity in morphology, ecology, breeding system, and behavior. Here, we present a comprehensive phylogeny of the Neotropical cotingas based on six nuclear and mitochondrial loci (∼7500 bp) for a sample of 61 cotinga species in all 25 genera, and 22 species of suboscine outgroups. Our taxon sample more than doubles the number of cotinga species studied in previous analyses, and allows us to test the monophyly of the cotingas as well as their intrageneric relationships with high resolution. We analyze our genetic data using a Bayesian species tree method, and concatenated Bayesian and maximum likelihood methods, and present a highly supported phylogenetic hypothesis. We confirm the monophyly of the cotingas, and present the first phylogenetic evidence for the relationships of Phibalura flavirostris as the sister group to Ampelion and Doliornis, and the paraphyly of Lipaugus with respect to Tijuca. In addition, we resolve the diverse radiations within the Cotinga, Lipaugus, Pipreola, and Procnias genera. We find no support for Darwin's (1871) hypothesis that the increase in sexual selection associated with polygynous breeding systems drives the evolution of color dimorphism in the cotingas, at least when analyzed at a broad categorical scale. Finally, we present a new comprehensive phylogenetic classification of all cotinga species.


The Principal and Nurse Perspective on Gaps in Asthma Care and Barriers to Physical Activity in New York City Schools: A Qualitative Study.
School officials and nurses play an important role in facilitating asthma management in schools. Little is known about their perspectives on in-school asthma management and barriers to physical activity (PA) at school. The goal of this study is to explore school officials' and nurses' perspectives on asthma care and barriers to PA in children with asthma attending New York City schools. We conducted qualitative, semistructured interviews with 10 principals, 3 assistant principals, and 9 nurses in 10 Bronx, New York elementary schools. Sampling continued until thematic saturation was reached. Interviews were recorded, transcribed, and coded for common themes. The thematic and content review was subsequently used to analyze interview data. Emerging themes were discussed and agreed on by both investigators. Three main categories arose from the analysis: (1) procedures and policies around asthma management in school, (2) barriers to effective medication administration in school, and (3) barriers to PA in children with asthma. Participants identified gaps to in-school asthma management and barriers to PA participation: ineffective ways of identifying students with asthma; lack of written procedures for asthma management; difficulty in meeting the administrative requirements to administer asthma medication; lack of knowledge and training on asthma management for the parents, students, and school staff; parental limitation of children's PA; and schools not meeting the state physical education requirement. Our findings suggest the need for policy reform on asthma management and PA in urban schools and should be considered in the design of future interventions.


Genome sequence of the chemoheterotrophic soil bacterium Saccharomonospora cyanea type strain (NA-134(T)).
Saccharomonospora cyanea Runmao et al. 1988 is a member of the genus Saccharomonospora in the family Pseudonocardiaceae that is moderately well characterized at the genome level thus far. Members of the genus Saccharomonospora are of interest because they originate from diverse habitats, such as soil, leaf litter, manure, compost, surface of peat, moist, over-heated grain, and ocean sediment, where they probably play a role in the primary degradation of plant material by attacking hemicellulose. Species of the genus Saccharomonospora are usually Gram-positive, non-acid fast, and are classified among the actinomycetes. S. cyanea is characterized by a dark blue (= cyan blue) aerial mycelium. After S. viridis, S. azurea, and S. marina, S. cyanea is only the fourth member in the genus for which a completely sequenced (non-contiguous finished draft status) type strain genome will be published. Here we describe the features of this organism, together with the draft genome sequence, and annotation. The 5,408,301 bp long chromosome with its 5,139 protein-coding and 57 RNA genes was sequenced as part of the DOE funded Community Sequencing Program (CSP) 2010 at the Joint Genome Institute (JGI).


Postnatal Care within One Week and Associated Factors among Women Who Gave Birth in Ameya District, Oromia Regional State, Ethiopia, 2018: Cross Sectional Study.
Globally recorded large number of maternal and neonatal deaths are related to complications during pregnancy, childbirth and post-partum. Most neonatal deaths occur during the first week of life. It is also evidenced that the level of postnatal care utilization in Ethiopia is very low. This study aimed to assess postnatal care utilization within one week and associated factors among women who had given birth in the last six weeks in Ameya district, Oromia, Ethiopia. Cross sectional study design was employed on 332 study participants who were selected by systemic sampling method and interviewed using structured questionnaires. The data were analyzed using SPSS version 23.0. Bivariate and multivariate logistic regression analysis was used to identify the associated factors with the outcome variable. Figures, tables and sentences were used for the presentation of descriptive statistics. The finding revealed that the proportion of postnatal care utilization within one-week in the study area is 25.3%. Partner occupation [AOR=5.575, 95% CI= (1.071, 29.023)], mothers who had complication during labor and delivery[AOR=7.841, 95% CI= (2.287, 26.879)], distance from mothers to health facilities[AOR= 5.127, 95% CI= (1.149, 22.878)] and awareness on postnatal care within one week services[AOR=4.161, 95% CI= (1.300, 13.314)] were the main contributing factors of postnatal care utilization within one-week. Postnatal care utilization within one-week is very low (25.3%). Partner occupation, complication during labor and delivery, distance from health facilities and awareness on postnatal care within one week service were the associated factors.


Predictors of malignancy and recommended follow-up in patients with negative endoscopic ultrasound-guided fine-needle aspiration of suspected pancreatic lesions.
Endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) can characterize and diagnose pancreatic lesions as malignant, but cannot definitively rule out the presence of malignancy. Outcome data regarding the length of follow-up in patients with negative or nondiagnostic EUS-FNA of pancreatic lesions are not well-established. To determine the long-term outcome and provide follow-up guidance for patients with negative EUS-FNA diagnosis of suspected pancreatic lesions based on imaging predictors. A retrospective review of patients undergoing EUS-FNA for suspected pancreatic lesions, but with negative or nondiagnostic FNA results was conducted at a tertiary care referral medical centre. Patient demographics, EUS imaging characteristics and follow-up data were examined. Seventeen of 55 patients (30.9%) with negative/nondiagnostic FNA were subsequently diagnosed with pancreatic malignancy. The risk of cancer was significantly higher for patients who had associated lymph nodes on EUS (P<0.001) and vascular involvement on EUS (P=0.001). The mean time to diagnosis in the group with falsenegative EUS-FNA diagnosis was 66 days. The true-negative EUSFNA patients were followed for a mean of 403 days after negative EUS-FNA results without the development of malignancy. For patients undergoing EUS-FNA for a suspected pancreatic lesion, a negative or nondiagnostic FNA does not provide conclusive evidence for the absence of cancer. Patients for whom vascular invasion and lymphadenopathy are detected on EUS are more likely to have a true malignant lesion and should be followed closely. When a patient has been monitored for six months or more with no cancer being diagnosed, there appears to be much less chance that a pancreatic malignancy is present.


Escape and avoidance learning in newly hatched domestic chicks.
Under the conditions specified, chicks fail to learn either to escape or to avoid shock on the day of hatching. Chicks trained for the first time on the day after hatching quickly learn to escape but do not learn to avoid shock. Avoidance learning first appears on the third day of life, and from that time the number of chicks learning to avoid increases with age, so that by the fifth day of life the majority are able to do so.


An ecological framework for cancer communication: implications for research.
The field of cancer communication has undergone a major revolution as a result of the Internet. As recently as the early 1990s, face-to-face, print, and the telephone were the dominant methods of communication between health professionals and individuals in support of the prevention and treatment of cancer. Computer-supported interactive media existed, but this usually required sophisticated computer and video platforms that limited availability. The introduction of point-and-click interfaces for the Internet dramatically improved the ability of non-expert computer users to obtain and publish information electronically on the Web. Demand for Web access has driven computer sales for the home setting and improved the availability, capability, and affordability of desktop computers. New advances in information and computing technologies will lead to similarly dramatic changes in the affordability and accessibility of computers. Computers will move from the desktop into the environment and onto the body. Computers are becoming smaller, faster, more sophisticated, more responsive, less expensive, and--essentially--ubiquitous. Computers are evolving into much more than desktop communication devices. New computers include sensing, monitoring, geospatial tracking, just-in-time knowledge presentation, and a host of other information processes. The challenge for cancer communication researchers is to acknowledge the expanded capability of the Web and to move beyond the approaches to health promotion, behavior change, and communication that emerged during an era when language- and image-based interpersonal and mass communication strategies predominated. Ecological theory has been advanced since the early 1900s to explain the highly complex relationships among individuals, society, organizations, the built and natural environments, and personal and population health and well-being. This paper provides background on ecological theory, advances an Ecological Model of Internet-Based Cancer Communication intended to broaden the vision of potential uses of the Internet for cancer communication, and provides some examples of how such a model might inform future research and development in cancer communication.


