Nicotine/cigarette smoke promotes metastasis of pancreatic cancer through α7nAChR-mediated MUC4 upregulation.
Despite evidence that long-term smoking is the leading risk factor for pancreatic malignancies, the underlying mechanism(s) for cigarette-smoke (CS)-induced pancreatic cancer (PC) pathogenesis has not been well established. Our previous studies revealed an aberrant expression of the MUC4 mucin in PC as compared with the normal pancreas, and its association with cancer progression and metastasis. Interestingly, here we explore a potential link between MUC4 expression and smoking-mediated PC pathogenesis and report that both cigarette smoke extract and nicotine, which is the major component of CS, significantly upregulates MUC4 in PC cells. This nicotine-mediated MUC4 overexpression was via the α7 subunit of nicotinic acetylcholine receptor (nAChR) stimulation and subsequent activation of the JAK2/STAT3 downstream signaling cascade in cooperation with the MEK/ERK1/2 pathway; this effect was blocked by the α7nAChR antagonists, α-bungarotoxin and mecamylamine, and by specific siRNA-mediated STAT3 inhibition. In addition, we demonstrated that nicotine-mediated MUC4 upregulation promotes the PC cell migration through the activation of the downstream effectors, such as HER2, c-Src and FAK; this effect was attenuated by shRNA-mediated MUC4 abrogation, further implying that these nicotine-mediated pathological effects on PC cells are MUC4 dependent. Furthermore, the in vivo studies showed a marked increase in the mean pancreatic tumor weight (low dose (100 mg/m(3) total suspended particulate (TSP)), P=0.014; high dose (247 mg/m(3) TSP), P=0.02) and significant tumor metastasis to various distant organs in the CS-exposed mice, orthotopically implanted with luciferase-transfected PC cells, as compared with the sham controls. Moreover, the CS-exposed mice had elevated levels of serum cotinine (low dose, 155.88±35.96 ng/ml; high dose, 216.25±29.95 ng/ml) and increased MUC4, α7nAChR and pSTAT3 expression in the pancreatic tumor tissues. Altogether, our findings revealed for the first time that CS upregulates the MUC4 mucin in PC via the α7nAChR/JAK2/STAT3 downstream signaling cascade, thereby promoting metastasis of PC.


Attribution of extreme weather and climate-related events.
Extreme weather and climate-related events occur in a particular place, by definition, infrequently. It is therefore challenging to detect systematic changes in their occurrence given the relative shortness of observational records. However, there is a clear interest from outside the climate science community in the extent to which recent damaging extreme events can be linked to human-induced climate change or natural climate variability. Event attribution studies seek to determine to what extent anthropogenic climate change has altered the probability or magnitude of particular events. They have shown clear evidence for human influence having increased the probability of many extremely warm seasonal temperatures and reduced the probability of extremely cold seasonal temperatures in many parts of the world. The evidence for human influence on the probability of extreme precipitation events, droughts, and storms is more mixed. Although the science of event attribution has developed rapidly in recent years, geographical coverage of events remains patchy and based on the interests and capabilities of individual research groups. The development of operational event attribution would allow a more timely and methodical production of attribution assessments than currently obtained on an ad hoc basis. For event attribution assessments to be most useful, remaining scientific uncertainties need to be robustly assessed and the results clearly communicated. This requires the continuing development of methodologies to assess the reliability of event attribution results and further work to understand the potential utility of event attribution for stakeholder groups and decision makers. WIREs Clim Change 2016, 7:23-41. doi: 10.1002/wcc.380 For further resources related to this article, please visit the WIREs website.


Assignment of Colletotrichum coccodes isolates into vegetative compatibility groups using infrared spectroscopy: a step towards practical application.
Colletotrichum coccodes (C. coccodes) is a pathogenic fungus that causes anthracnose on tomatoes and black dot disease in potatoes. It is considered as a seed tuber and soil-borne pathogen that is difficult to control. C. coccodes isolates are classified into Vegetative Compatibility Groups (VCGs). Early classification of isolates into VCGs is of great importance for a better understanding of the epidemiology of the disease and improving its control. Moreover, the differentiation among these isolates and the assignment of newly-discovered isolates enable control of the disease at its early stages. Distinguishing between isolates using microbiological or genetic methods is time-consuming and not readily available. Our results show that it is possible to assign the isolates into their VCGs and to classify them at the isolate level with a high success rate using Principal Component Analysis (PCA) and Linear Discriminant Analysis (LDA).