Inactivation of the von Hippel-Lindau tumor suppressor leads to selective expression of a human endogenous retrovirus in kidney cancer.
A human endogenous retrovirus type E (HERV-E) was recently found to be selectively expressed in most renal cell carcinomas (RCCs). Importantly, antigens derived from this provirus are immunogenic, stimulating cytotoxic T cells that kill RCC cells in vitro and in vivo. Here, we show HERV-E expression is restricted to the clear cell subtype of RCC (ccRCC) characterized by an inactivation of the von Hippel-Lindau (VHL) tumor-suppressor gene with subsequent stabilization of hypoxia-inducible transcription factors (HIFs)-1α and -2α. HERV-E expression in ccRCC linearly correlated with HIF-2α levels and could be silenced in tumor cells by either transfection of normal VHL or small interfering RNA inhibition of HIF-2α. Using chromatin immunoprecipitation, we demonstrated that HIF-2α can serve as transcriptional factor for HERV-E by binding with HIF response element (HRE) localized in the proviral 5' long terminal repeat (LTR). Remarkably, the LTR was found to be hypomethylated only in HERV-E-expressing ccRCC while other tumors and normal tissues possessed a hypermethylated LTR preventing proviral expression. Taken altogether, these findings provide the first evidence that inactivation of a tumor suppressor gene can result in aberrant proviral expression in a human tumor and give insights needed for translational research aimed at boosting human immunity against antigenic components of this HERV-E.


The effect of job stress on smoking and alcohol consumption.
This paper examines the effect of job stress on two key health risk-behaviors: smoking and alcohol consumption, using data from the Canadian National Population Health Survey. Findings in the extant literature are inconclusive and are mainly based on standard models which can model differential responses to job stress only by observed characteristics. However, the effect of job stress on smoking and drinking may largely depend on unobserved characteristics such as: self control, stress-coping ability, personality traits and health preferences. Accordingly, we use a latent class model to capture heterogeneous responses to job stress. Our results suggest that the effects of job stress on smoking and alcohol consumption differ substantially for at least two "types" of individuals, light and heavy users. In particular, we find that job stress has a positive and statistically significant impact on smoking intensity, but only for light smokers, while it has a positive and significant impact on alcohol consumption mainly for heavy drinkers. These results provide suggestive evidence that the mixed findings in previous studies may partly be due to unobserved individual heterogeneity which is not captured by standard models.


Dynamin and perforin are associated with neovascularisation in advanced carotid plaques.
Intimal plaque neovascularization is associated with the development of symptomatic disease and thrombosis, with new 'leaky' fragile microvessels prone to haemorrhage. Perforin or pore forming protein is involved in vascular cell death by forming pores in target cells. Enzymes, in particular, granzyme B are secreted by immune infiltrates present in inflammatory plaque regions and have been shown to induce endothelial cell apoptosis. Similarly, dynamin-2 is a GTPase which mediates oxidised low density lipoprotein-induced apoptosis and is also required for granzyme B-mediated exocytosis and apoptosis. Our pilot studies identified increased expression of these proteins in complicated atherosclerotic plaques. Here we demonstrate by immunohistochemistry that both proteins are over-expressed in angiogenic regions of complicated carotid plaques. Dynamin-2 was extensively localised around microvessels and in immune infiltrating cells whilst perforin was localised in immune infiltrating cells, endothelial cells and smooth muscle cells. Over-expression of these proteins may contribute to plaque destabilisation by increasing cellular apoptosis in vulnerable atherosclerotic plaques.


Reasons for delayed admission after stroke: results of a qualitative and quantitative survey.
Background: Acute stroke treatment shows time-dependent benefit to prevent disability. Public information campaigns and streamlining of emergency management have been performed, but still, only one-third of acute stroke patients are admitted >4.5 hrs after symptom onset. Patients and methods: We interviewed 15 patients, presenting >4.5 hrs after symptom onset, regarding symptom recognition, emotions and their first action after symptom onset. Recorded interviews were analyzed by standardized descriptive analysis. Based on the results, a quantitative survey was developed. One hundred consecutive stroke unit patients surveyed to compare patients presenting within 4.5 hrs and more than 4.5 hrs of symptom onset. Results: Patients predominantly noticed symptoms by themselves. The most commonly expressed feelings were uncertainty and shame. The most frequent action was waiting. Patients described moderate knowledge about stroke in general, but felt less informed regarding their stroke risk. Magazines (51%) were the most frequently indicated source of information, while general practitioners only accounted for 26%. Significantly better knowledge was shown in the answers on closed questions compared to open questions, although the same items were named. Conclusion: Shame, uncertainty and insufficient individual risk knowledge about stroke were the most important factors delaying admission after stroke. Individual risk counseling could be investigated to close the gap between general stroke knowledge and recognition of own stroke risk.


Conditions under which arousal does and does not elevate height estimates.
We present a series of experiments that explore the boundary conditions for how emotional arousal influences height estimates. Four experiments are presented, which investigated the influence of context, situation-relevance, intensity, and attribution of arousal on height estimates. In Experiment 1, we manipulated the environmental context to signal either danger (viewing a height from above) or safety (viewing a height from below). High arousal only increased height estimates made from above. In Experiment 2, two arousal inductions were used that contained either 1) height-relevant arousing images or 2) height-irrelevant arousing images. Regardless of theme, arousal increased height estimates compared to a neutral group. In Experiment 3, arousal intensity was manipulated by inserting an intermediate or long delay between the induction and height estimates. A brief, but not a long, delay from the arousal induction served to increase height estimates. In Experiment 4, an attribution manipulation was included, and those participants who were made aware of the source of their arousal reduced their height estimates compared to participants who received no attribution instructions. Thus, arousal that is attributed to its true source is discounted from feelings elicited by the height, thereby reducing height estimates. Overall, we suggest that misattributed, embodied arousal is used as a cue when estimating heights from above that can lead to overestimation.


Changing ABRA protein peptide to fit into the HLA-DRbeta1*0301 molecule renders it protection-inducing.
The Plasmodium falciparum acidic-basic repeat antigen represents a potential malarial vaccine candidate. One of this protein's high activity binding peptides, named 2150 ((161)KMNMLKENVDYIQKNQNLFK(180)), is conserved, non-immunogenic, and non-protection-inducing. Analogue peptides whose critical binding residues (in bold) were replaced by amino-acids having similar mass but different charge were synthesized and tested to try to modify such immunological properties. These analogues' HLA-DRbeta1* molecule binding ability were also studied in an attempt to explain their biological mechanisms and correlate binding capacity and immunological function with their three-dimensional structure determined by (1)H NMR. A 3(10) distorted helical structure was identified in protective and immunogenic peptide 24922 whilst alpha-helical structure was found for non-immunogenic, non-protective peptides having differences in alpha-helical position. The changes performed on immunogenic, protection-inducing peptide 24922 allowed it to bind specifically to the HLA-DRbeta1*0301 molecule, suggesting that these changes may lead to better interaction with the MHC Class II-peptide-TCR complex rendering it immunogenic and protective, thus suggesting a new way of developing multi-component, sub-unit-based anti-malarial vaccines.


Anti-androgen effects of extracts and compounds from Ganoderma lucidum.
The 30% EtOH extracts of Ganoderma lucidum Fr. Karst (Ganodermateceae) showed weak 5alpha-reductase inhibitory activity and binding ability to androgen receptor. When LNCaP (lymph-node carcinoma of the prostate) cells were treated with the EtOH extracts, cell proliferation was inhibited. Treatment with the extracts significantly inhibited the testosterone-induced growth of the ventral prostate in castrated rats. These results showed that G. lucidum might be a useful ingredient in the treatment of androgen-induced diseases, such as benign prostatic hyperplasia or prostate cancer. From the 30% EtOH extracts, we isolated ganoderiol F, which showed binding activity to androgen receptor and inhibited LNCaP cell proliferation, as one of the active compounds in the 30% EtOH extracts.


Parenthood, Child Care, and Heroin Use: Outcomes After Three Years.
Internationally there is a lack of measurement on the impact of childcare on people who use drugs. The aim of this article was to longitudinally measure drug use, familial and social status and criminal involvement between parents and nonparents who use heroin and have children in their care. From 2003 to 2006, 404 participants were recruited to the Research Outcome Study in Ireland Evaluating Drug Treatment Effectiveness (ROSIE) as part of a longitudinal cohort study design. Participants completed the Maudsley Addiction Profile and 88% (n = 356) completed interviews at the 3-year period. One way between groups ANOVA with post hoc tests and backward, stepwise multiple regression were employed for analysis. At follow-up, parents who had children in their care used heroin (p = .004), illicit methadone (p ≤ .001) and cocaine (p = .024) on fewer days than those who had no children, or those who had children but did not have children in their care. These differences were not observed at intake. Living with someone at intake who used drugs was found to be significantly associated with increased heroin (p ≤ .001), benzodiazepine (p = .039), and tobacco (p = .030) use at 3 years. Furthermore, a change in childcare status to caring for a child was associated with increased cannabis use (p = .025). Conclusion/Importance: While caring for children was associated with reduced heroin use at 3 years, living with a person who used at intake removed this effect, thus indicating that while individual based addiction theories reflected observed outcomes, social network connectedness was more influential.


A study of the graduates of health economics masters programs in Spain.
To identify the characteristics, motivations and employment implications among graduates of Masters programmes in health-economics (MPHE). The most renowned MPHE in Spain were contacted to assist in this research study. Participants submitted an online survey comprising 30 items designed specifically for the purpose. Our sample consisted of 439 graduates. Different statistical analysis, including a logistic model, were performed to describe the sample. The main motivation for undertaking an MPHE is academic, and to acquire new or enhance previous knowledge. The general profile of graduates is that of a woman aged 37.8 and a health professional. Those looking for a job in Health Economics generally found employment in the first (54.9%) or second year (29.7%). MPHE were very highly assessed. The most useful subject was health management (46.3%). Undertaking an MPHE is a good investment because most of the graduates believed that their training enabled them to find a job. The graduates showed a high degree of confidence in the usefulness of the training. MPHE are highly evaluated irrespective of consequent employment. The subjects in which the curriculum vitae of the health professionals were weaker, such as those concerning management, were evaluated the highest as they were assumed to enhance promotion opportunities.


Domain separation in the activation of glycogen phosphorylase a.
The crystal structure of glycogen phosphorylase a complexed with its substrates, orthophosphate and maltopentaose, has been determined and refined at a resolution of 2.8 angstroms. With oligosaccaride bound at the glycogen storage site, the phosphate ion binds at the catalytic site and causes the regulatory and catalytic domains to separate with the loss of stabilizing interactions between them. Homotropic cooperativity between the active sites of the allosteric dimer results from rearrangements in isologous contacts between symmetry-related helices in the subunit interface. The conformational changes in the core of the interface are correlated with those observed on covalent activation by phosphorylation at Ser14 (phosphorylase b----a).


Larval rearing temperature influences amount and composition of the marking pheromone of the male beewolf, Philanthus triangulum.
Pheromones play an important role for courtship and mating in many insect species, and they are shaped by a complex interaction of genetic and environmental factors. Developmental temperature is known to have a strong influence on adult life history, morphology, and physiology, but little is known about its effect on pheromone characteristics. In the present study, the influence of temperature during larval development on the amount and composition of the complex marking pheromone from the cephalic glands of the adult male beewolf, Philanthus triangulum F. (Hymenoptera: Crabronidae), was investigated. Additionally, the effects of temperature on several life-history traits were examined. European beewolf larvae were reared at three constant temperatures (20, 25, and 30 degrees C). Males reared at 20 degrees C showed longer development times and higher mortality, suggesting that low temperatures constitute stressful conditions for developing larvae. After eclosion, the amount and composition of the scent marking secretion of the adult males was analyzed by coupled gas chromatography-mass spectrometry. Males that had been reared at 20 degrees C had significantly less secretion than individuals reared under warmer conditions (25 degrees C and 30 degrees C). Furthermore, larval rearing temperature had a significant effect on the composition of the adult males' pheromone gland content, with warmer rearing conditions leading to higher relative amounts of compounds with high molecular weight. The results show that the temperature during larval development significantly affected the amount and composition of the content of the male pheromone glands, probably due to physiological constraints and competing processes for limited energetic resources. Thus, the pheromone gland content may contain information on developmental conditions of males, which may have consequences for female mate choice decisions and male reproductive success.


Genomic Privacy.
Genetic information is unique among all laboratory data because it not only informs the current health of the specific person tested but may also be predictive of the future health of the individual and, to varying degrees, all biological relatives. As DNA sequencing has become ubiquitous with decreasing cost, large repositories of genomic data have emerged from the domains of research, healthcare, law enforcement, international security, and recreational consumer interest (i.e., genealogy). Broadly shared genomic data are believed to be a key element for future discoveries in human disease. For example, the National Cancer Institute's Genomic Data Commons is designed to promote cancer research discoveries by providing free access to the genome data sets of 12000 cancer patients. However, in parallel with the promise of curing diseases, genomic data also have the potential for harm. Genomic data that are deidentified by standard healthcare practices (e.g., removal of name, date of birth) can be reidentified by methods that combine genomic software with publicly available demographic databases (e.g., phone book). Recent law enforcement cases (i.e., Bear Brook Murders, Golden State Killer) in the US have demonstrated the power of combining DNA profiles with genealogy databases. We examine the current environment of genomic privacy and confidentiality in the US and describe current and future risks to genomic privacy. Reidentification and inference of genetic information of biological relatives will become more important as larger databases of clinical, criminal, and recreational genomic information are developed over the next decade.


Range Expansion of Moose in Arctic Alaska Linked to Warming and Increased Shrub Habitat.
Twentieth century warming has increased vegetation productivity and shrub cover across northern tundra and treeline regions, but effects on terrestrial wildlife have not been demonstrated on a comparable scale. During this period, Alaskan moose (Alces alces gigas) extended their range from the boreal forest into tundra riparian shrub habitat; similar extensions have been observed in Canada (A. a. andersoni) and Eurasia (A. a. alces). Northern moose distribution is thought to be limited by forage availability above the snow in late winter, so the observed increase in shrub habitat could be causing the northward moose establishment, but a previous hypothesis suggested that hunting cessation triggered moose establishment. Here, we use recent changes in shrub cover and empirical relationships between shrub height and growing season temperature to estimate available moose habitat in Arctic Alaska c. 1860. We estimate that riparian shrubs were approximately 1.1 m tall c. 1860, greatly reducing the available forage above the snowpack, compared to 2 m tall in 2009. We believe that increases in riparian shrub habitat after 1860 allowed moose to colonize tundra regions of Alaska hundreds of kilometers north and west of previous distribution limits. The northern shift in the distribution of moose, like that of snowshoe hares, has been in response to the spread of their shrub habitat in the Arctic, but at the same time, herbivores have likely had pronounced impacts on the structure and function of these shrub communities. These northward range shifts are a bellwether for other boreal species and their associated predators.


Overfed but undernourished: recognizing nutritional inadequacies/deficiencies in patients with overweight or obesity.
Overweight and obesity are highly prevalent throughout the world and can adversely affect the nutritional status of individuals. Studies have shown that many people with obesity have inadequate intake of iron, calcium, magnesium, zinc, copper, folate and vitamins A and B12, likely as a result of poor diet quality. Nutritional inadequacies or deficiencies may also occur due to altered pharmacokinetics in the individual with obesity and due to interactions in those with overweight or obesity with various pharmaceuticals. However, it has been demonstrated that the adult population in the United States as a whole is deficient in certain micronutrients as a result of the availability and overconsumption of high-calorie, low-nutrient processed foods. Poor nutrition may contribute to the development of certain chronic conditions, such as type 2 diabetes, which is already more prevalent in those with obesity. Clinicians need to be aware of these gaps, particularly in those individuals with obesity who are undergoing bariatric surgery or taking pharmaceutical products long term to facilitate weight loss. Patients with overweight or obesity likely struggle to achieve a balanced diet and may benefit from consultation with a dietitian. Along with providing recommendations for healthy eating and exercise, supplementation with specific micronutrients or multivitamins should be considered for individuals at the highest risk for or with established deficiencies. Further research is needed to understand the factors underlying nutritional inadequacies in individuals with overweight or obesity, as well as the outcomes of treatment strategies employed to address them.


An empirical evaluation of software quality assurance practices and challenges in a developing country: a comparison of Nigeria and Turkey.
The importance of quality assurance in the software development process cannot be overemphasized because its adoption results in high reliability and easy maintenance of the software system and other software products. Software quality assurance includes different activities such as quality control, quality management, quality standards, quality planning, process standardization and improvement amongst others. The aim of this work is to further investigate the software quality assurance practices of practitioners in Nigeria. While our previous work covered areas on quality planning, adherence to standardized processes and the inherent challenges, this work has been extended to include quality control, software process improvement and international quality standard organization membership. It also makes comparison based on a similar study carried out in Turkey. The goal is to generate more robust findings that can properly support decision making by the software community. The qualitative research approach, specifically, the use of questionnaire research instruments was applied to acquire data from software practitioners. In addition to the previous results, it was observed that quality assurance practices are quite neglected and this can be the cause of low patronage. Moreover, software practitioners are neither aware of international standards organizations or the required process improvement techniques; as such their claimed standards are not aligned to those of accredited bodies, and are only limited to their local experience and knowledge, which makes it questionable. The comparison with Turkey also yielded similar findings, making the results typical of developing countries. The research instrument used was tested for internal consistency using the Cronbach's alpha, and it was proved reliable. For the software industry in developing countries to grow strong and be a viable source of external revenue, software assurance practices have to be taken seriously because its effect is evident in the final product. Moreover, quality frameworks and tools which require minimum time and cost are highly needed in these countries.


Decomposing the gap in satisfaction with provider communication between English- and Spanish-speaking Hispanic patients.
Disparities in patient-provider communication exist among racial/ethnic groups. Hispanics report the lowest satisfaction with provider communication compared to whites and blacks; these differences may be due to level of acculturation or patient-provider concordance according to their ability to speak English. Using data from the 2007-2009 Medical Expenditure Panel Survey, this study identifies and quantifies the components that constitute the gap in satisfaction with provider communication between English- and Spanish-speaking Hispanics. English-speaking Hispanics are 7.3 percentage points more likely to be satisfied with the amount of time their providers spent with them compared to Spanish-speaking Hispanics. Differences in acculturation between the two groups account for 77% of this gap. Satisfaction with provider listening is 6.8 percentage points higher for English-speaking Hispanics. Hispanics who speak English are more satisfied with provider communication. The gap in satisfaction is largely attributable to differences in health insurance, acculturation, and education.