Toxicoepidemiology of fatal poisonings in Southern India.
An autopsy based retrospective study was conducted from January 2000 to December 2006 at Manipal in Southern India, and a profile of the victims of poisoning was prepared. The study was done to understand the magnitude and pattern of all poisoning fatalities in relation to the manner of death in Manipal region of Southern India. The study included a total of 198 cases of fatal poisoning. Self-poisoning was reported in 92.9% cases. Fatal accidental poisoning was seen in 6.1% cases. Homicide by poisoning was not reported during the study period. Uncertainty regarding the manner of death due to poisoning was observed only in two cases. Males were predominantly affected (71.2%). The majority of the victims were in the 3rd decade (28.3%) of life. The age of the victims ranged from 2 to 82 years with a mean age of 38.4 years. While majority of the victims consumed poison during daytime, most of the poisoning fatalities were reported during summer months. Organophosphate compounds were implicated in 68.7% of the total poisoning related fatalities. Males in the 3rd to 5th decades were prone to self-poisoning with organophosphate compounds. Accidental poisoning deaths were uncommon and poisoning was not a preferred method of homicide in this region. Our approach to the study reveals that quantitative chemical (toxicological) analysis is required to further strengthen and improve the databases of epidemiology of poisoning in our region.


Relationship between sensitivity to dietary fat and dietary cholesterol.
A group of 56 hypercholesterolemic and normocholesterolemic men and women were given approximately 700 mg a day of egg yolk cholesterol in a double-blind, crossover study while they were on a background diet containing approximately 30% of energy as fat. Overall there was a 0.23 mmol/l rise in plasma cholesterol (3.7%, p less than 0.001) after 4 weeks, a 0.19 mmol/l rise in low density lipoprotein (LDL) cholesterol (4.9%, p = 0.002), and a 0.07 mmol/l rise in high density lipoprotein (HDL) cholesterol (5.4%, p less than 0.001). Plasma triglycerides fell by 0.07 mmol/l (5.1%). Normocholesterolemic individuals (plasma cholesterol less than 5.2 mmol/l) experienced small, nonsignificant rises of 0.06, 0.02, and 0.05 mmol/l in total, LDL, and HDL cholesterol, respectively. Hypercholesterolemic subjects were classified on the basis of their response to a low fat diet. Diet-sensitive subjects were defined by a greater than 10% fall in plasma cholesterol on a 25% fat, low cholesterol (less than 200 mg/day) diet. These individuals were found to be more responsive to the effect of dietary cholesterol than were diet-insensitive subjects; the respective changes in the two groups were rises of 0.36 mmol/l versus 0.19 mmol/l in plasma cholesterol (p = 0.06) and rises of 0.30 versus 0.15 mmol/l in LDL cholesterol (p = 0.06). In addition to elevating HDL cholesterol by 0.09 mmol/l and 0.07 mmol/l, respectively, dietary cholesterol also produced an increase in the proportion of HDL2, from 40% to 44% of HDL protein (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)


Dual-wavelength optical head with a wavelength-selective filter for 0.6- and 1.2-mm-thick-substrate optical disks.
A dual-wavelength optical head, believed to be new in design, for 0.6- and 1.2-mm-thick-substrate optical disks was developed by use of 650- and 780-nm-wavelength light and a wavelength-selective filter, which reduces the spherical aberration that is due to the difference in substrate thicknesses and restricts the numerical aperture for 780-nm-wavelength light. According to this configuration, both high light power efficiency and wide image field characteristics are obtained, which are suitable not only for read-only but also for recordable or rewritable optical disk systems. A reading operation for a digital video disc and for a compact disc and a recording operation for a phase change optical disk were successfully demonstrated.