Neutrophil and platelet to lymphocyte ratio in patients with hypothyroid Hashimoto's thyroiditis.
Chronic lymphocytic thyroiditis is among the most common causes of hypothyroidism along with HT (Hashimoto's thyroiditis) goitre, which is also named as autoimmune thyroiditis. Our study aims to determine the usefulness of PLR (platelet to lymphocyte ratio) and NLR (neutrophil to lymphocyte ratio), which can be obtained with a hemogram, at the clinical course or the severity of the disease in patients with Hashimoto's thyroiditis. Our study is a retrospective cross-sectional study that included 121 hypothyroid or subclinical hypothyroid Hashimoto's thyroiditis patients and a healthy control group comprised of 100 individuals. Thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), anti-thyroid peroxidase (anti-TPO), complete blood count (CBC), and C-reactive protein (CRP) results were obtained from patient files for both HT patients and the control group, and we computed PLR and NLR for both groups. PLR was lower in patients diagnosed with HT compared to the healthy control group, with statistical significance (respectively, 130.8±50.5 versus 145.3±58.5; p<0,05). NLR was higher in patients diagnosed with HT compared to the control group and a statistically significant relationship was determined (respectively, 2.43±0.94 versus 2,11±0,81; p<0,05). In addition to the present findings, we determined that PLR and NLR were correlated with anti-TPO, TSH, and FT4, although without statistical significance. As values that can be measured with an inexpensive and easily accessible routine hemogram, PLR and NLR can serve as practical and valuable markers at the clinical course or the severity of the disease and other diseases that are autoimmune and progress with chronic inflammation.


Morphine-induced analgesia in the rat paw pressure test is blocked by CCK and enhanced by the CCK antagonist MK-329.
The effects of cholecystokinin octapeptide sulphated (CCK) and the potent CCK antagonist MK-329 (L-364, 718) on analgesia induced by morphine in the paw pressure test in the rat were examined. Both CCK (4-16 micrograms/kg) and MK-329 (0.1-8.0 mg/kg) had no significant effect on thresholds for pain when given alone, whereas morphine (2-16 mg/kg) induced dose-dependent analgesia. Cholecystokinin (4-16 micrograms/kg) abolished the analgesia induced by 8 mg/kg morphine. In contrast, doses of 1 and 2 mg/kg MK-329 enhanced the analgesia induced by 8 and 4 mg/kg morphine, respectively. The present data are consistent with previous reports that CCK blocks, and CCK antagonists enhance, opiate-induced analgesia in response to thermal pain stimuli. In addition, the results show that CCK/opiate interactions extend to mechanical pain stimuli. Recent ligand binding studies have shown that CCK receptors in the spinal cord of the rat (where CCK/opiate interactions are thought to occur) are predominantly of the CCK-B subtype. The drug MK-329 has a relatively weak (micromolar) affinity for CCK-B receptors and a high affinity (nanomolar) for CCK-A receptors. As relatively large doses (1-2 mg/kg) of MK-329 are required to enhance opiate-induced analgesia in the paw pressure test and tail flick test in rats it appears that CCK/opiate interactions in this species involve CCK-B receptors.


Model-based fMRI reveals dissimilarity processes underlying base rate neglect.
Extensive evidence suggests that people use base rate information inconsistently in decision making. A classic example is the inverse base rate effect (IBRE), whereby participants classify ambiguous stimuli sharing features of both common and rare categories as members of the rare category. Computational models of the IBRE have posited that it arises either from associative similarity-based mechanisms or from dissimilarity-based processes that may depend on higher-level inference. Here we develop a hybrid model, which posits that similarity- and dissimilarity-based evidence both contribute to the IBRE, and test it using functional magnetic resonance imaging data collected from human subjects completing an IBRE task. Consistent with our model, multivoxel pattern analysis reveals that activation patterns on ambiguous test trials contain information consistent with dissimilarity-based processing. Further, trial-by-trial activation in left rostrolateral prefrontal cortex tracks model-based predictions for dissimilarity-based processing, consistent with theories positing a role for higher-level symbolic processing in the IBRE.


The Validity, Reliability, and Feasibility of Measurement Tools Used to Assess Sleep of Pre-school Aged Children: A Systematic Rapid Review.
Background: Sleep of pre-school aged children is important for their health and development, but there are currently no standards for measuring sleep in this age group. We aimed to examine the validity, reliability and feasibility of tools used to assess sleep of pre-school aged children. Methods: Studies were eligible for inclusion if they examined the validity and/or reliability and/or feasibility of a measurement tool used to examine sleep of pre-school aged children (aged 3-7 years). We systematically searched six electronic databases, grey literature and trial registries. We manually searched topic specific journals, reference and citations of included studies, and reference lists of existing reviews. We extracted data and conducted a risk of bias assessment on the included studies using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) risk of bias checklist. We used a narrative synthesis to present the results. Results: Sixteen studies met the inclusion criteria: these explored accelerometers (n = 3) and parental reported tools (n = 13; nine questionnaires, six diaries). Studies assessed construct validity (n = 3), criterion validity (n = 1), convergent validity (n = 13), test-retest reliability (n = 2), internal consistency (n = 4) and feasibility (n = 12). Most studies assessed the convergent validity of questionnaires and diaries compared with accelerometers, but the validity of accelerometers for sleep in this age group is unknown. Of studies with a low risk of bias, one sleep diary was shown to be valid for measuring sleep duration. No measurement tools were appropriate for determining sleep quality. Reporting of reliability and feasibility was minimal. Discussion: The evidence base in this field is limited, and most studies had high risk of bias. Future research on sleep in pre-school aged children should focus on assessing the validity, reliability and feasibility of accelerometers, which in turn will improve the quality of studies that assess questionnaires and diaries against accelerometers. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021230900; PROSPERO: CRD42021230900.


Hippocampal lesions impair rapid learning of a continuous spatial alternation task.
The hippocampus is essential for the formation of memories for events, but the specific features of hippocampal neural activity that support memory formation are not yet understood. The ideal experiment to explore this issue would be to monitor changes in hippocampal neural coding throughout the entire learning process, as subjects acquire and use new episodic memories to guide behavior. Unfortunately, it is not clear whether established hippocampally-dependent learning paradigms are suitable for this kind of experiment. The goal of this study was to determine whether learning of the W-track continuous alternation task depends on the hippocampal formation. We tested six rats with NMDA lesions of the hippocampal formation and four sham-operated controls. Compared to controls, rats with hippocampal lesions made a significantly higher proportion of errors and took significantly longer to reach learning criterion. The effect of hippocampal lesion was not due to a deficit in locomotion or motivation, because rats with hippocampal lesions ran well on a linear track for food reward. Rats with hippocampal lesions also exhibited a pattern of perseverative errors during early task experience suggestive of an inability to suppress behaviors learned during pretraining on a linear track. Our findings establish the W-track continuous alternation task as a hippocampally-dependent learning paradigm which may be useful for identifying changes in the neural representation of spatial sequences and reward contingencies as rats learn and apply new task rules.


Nox2/ROS-dependent human antigen R translocation contributes to TNF-α-induced SOCS-3 expression in human tracheal smooth muscle cells.
Elevated levels of TNF-α have been detected in the airway fluids, which may induce upregulation of inflammatory proteins. Suppressors of cytokine signaling (SOCS)-3 proteins can be induced by various cytokines and negatively regulated inflammatory responses. Although TNF-α has been shown to induce SOCS-3 expression, the mechanisms underlying TNF-α-induced SOCS-3 expression in human tracheal smooth muscle cells (HTSMCs) remain unclear. Here, we showed that TNF-α induced SOCS-3 expression, which was inhibited by pretreatment with the inhibitor of transcription level (actinomycin D), translation level (cycloheximide), JNK1/2 (SP600125), MEK1/2 (U0126), NADPH oxidase (Nox; apocynin and diphenyleneiodonium chloride), or reactive oxygen species (ROS; N-acetyl-l-cysteine) and transfection with siRNA of JNK1, p47(phox), p42, Nox2, or human antigen R (HuR). In addition, TNF-α-stimulated JNK1/2 and p42/p44 MAPK phosphorylation, Nox activation, and ROS generation were inhibited by pretreatment with U0126 or SP600125 and transfection with siRNA of JNK1 or p42. We further showed that TNF-α markedly induced HuR protein expression and translocation from the nucleus to the cytosol, which could stabilize SOCS-3 mRNA. Moreover, TNF-α-enhanced HuR translocation was reduced by transfection with siRNA of p42, JNK1, or p47(phox). These results suggested that TNF-α induces SOCS-3 protein expression and mRNA stabilization via a TNFR1/JNK1/2, p42/p44 MAPK/Nox2/ROS-dependent HuR signaling in HTSMCs. Lipopolysaccharide (LPS) has been shown to play a key role in inflammation via induction of adhesion molecules and then causes airway and lung injury. Moreover, we also demonstrated that overexpression of SOCS-3 protects against LPS-induced adhesion molecules expression and airway inflammation.


Acetylcholine receptor delta subunit mutations underlie a fast-channel myasthenic syndrome and arthrogryposis multiplex congenita.
Limitation of movement during fetal development may lead to multiple joint contractures in the neonate, termed arthrogryposis multiplex congenita. Neuromuscular disorders are among the many different causes of reduced fetal movement. Many congenital myasthenic syndromes (CMSs) are due to mutations of the adult-specific epsilon subunit of the acetylcholine receptor (AChR), and, thus, functional deficits do not arise until late in gestation. However, an earlier effect on the fetus might be predicted with some defects of other AChR subunits. We studied a child who presented at birth with joint contractures and was subsequently found to have a CMS. Mutational screening revealed heteroallelic mutation within the AChR delta subunit gene, delta 756ins2 and delta E59K. Expression studies demonstrate that delta 756ins2 is a null mutation. By contrast, both fetal and adult AChR containing delta E59K have shorter than normal channel activations that predict fast decay of endplate currents. Thus, delta E59K causes dysfunction of fetal as well as the adult AChR and would explain the presence of joint contractures on the basis of reduced fetal movement. This is the first report of the association of AChR gene mutations with arthrogryposis multiplex congenita. It is probable that mutations that severely disrupt function of fetal AChR will underlie additional cases.


Optimizing trauma system design: the GEOS (Geospatial Evaluation of Systems of Trauma Care) approach.
Trauma systems have been shown to reduce death and disability from injury but must be appropriately configured. A systematic approach to trauma system design can help maximize geospatial effectiveness and reassure stakeholders that the best configuration has been chosen. This article describes the GEOS [Geospatial Evaluation of Systems of Trauma Care] methodology, a mathematical modeling of a population-based data set, which aims to derive geospatially optimized trauma system configurations for a geographically defined setting. GEOS considers a region's spatial injury profile and the available resources and uses a combination of travel time analysis and multiobjective optimization. The methodology is described in general and with regard to its application to our case study of Scotland. The primary outcome will be trauma system configuration. GEOS will contribute to the design of a trauma system for Scotland. The methodology is flexible and inherently transferable to other settings and could also be used to provide assurance that the configuration of existing trauma systems is fit for purpose.


Microfabricated scaffold-guided endothelial morphogenesis in three-dimensional culture.
Morphogenesis is a fundamental process by which new blood vessels are formed during angiogenesis. The ability to control angiogenesis would lead to improvements in tissue engineering constructions; indeed, the study of angiogenesis has numerous clinical applications, for example, in the investigation of metastatic cancer, peripheral and coronary vascular disease, and wound healing. Conventional in vitro organotypic cell culture approaches to these studies are limited primarily by their reliance on microvascular vessel formation through a random process of morphogenesis that lacks the spatial reproducibility and orientation needed for high-throughput drug testing. We have developed a bioreactor system for scaffold-guided tubulogenesis coupled with 3-D organotypic culture to spatially control vessel formation and its orientation. To create microchannels to guide microvessel formation, we fabricated rigid scaffolds using photolithography and light curing epoxy, and soft scaffolds formed by a polydimethylsiloxane (PDMS) stamp directly into collagen. Scaffolds seeded with dermal microvascular endothelial cells were placed between gelled layers of collagen containing dermal fibroblasts within a Transwell filter system and cultured for up to 2 weeks to allow for vessel maturation. Morphological analysis of thin tissue sections following standard histology and immunohistochemical detection of endothelial cells, fibroblasts, and basement membrane confirmed vessel formation along the microchannel walls with either scaffold. This system may also provide a means to explore revascularization within decellularized extracellular matrices, the culture of microvessel networks with controlled geometries, and possibly the spatial guidance of angiogenesis for interfacing with an external microfluidic supply network. As a new tool for guided angiogenesis, our approach introduces new possibilities for identification of anti-angiogenic therapeutics.


Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer.
Pancreatic stellate cells (PSCs) differentiate into cancer-associated fibroblasts (CAFs) that produce desmoplastic stroma, thereby modulating disease progression and therapeutic response in pancreatic ductal adenocarcinoma (PDA). However, it is unknown whether CAFs uniformly carry out these tasks or if subtypes of CAFs with distinct phenotypes in PDA exist. We identified a CAF subpopulation with elevated expression of α-smooth muscle actin (αSMA) located immediately adjacent to neoplastic cells in mouse and human PDA tissue. We recapitulated this finding in co-cultures of murine PSCs and PDA organoids, and demonstrated that organoid-activated CAFs produced desmoplastic stroma. The co-cultures showed cooperative interactions and revealed another distinct subpopulation of CAFs, located more distantly from neoplastic cells, which lacked elevated αSMA expression and instead secreted IL6 and additional inflammatory mediators. These findings were corroborated in mouse and human PDA tissue, providing direct evidence for CAF heterogeneity in PDA tumor biology with implications for disease etiology and therapeutic development.


Decomposing the neural mechanisms of visual search through model-based analysis of fMRI: top-down excitation, active ignoring and the use of saliency by the right TPJ.
Despite being studied intensively over the past 30 years, the neural processes underlying visual search are not yet fully understood. In the current study we extend prior work using model-based analysis to decompose fMRI data. fMRI data on human search were assessed using activation functions predicted from the spiking Search over Time and Space model (sSoTS; Mavritsaki et al., 2006). Going beyond previous work, we show for the first time that activity in a central location map in the model, which computes the saliency of a target relative to distractors, correlated with the BOLD response in the right temporo-parietal junction (TPJ)--a key region implicated in clinical studies of unilateral neglect. This is consistent with the right TPJ responding to the relative saliency of visual stimuli. In addition, a re-analysis of search performance, with a larger participant set and a psychologically plausible response rule, showed distinct neural regions in parietal and occipital cortices linked to top-down excitation and the to active ignoring of distractors. The results indicate that excitatory and inhibitory circuits for visual selection can be separated, and that the right TPJ may be critical for responding to salient targets. The value of using a model-based approach is discussed.


Personality traits and dispersal tendency in the invasive mosquitofish (Gambusia affinis).
Ecological invasions, where non-native species spread to new areas, grow to high densities and have large, negative impacts on ecological communities, are a major worldwide problem. Recent studies suggest that one of the key mechanisms influencing invasion dynamics is personality-dependent dispersal: the tendency for dispersers to have a different personality type than the average from a source population. We examined this possibility in the invasive mosquitofish (Gambusia affinis). We measured individual tendencies to disperse in experimental streams and several personality traits: sociability, boldness, activity and exploration tendency before and three weeks after dispersal. We found that mosquitofish display consistent behavioural tendencies over time, and significant positive correlations between all personality traits. Most notably, sociability was an important indicator of dispersal distance, with more asocial individuals dispersing further, suggesting personality-biased dispersal on an invasion front. These results could have important ecological implications, as invasion by a biased subset of individuals is likely to have different ecological impacts than invasion by a random group of colonists.


Lessons from bioengineering the ovarian follicle: a personal perspective.
The ovarian follicle and its maturation captivated my imagination and inspired my scientific journey - what we know now about this remarkable structure is captured in this invited review. In the past decade, our knowledge of the ovarian follicle expanded dramatically as cross-disciplinary collaborations brought new perspectives to bear, ultimately leading to the development of extragonadal follicles as model systems with significant clinical implications. Follicle maturation in vitro in an 'artificial' ovary became possible by learning what the follicle is fundamentally and autonomously capable of - which turns out to be quite a lot. Progress in understanding and harnessing follicle biology has been aided by engineers and materials scientists who created hardware that enables tissue function for extended periods of time. The EVATAR system supports extracorporeal ovarian function in an engineered environment that mimics the endocrine environment of the reproductive tract. Finally, applying the tools of inorganic chemistry, we discovered that oocytes require zinc to mature over time - a truly new aspect of follicle biology with no antecedent other than the presence of zinc in sperm. Drawing on the tools and ideas from the fields of bioengineering, materials science and chemistry unlocked follicle biology in ways that we could not have known or even predicted. Similarly, how today's basic science discoveries regarding ovarian follicle maturation are translated to improve the experience of tomorrow's patients is yet to be determined.


Kit/stem cell factor receptor-induced activation of phosphatidylinositol 3'-kinase is essential for male fertility.
The c-kit-encoded transmembrane tyrosine kinase receptor for stem cell factor (Kit/SCF-R) is required for normal haematopoiesis, melanogenesis and gametogenesis. However, the roles of individual Kit/SCF-R-induced signalling pathways in the control of developmental processes in the intact animal are completely unknown. To examine the function of SCF-induced phosphatidylinositol (PI) 3'-kinase activation in vivo, we employed the Cre-loxP system to mutate the codon for Tyr719, the PI 3'-kinase binding site in Kit/SCF-R, to Phe in the genome of mice by homologous recombination. Homozygous (Y719F/Y719F) mutant mice are viable. The mutation completely disrupted PI 3'-kinase binding to Kit/SCF-R and reduced SCF-induced PI 3'-kinase-dependent activation of Akt by 90%. The mutation induced a gender- and tissue-specific defect. Although there are no haematopoietic or pigmentation defects in homozygous mutant mice, males are sterile due to a block in spermatogenesis, with initially decreased proliferation and subsequent extensive apoptosis occurring at the spermatogonial stem-cell level. In contrast, female homozygotes are fully fertile. This is the first report so far demonstrating the role of an individual signalling pathway downstream of Kit/SCF-R in the intact animal. It provides the first in vivo model for male sterility caused by a discrete signalling pathway defect affecting early germ cells.