Delayed clearance of Sendai virus in mice lacking class I MHC-restricted CD8+ T cells.
The role and interdependence of CD8+ and CD4+ alpha beta-T cells in the acute response after respiratory infection with the murine parainfluenza type 1 virus, Sendai virus, has been analyzed for H-2b mice. Enrichment of CD8+ virus-specific CTL effectors in the lungs of immunologically intact C57BL/6 animals coincided with the clearance of the virus from this site by day 10 after infection. Removal of the CD4+ T cells by in vivo mAb treatment did not affect appreciably either the recruitment of CD8+ T cells to the infected lung, or their development into virus-specific cytotoxic effectors. In contrast, depletion of the CD8+ subset delayed virus clearance, although most mice survived the infection. Transgenic H-2b F3 mice homozygous (-/-) for a beta 2 microglobulin (beta 2-m) gene disruption, which lack both class I MHC glycoproteins and mature CD8+ alpha beta-T cells, showed a comparable, delayed clearance of Sendai virus from the lung. Virus-specific, class II MHC-restricted CTL were demonstrated in both freshly isolated bronchoalveolar lavage populations and cultured lymph node and spleen tissue from the beta 2-m (-/-) transgenics. Treatment of the beta 2-m (-/-) mice with the mAb to CD4 led to delayed virus clearance and death, which was also the case for normal mice that were depleted simultaneously of the CD4+ and CD8+ subsets. These results indicate that, although classical class I MHC-restricted CD8+ cytotoxic T cells normally play a dominant role in the recovery of mice acutely infected with Sendai virus, alternative mechanisms involving CD4+ T cells exist and can compensate, in time, for the loss of CD8+ T cell function.


Peripheral Vision in Martial Arts Experts: The Cost-Dependent Anchoring of Gaze.
Research on martial arts has suggested that gaze anchoring is functional for optimizing the use of peripheral visual information. The current study predicted that the height of gaze anchoring on the opponent's body would depend on the potential attacking locations that need to be monitored. To test this prediction, the authors compared high-level athletes in kung fu (Qwan Ki Do), who attack with their arms and legs, with Tae Kwon Do fighters, who attack mostly with their legs. As predicted, the results show that Qwan Ki Do athletes anchor their gaze higher than Tae Kwon Do athletes do before and even during the first attack. In addition, gaze anchoring seems to depend on 3 factors: the particulars of the evolving situation, crucial cues, and specific visual costs (especially suppressed information pickup during saccades). These 3 factors should be considered in future studies on gaze behavior in sports to find the most functional, that is, cost-benefit-optimized, gaze pattern.


Motivational intervention to reduce rapid subsequent births to adolescent mothers: a community-based randomized trial.
One-quarter of adolescent mothers bear another child within 2 years, compounding their risk of poorer medical, educational, economic, and parenting outcomes. Most efforts to prevent rapid subsequent birth to teenagers have been unsuccessful but have seldom addressed motivational processes. We conducted a randomized trial to determine the effectiveness of a computer-assisted motivational intervention (CAMI) in preventing rapid subsequent birth to adolescent mothers. Pregnant teenagers (N = 235), aged 18 years and older who were at more than 24 weeks' gestation, were recruited from urban prenatal clinics serving low-income, predominantly African American communities. After completing baseline assessments, they were randomly assigned to 3 groups: (1) those in CAMI plus enhanced home visit (n = 80) received a multi-component home-based intervention (CAMI+); (2) those in CAMI-only (n = 87) received a single component home-based intervention; (3) and those in usual-care control (n = 68) received standard usual care. Teens in both intervention groups received CAMI sessions at quarterly intervals until 2 years' postpartum. Those in the CAMI+ group also received monthly home visits with parenting education and support. CAMI algorithms, based on the transtheoretical model, assessed sexual relationships and contraception-use intentions and behaviors, and readiness to engage in pregnancy prevention. Trained interventionists used CAMI risk summaries to guide motivational interviewing. Repeat birth by 24 months' postpartum was measured with birth certificates. Intent-to-treat analysis indicated that the CAMI+ group compared with the usual-care control group exhibited a trend toward lower birth rates (13.8% vs 25.0%; P = .08), whereas the CAMI-only group did not (17.2% vs 25.0%; P = .32). Controlling for baseline group differences, the hazard ratio (HR) for repeat birth was significantly lower for the CAMI+ group than it was with the usual-care group (HR = 0.45; 95% CI, 0.21-0.98). We developed complier average causal effects models to produce unbiased estimates of intervention effects accounting for variable participation. Completing 2 or more CAMI sessions significantly reduced the risk of repeat birth in both groups: CAMI+ (HR = 0.40; 95% CI, 0.16-0.98) and CAMI-only (HR = 0.19; 95% CI, 0.05-0.69). Receipt of 2 or more CAMI sessions, either alone or within a multicomponent home-based intervention, reduced the risk of rapid subsequent birth to adolescent mothers.