Advanced arthroscopic surgery.
Improvements in camera and lens technology have advanced the ability to diagnose a multitude of pathologic conditions within the temporomandibular joint. Laser advances have allowed for precise surgical procedures to be performed in small joints with limited access. The creativity and ingenuity of oral and maxillofacial surgeons has taken these technologic advances and applied them to the treatment of this important joint.


Comparison of human trichinellosis caused by Trichinella spiralis and by Trichinella britovi.
The first documented report of an outbreak of human trichinellosis caused by Trichinella spiralis in Italy is described. Two family groups were involved. The source was wild boar meat products. The principal clinical features were fever (60%), myalgia (50%), and diarrhea (40%). The most useful laboratory indicators were eosinophilia (100%), elevated levels of creatine phosphokinase (CPK) (90%) and other muscle enzymes, parasite-specific IgG titers (100%), and anti-newborn larvae antibodies (30%). The levels of these responses correlated with the number of infective muscle larvae ingested, which was influenced by the length of time the ingested meat was cured. The clinical and biological features observed during human infection with T. spiralis appear to have been different from those reported during two outbreaks due to T. britovi, which occurred in southern Italy. The main distinctions between the two types of infections were a longer duration of parasite-specific IgG, increased CPK levels, and a more severe intestinal symptomatology in T. spiralis-infected patients than in those infected with T. britovi.


Next-generation sequencing coupled with a cell-free display technology for high-throughput production of reliable interactome data.
Next-generation sequencing (NGS) has been applied to various kinds of omics studies, resulting in many biological and medical discoveries. However, high-throughput protein-protein interactome datasets derived from detection by sequencing are scarce, because protein-protein interaction analysis requires many cell manipulations to examine the interactions. The low reliability of the high-throughput data is also a problem. Here, we describe a cell-free display technology combined with NGS that can improve both the coverage and reliability of interactome datasets. The completely cell-free method gives a high-throughput and a large detection space, testing the interactions without using clones. The quantitative information provided by NGS reduces the number of false positives. The method is suitable for the in vitro detection of proteins that interact not only with the bait protein, but also with DNA, RNA and chemical compounds. Thus, it could become a universal approach for exploring the large space of protein sequences and interactome networks.


Extracellular vesicles from seminal plasma to improve fertilizing capacity of bulls.
Seminal plasma contains extracellular vesicles (EVs) that vehicle RNA, proteins, and other molecules able to influence the biological function of sperm. The aim of this study was to improve the fertilizing capacity of male gametes of low-fertility bulls using EVs isolated by ultracentrifugation from the seminal plasma of a bull of proven fertility. After dose-response curve, 10×106 sperm of low-fertility bulls were co-incubated for an hour with 400×106 EVs/ml. In addition, it has been verified that the incorporation of EVs, which takes place in the sperm midpiece, is maintained for 5 hours and even after cryopreservation. Subsequently, the spermatozoa of low-fertility bulls, with EVs incorporated, were used for the in vitro production of embryos. The rate of blastocyst at seventh day yield in vitro, with the use of sperm with EVs incorporated, increased by about twice the yield obtained with the same sperm in the absence of EVs: bulls having an average embryonic yield of 6.41±1.48%, 10.32±4.34% and 10.92±0.95% improved their yield to 21.21±1.99%, 22.17±6.09% and 19.99±5.78%, respectively (P<0.05). These encouraging results suggest that it might be possible to keep breeding bulls with poor fertility. Further studies will be needed to evaluate the in vivo fertility of sperm treated with EVs and understand how the content of EVs is involve in the sperm-vesicle interaction and in the improved sperm performance.


Assessment of the mechanical properties of the muscle-tendon unit by supersonic shear wave imaging elastography: a review.
This review aimed to describe the state of the art in muscle-tendon unit (MTU) assessment by supersonic shear wave imaging (SSI) elastography in states of muscle contraction and stretching, during aging, and in response to injury and therapeutic interventions. A consensus exists that MTU elasticity increases during passive stretching or contraction, and decreases after static stretching, electrostimulation, massage, and dry needling. There is currently no agreement regarding changes in the MTU due to aging and injury. Currently, the application of SSI for the purpose of diagnosis, rehabilitation, and physical training remains limited by a number of issues, including the lack of normative value ranges, the lack of consensus regarding the appropriate terminology, and an inadequate understanding of the main technical limitations of this novel technology.


Major histocompatibility class II peptide occupancy, antigen presentation, and CD4+ T cell function in mice lacking the p41 isoform of invariant chain.
We used a "hit and run" gene targeting strategy to generate mice expressing only the p31 isoform of the conserved invariant (Ii) chain associated with major histocompatibility complex (MHC) class II molecules. Spleen cells from these mice appear indistinguishable from wild type with respect to class II subunit assembly, transport, peptide acquisition, surface expression, and the ability to present intact protein antigens. Moreover, these mutant mice have normal numbers of thymic and peripheral CD4+ T cells, and intact CD4+ T-dependent proliferative responses towards a soluble antigen. In short, MHC class II expression and function are surprisingly unaffected in mice lacking p41 invariant chain, implying that the p31 and p41 isoforms may be functionally redundant in the intact animal.


Ethical analysis of arguments supporting the use of certain exclusion criteria in organ transplantation.
The author analyses the arguments put forward by Eike Henner Kluge, in a paper entitled "Drawing the Ethical Line Between Organ Transplantation and Lifestyle Abuse" (CMAJ, 150 (5), 1994), supporting the idea that nicotine and alcohol abusers should not have an equal access to organ transplantation. Referring to an egalitarian justice, Kluge argues that one who has caused one's bad health condition should not be permitted to compete on the same basis as other candidates in order to have access to a scarce health care resource because in doing so one penalizes those who are not responsible for their bad health condition, diminishing their own chances of obtaining an available organ. After considering certain empirical facts in scarce health care resources, particularly in organ transplantation, the author defines the main characteristics of a just treatment in terms of an equal access to health care and demonstrates that Kluge's arguments are not supported by an egalitarian conception of justice. In fact, the proposed distribution of services is based on individual merit.


Short-term quality of life after myomectomy for uterine fibroids from the COMPARE-UF Fibroid Registry.
Uterine fibroids may decrease quality of life in a significant proportion of affected women. Myomectomy offers a uterine-sparing treatment option for patients with uterine fibroids that can be performed abdominally, laparoscopically (with or without robotic assistance), and hysteroscopically. Quality of life information using validated measures for different myomectomy routes, especially hysteroscopic myomectomy, is limited. To compare women's perception of their short-term health-related quality of life measures and reported time to return to usual activities and return to work for different routes of myomectomy. Comparing Options for Management: Patient-centered Results for Uterine Fibroids (COMPARE-UF) is a prospective nationwide fibroid registry that enrolled premenopausal women seeking treatment for uterine fibroids at 8 clinical sites. For this analysis, we included women undergoing hysteroscopic, abdominal, or laparoscopic myomectomy who completed the postprocedure questionnaire scheduled between 6 and 12 weeks after surgery. Health-related quality of life outcomes, such as pain, anxiety, and return to usual activitie, were assessed for each route. The hysteroscopic myomectomy group had large differences in demographics, fibroid number, and uterine size compared to the other groups; thus, a direct comparison of quality of life measures was performed only for abdominal and laparoscopic approaches after propensity weighting. Propensity weighting was done using 24 variables that included demographics, quality of life baseline measures, and fibroid and uterine measurements. A total of 1206 women from 8 COMPARE-UF sites underwent myomectomy (338 hysteroscopic, 519 laparoscopic, and 349 abdominal). All women had substantial improvement in short-term health-related quality of life and symptom severity scores, which was not different among groups. Average symptom severity scores decreased about 30 points in each group. Return to usual activities averaged 0 days (interquartile range, 0-14 days) for hysteroscopic myomectomy, 21 days (interquartile range, 14-28 days) for laparoscopic myomectomy, and 28 days (interquartile range, 14-35 days) for abdominal myomectomy. After propensity adjustment, quality of life outcomes in the laparoscopic and abdominal myomectomy groups were similar except for more anxiety in the laparoscopic myomectomy group and slightly more pain in the abdominal myomectomy group. After propensity weighting, return to usual activities favored laparoscopic compared to abdominal procedures; median time was the same at 21 days, but the highest quartile of women in the abdominal group needed an additional week of recovery (interquartile range,14.0-28.0 for laparoscopic versus 14.0-35.0 for abdominal, P < .01). Time to return to work was also longer in the abdominal arm (median, 22 days; interquartile range, 14-40 days, versus median, 42; interquartile range, 27-56). Women who underwent myomectomy had substantial improvement in health-related quality of life, regardless of route of myomectomy. After propensity weighting, abdominal myomectomy was associated with a nearly 2-week longer time to return to work than laparoscopic myomectomy.


Administration of Downstream ApoE Attenuates the Adverse Effect of Brain ABCA1 Deficiency on Stroke.
The ATP-binding cassette transporter member A1 (ABCA1) and apolipoprotein E (ApoE) are major cholesterol transporters that play important roles in cholesterol homeostasis in the brain. Previous research demonstrated that specific deletion of brain-ABCA1 (ABCA1-B/-B) reduced brain grey matter (GM) and white matter (WM) density in the ischemic brain and decreased functional outcomes after stroke. However, the downstream molecular mechanism underlying brain ABCA1-deficiency-induced deficits after stroke is not fully understood. Adult male ABCA1-B/-B and ABCA1-floxed control mice were subjected to distal middle-cerebral artery occlusion and were intraventricularly infused with artificial mouse cerebrospinal fluid as vehicle control or recombinant human ApoE2 into the ischemic brain starting 24 h after stroke for 14 days. The ApoE/apolipoprotein E receptor 2 (ApoER2)/high-density lipoprotein (HDL) levels and GM/WM remodeling and functional outcome were measured. Although ApoE2 increased brain ApoE/HDL levels and GM/WM density, negligible functional improvement was observed in ABCA1-floxed-stroke mice. ApoE2-administered ABCA1-B/-B stroke mice exhibited elevated levels of brain ApoE/ApoER2/HDL, increased GM/WM density, and neurogenesis in both the ischemic ipsilateral and contralateral brain, as well as improved neurological function compared with the vehicle-control ABCA1-B/-B stroke mice 14 days after stroke. Ischemic lesion volume was not significantly different between the two groups. In vitro supplementation of ApoE2 into primary cortical neurons and primary oligodendrocyte-progenitor cells (OPCs) significantly increased ApoER2 expression and enhanced cholesterol uptake. ApoE2 promoted neurite outgrowth after oxygen-glucose deprivation and axonal outgrowth of neurons, and increased proliferation/survival of OPCs derived from ABCA1-B/-B mice. Our data indicate that administration of ApoE2 minimizes the adverse effects of ABCA1 deficiency after stroke, at least partially by promoting cholesterol traffic/redistribution and GM/WM remodeling via increasing the ApoE/HDL/ApoER2 signaling pathway.


A multidisciplinary approach to study the effects of balneotherapy and mud-bath therapy treatments on fibromyalgia.
To study the effects of both balneotherapy and mud-bath therapy treatments in patients affected by primary fibromyalgia (FM) using rheumatological, psychiatric, biochemical and proteomic approaches. Forty-one FM patients (39 females, 2 males), who fulfilled the American College of Rheumatology criteria received a 2-week thermal therapy programme consisting of therapy once daily for 6 days/week. Twenty-one patients received mud-bath treatment, while the other twenty balneotherapy. Pain, symptoms, and quality of life were assessed. Oxytocin, brain-derived neurotrophic factor (BDNF), ATP and serotonin transporter levels during therapy were assayed. Comparative whole saliva (WS) proteomic analysis was performed using a combination of two-dimensional electrophoresis (2DE) and mass spectrometry techniques. We observed a reduction in pain, FIQ values and improvement of SF36 in both groups of patients treated with mud-bath or balneotherapy. The improvement of the outcome measures occurred with different timing and duration in the two spa treatments. A significant decrease in BDNF concentrations was observed either after balneotherapy or mud-bath therapy when assayed after twelve weeks, while no significant change in oxytocin levels, ATP levels and serotonin transporter were detected. Significant differences were observed for phosphoglycerate mutase1 (PGAM1) and zinc alpha-2-glycoprotein 1 (AZGP1) protein expression. Our results showed that the thermal treatment might have a beneficial effect on the specific symptoms of the disease. In particular, while balneotherapy gives results that in most patients occur after the end of the treatment but which are no longer noticeable after 3 months, the mud-bath treatment gives longer lasting results.


Pathophysiology of internal hemorrhoids.
Hemorrhoidal disease is a fairly common and debilitating clinical entity. Despite centuries' of attempts to shed light on its pathophysiology, to cure those affected and to improve sufferers' quality of life, many aspects of the disease remain elusive. Individual beliefs and historical legends, accompanied by undocumented theories, have established and perpetuated the confusion regarding the mechanisms leading to the development of the disease and the rules governing its treatment. Hemorrhoids are classified as internal or external and are viewed as a disease when they become symptomatic. Returning to basic medical sciences, this mini-review focuses on internal hemorrhoids and aims to define the histology and anatomy of the normal and abnormal internal hemorrhoidal plexus and to encourage clinicians to comprehend the pathophysiology of the disease. If doctors can understand the pathophysiology of hemorrhoidal disease, they will be able to clarify the nature of the associated symptoms and complications and to make the correct therapeutic decision.


Lower extremity amputation in scleroderma.
Scleroderma or Systemic Sclerosis (SSC) is a disorder characterized by fibrosis of the skin and multiple internal organs. The pathological lesion is a triad of small artery intimal proliferation, medial thinning and adventitial scarring. Autoamputation of fingers and toes is often seen, but only a few cases of limb amputation in scleroderma patients have been reported. The Pittsburgh Scleroderma databank includes 1,030 patients with SSC. Among these were seven patients who sustained lower limb amputation. There were four patients with the CREST variant of SSC, two with diffuse scleroderma, and one who had SSC/rheumatoid arthritis/polymyositis overlap who sustained limb amputation. Of the seven, three were male and five had a significant smoking history. Ages ranged from 46 to 71 years. All patients underwent amputation for nonhealing ulcerations. No problems with postoperative wound healing were seen. Pathologic changes typical of SSC in addition to atherosclerotic peripheral vascular disease were described in one case. Three patients were successfully fitted with prostheses and became independent ambulators. Four patients could not be fitted with prostheses. No skin problems were reported related to prosthetic use. Our review demonstrates that SSC patients who undergo amputation can become successful prosthetic users and should be considered for prosthetic prescription.


Covariance of the absorption of phytoplankton, colored dissolved organic matter, and detritus in case I waters, as deduced from the Coastal Zone Color Scanner bio-optical algorithm.
The universal bio-optical algorithm of the Coastal Zone Color Scanner (CZCS) for case I waters implicitly contains an average covariance of the absorption by phytoplankton and colored dissolved organic matter (CDOM) and detritus. We made that covariance explicit by combining the CZCS algorithm with an expression for reflectance. The spectral variation of absorption by CDOM plus detritus for case I waters may be estimated by the expression a(gd(λ)) = 2a(ph)(443)*chl{exp[-0.013(λ - 443)].


Macroautophagy is not directly involved in the metabolism of amyloid precursor protein.
Alterations in the metabolism of amyloid precursor protein (APP) are believed to play a central role in Alzheimer disease pathogenesis. Burgeoning data indicate that APP is proteolytically processed in endosomal-autophagic-lysosomal compartments. In this study, we used both in vivo and in vitro paradigms to determine whether alterations in macroautophagy affect APP metabolism. Three mouse models of glycosphingolipid storage diseases, namely Niemann-Pick type C1, GM1 gangliosidosis, and Sandhoff disease, had mTOR-independent increases in the autophagic vacuole (AV)-associated protein, LC3-II, indicative of impaired lysosomal flux. APP C-terminal fragments (APP-CTFs) were also increased in brains of the three mouse models; however, discrepancies between LC3-II and APP-CTFs were seen between primary (GM1 gangliosidosis and Sandhoff disease) and secondary (Niemann-Pick type C1) lysosomal storage models. APP-CTFs were proportionately higher than LC3-II in cerebellar regions of GM1 gangliosidosis and Sandhoff disease, although LC3-II increased before APP-CTFs in brains of NPC1 mice. Endogenous murine Aβ40 from RIPA-soluble extracts was increased in brains of all three mice. The in vivo relationship between AV and APP-CTF accumulation was also seen in cultured neurons treated with agents that impair primary (chloroquine and leupeptin + pepstatin) and secondary (U18666A and vinblastine) lysosomal flux. However, Aβ secretion was unaffected by agents that induced autophagy (rapamycin) or impaired AV clearance, and LC3-II-positive AVs predominantly co-localized with degradative LAMP-1-positive lysosomes. These data suggest that neuronal macroautophagy does not directly regulate APP metabolism but highlights the important anti-amyloidogenic role of lysosomal proteolysis in post-secretase APP-CTF catabolism.


T-cell epitope mapping of the Borrelia garinii outer surface protein A in lyme neuroborreliosis.
We studied the T-cell reactivity to overlapping peptides of B. garinii OspA, in order to locate possible immunodominant T-cell epitopes in neuroborreliosis. Cells from cerebrospinal fluid (CSF) and blood from 39 patients with neuroborreliosis and 31 controls were stimulated with 31 overlapping peptides, and interferon-gamma secreting cells were detected by ELISPOT. The peptides OspA(17-36), OspA(49-68), OspA(105-124), OspA(137-156), OspA(193-212) and OspA(233-252) showed the highest frequency of positive responses, being positive in CSF from 38% to 50% of patients with neuroborreliosis. These peptides also elicited higher responses in CSF compared with controls (P = 0.004). CSF cells more often showed positive responses to these peptides than blood cells (P = 0.001), in line with a compartmentalization to the central nervous system. Thus, a set of potential T-cell epitopes were identified in CSF cells from patients with neuroborreliosis. Further studies may reveal whether these epitopes can be used diagnostically and studies involving HLA interactions may show their possible pathogenetic importance.


Audio-visual preferences, perception, and use of water features in open-plan offices.
This paper examines the use of water features for masking irrelevant speech and improving the soundscape of open-plan offices. Two laboratory experiments were carried out, as well as acoustic simulations and field tests. Experiment 1 aimed to identify the preferred sound level of water sounds against irrelevant speech. Experiment 2 examined the audio-only and audio-visual preferences and perception of waterscapes. Acoustic simulations and field tests examined the impact of design factors. The results showed that, when played against a constant level of irrelevant speech of 48 dBA, people prefer to listen to water sounds of 42-48 dBA (45 dBA being best). These results and results from previous research suggest that water sounds work mainly as informational maskers rather than energetic maskers. Furthermore, the introduction of a water feature improved the perception of the sound environment, and adding visual stimuli improved perception by up to 2.5 times. Acoustic simulations indicated that features at each corner and one at the center (or a single feature with an array of speakers) can provide appropriate masking for a large open-plan office, whilst field tests showed that water sounds decrease the distraction and privacy distances significantly (clusters of workstations benefitting more than rows of workstations).


Classification of canine malignant lymphomas according to the World Health Organization criteria.
A study was carried out to test the accuracy and consistency of veterinary pathologists, not specialists in hematopathology, in applying the World Health Organization (WHO) system of classification of canine lymphomas. This study represents an initiative of the ACVP Oncology Committee, and the classification has been endorsed by the World Small Animal Veterinary Association (WASVA). Tissue biopsies from cases of canine lymphoma were received from veterinary oncologists, and a study by pathologists given only signalment was carried out on 300 cases. Twenty pathologists reviewed these 300 cases with each required to choose a diagnosis from a list of 43 B and T cell lymphomas. Three of the 20 were hematopathologists who determined the consensus diagnosis for each case. The 17 who formed the test group were experienced but not specialists in hematopathology, and most were diplomates of the American or European Colleges of Veterinary Pathology. The overall accuracy of the 17 pathologists on the 300 cases was 83%. When the analysis was limited to the 6 most common diagnoses, containing 80% of all cases, accuracy rose to 87%. In a test of reproducibility enabled by reintroducing 5% of cases entered under a different identity, the overall agreement between the first and second diagnosis ranged from 40 to 87%. The statistical review included 43,000 data points for each of the 20 pathologists.


Distinct domain-dependent effect of syntaxin1A on amiloride-sensitive sodium channel (ENaC) currents in HT-29 colonic epithelial cells.
The amiloride-sensitive epithelial sodium channel (ENaC), a plasma membrane protein mediates sodium reabsorption in epithelial tissues, including the distal nephron and colon. Syntaxin1A, a trafficking protein of the t-SNARE family has been reported to inhibit ENaC in the Xenopus oocyte expression and artificial lipid bilayer systems. The present report describes the regulation of the epithelial sodium channel by syntaxin1A in a human cell line that is physiologically relevant as it expresses both components and also responds to aldosterone stimulation. In order to evaluate the physiological significance of syntaxin1A interaction with natively expressed ENaC, we over-expressed HT-29 with syntaxin1A constructs comprising various motifs. Unexpectedly, we observed the augmentation of amiloride-sensitive currents with wild-type syntaxin1A full-length construct (1-288) in this cell line. Both gammaENaC and neutralizing syntaxin1A antibodies blocked native expression as amiloride-sensitive sodium currents were inhibited while munc18-1 antibody reversed this effect. The coiled-coiled domain H3 (194-266) of syntaxin1A inhibited, however the inclusion of the transmembrane domain to this motif (194-288) augmented amiloride sensitive currents. More so, data suggest that ENaC interacts with multiple syntaxin1A domains, which differentially regulate channel function. This functional modulation is the consequence of the physical enhancement of ENaC at the cell surface in cells over-expressed with syntaxin(s). Our data further suggest that syntaxin1A up-regulates ENaC function by multiple mechanisms that include PKA, PLC, PI3 and MAP Kinase (p42/44) signaling systems. We propose that syntaxin1A possesses distinct inhibitory and stimulatory domains that interact with ENaC subunits, which critically determines the overall ENaC functionality/regulation under distinct physiological conditions.


Cosmological Constraints from Multiple Probes in the Dark Energy Survey.
The combination of multiple observational probes has long been advocated as a powerful technique to constrain cosmological parameters, in particular dark energy. The Dark Energy Survey has measured 207 spectroscopically confirmed type Ia supernova light curves, the baryon acoustic oscillation feature, weak gravitational lensing, and galaxy clustering. Here we present combined results from these probes, deriving constraints on the equation of state, w, of dark energy and its energy density in the Universe. Independently of other experiments, such as those that measure the cosmic microwave background, the probes from this single photometric survey rule out a Universe with no dark energy, finding w=-0.80_{-0.11}^{+0.09}. The geometry is shown to be consistent with a spatially flat Universe, and we obtain a constraint on the baryon density of Ω_{b}=0.069_{-0.012}^{+0.009} that is independent of early Universe measurements. These results demonstrate the potential power of large multiprobe photometric surveys and pave the way for order of magnitude advances in our constraints on properties of dark energy and cosmology over the next decade.


Incidence rates of carbapenemase-producing Enterobacteriaceae clinical isolates in France: a prospective nationwide study in 2011-12.
To determine proportions and incidence rates of Enterobacteriaceae producing carbapenemase among those non-susceptible (NS) to carbapenems in France. From November 2011 to April 2012, 71 laboratories recorded non-duplicate Enterobacteriaceae clinical isolates NS to at least one carbapenem and the total number of isolates of the different species. Carbapenem MICs were determined by broth microdilution and the β-lactamase content by DNA microarray. During the study period, the 71 laboratories identified 133 244 Enterobacteriaceae isolates, of which 846 (0.63%) were NS to at least one carbapenem. Carbapenem-NS isolates accounted for 0.07% (61/90 148) among Escherichia coli isolates, 1.1% (111/10 436) among Klebsiella pneumoniae, 8.2% (492/5971) among Enterobacter cloacae and 4.0% (84/2104) among Enterobacter aerogenes. Among the 541 available carbapenem-NS isolates, 222 (including 63 randomly selected E. cloacae) were further analysed after confirmation of carbapenem non-susceptibility. None of the Enterobacter spp. isolates produced carbapenemase. Among the other species, 28 isolates produced carbapenemases (22 OXA-48, 4 KPC and 2 NDM), accounting for an estimated proportion of carbapenemase-producing isolates of 0.08% for all species, 0.01% for E. coli and 0.27% for K. pneumoniae. The incidence-density rate in the participating hospitals was 0.0041 per 1000 hospital-days and the incidence rate was 0.0027 per 100 admissions. The incidence-density rate of carbapenemase-producing isolates per 1000 hospital-days was low and 30-fold lower than that of carbapenem-NS isolates (0.125) and almost 300-fold lower than that of ESBL-producing isolates (1.104) in these French hospitals.


Inhibition of voltage-sensitive sodium channels in neuroblastoma cells and synaptosomes by the anticonvulsant drugs diphenylhydantoin and carbamazepine.
The inhibitory action of a number of clinically effective anticonvulsants on neurotoxin-activated sodium channels in cultured neuroblastoma cells and rat brain synaptosomes has been examined. Diphenylhydantoin (KI = 35 microM) and carbamazepine (KI = 41 microM) inhibited batrachotoxin-activated 22Na+ influx in N18 cells. Similarly, batrachotoxin-activated 22Na+ influx in rat brain synaptosomes was also inhibited by diphenylhydantoin (KI = 38 microM) and carbamazepine (KI = 22 microM). Comparison of KI values with mean brain levels of these drugs achieved during prevention of electroshock seizures indicates that diphenylhydantoin and carbamazepine occupy 35% and 50%, respectively, of their receptor sites associated with sodium channels at mean therapeutic concentrations. Diazepam (KI = 51 to 63 microM) and phenobarbital (KI = 1.2 to 1.3 mM) inhibited batrachotoxin-activated 22Na+ flux in N18 cells and synaptosomes at concentrations in excess of mean therapeutic central nervous system levels. Carbamazepine, like diphenylhydantoin, acts as a competitive inhibitor of sodium channel activation by the full agonist batrachotoxin, but produces mixed inhibition of veratridine-activated channels. This finding is consistent with the conclusion that both carbamazepine and diphenylhydantoin act as allosteric inhibitors of neurotoxin-activated sodium channels. The dose-response relationships for carbamazepine and diphenylhydantoin inhibition of 22Na+ flux in N18 cells are shifted 1.5-fold to higher concentrations when 22Na+ flux measurements are made in the presence of physiological concentrations of sodium and calcium ions. These results suggest that anticonvulsant inhibition of neurotoxin-activated 22Na+ flux in our standard ion flux media, containing low concentrations of Na+ and no Ca2+, is likely to reflect an effect of these agents expected in vivo. The results of this study provide further evidence to support the hypothesis that diphenylhydantoin and carbamazepine, both of which possess similar therapeutic profiles in the treatment of grand mal and partial seizures, may exert their pharmacological effects by occupancy of receptor sites associated with the activation of voltage-sensitive sodium channels in the central nervous system.