Effect of calcium hydroxide and triple antibiotic paste as intracanal medicaments on the incidence of inter-appointment flare-up in diabetic patients: An in vivo study.
To evaluate and compare the effect of antibacterial intracanal medicaments on inter-appointment flare-up in diabetic patients. Fifty diabetic patients requiring root canal treatment were assigned into groups I, II, and III. In group I, no intracanal medicament was placed. In groups II and III, calcium hydroxide and triple antibiotic pastes were placed as intracanal medicaments, respectively. Patients were instructed to record their pain on days 1, 2, 3, 7, and 14. Inter-appointment flare-up was evaluated using verbal rating scale (VRS). Overall incidence of inter-appointment flare-up among diabetic patients was found to be 16%. In group I, 50% of the patients and in group II, 15% of the patients developed inter-appointment flare-up. However, no patients in group III developed inter-appointment flare-up. The comparison of these results was found to be statistically significant (P = 0.002; χ(2) = 12.426). However, with respect to intergroup comparison, only the difference between groups I and III was found to be statistically significant (P = 0.002; χ(2) = 12.00). Calcium hydroxide and triple antibiotic paste are effective for managing inter-appointment flare-ups in diabetic patients. Triple antibiotic paste is more effective than calcium hydroxide in preventing the occurrence of flare-up in diabetic patients.


A global optimisation approach to range-restricted survey calibration.
Survey calibration methods modify minimally sample weights to satisfy domain-level benchmark constraints (BC), e.g. census totals. This allows exploitation of auxiliary information to improve the representativeness of sample data (addressing coverage limitations, non-response) and the quality of sample-based estimates of population parameters. Calibration methods may fail with samples presenting small/zero counts for some benchmark groups or when range restrictions (RR), such as positivity, are imposed to avoid unrealistic or extreme weights. User-defined modifications of BC/RR performed after encountering non-convergence allow little control on the solution, and penalisation approaches modelling infeasibility may not guarantee convergence. Paradoxically, this has led to underuse in calibration of highly disaggregated information, when available. We present an always-convergent flexible two-step global optimisation (GO) survey calibration approach. The feasibility of the calibration problem is assessed, and automatically controlled minimum errors in BC or changes in RR are allowed to guarantee convergence in advance, while preserving the good properties of calibration estimators. Modelling alternatives under different scenarios using various error/change and distance measures are formulated and discussed. The GO approach is validated by calibrating the weights of the 2012 Health Survey for England to a fine age-gender-region cross-tabulation (378 counts) from the 2011 Census in England and Wales.


A life course approach to health literacy: the role of gender, educational attainment and lifetime cognitive capability.
social inequalities in health are believed to arise in part because individuals make use of social and economic resources in order to improve survival. In recent years, health literacy has received increased attention as a factor that can help explain differences in health outcomes. However, examination of life course predictors of health literacy has been limited. life course data from the Wisconsin Longitudinal Study 1957-2011 were used to examine predictors of health literacy in old age (N = 2,122), using the Newest Vital Sign. Generalised structural equation modelling was used to model pathways to health literacy. predictors of health literacy included educational attainment, and adolescent cognitive and non-cognitive skills, and, in men, rate of cognitive decline from middle to later life. numerous studies have documented health literacy issues among older adults, and recommendations have been made for ways to improve health literacy for this population. This study reports on risk factors across the life course that are associated with health literacy later in life, identifying possible intervention targets to reduce risk of poor health as people age. Our results suggest that a range of life course factors, beginning in early life, predict health literacy. Further research studying health literacy over the life course is warranted.


Interleukin-22 is elevated in lavage from patients with lung cancer and other pulmonary diseases.
Interleukin-22 (IL-22) is involved in lung diseases such as pneumonia, asthma and lung cancer. Lavage mirrors the local environment, and may provide insights into the presence and role of IL-22 in patients. Bronchoscopic lavage (BL) samples (n = 195, including bronchoalveolar lavage and bronchial washings) were analysed for IL-22 using an enzyme-linked immunosorbent assay. Clinical characteristics and parameters from lavage and serum were correlated with lavage IL-22 concentrations. IL-22 was higher in lavage from patients with lung disease than in controls (38.0 vs 15.3 pg/ml, p < 0.001). Patients with pneumonia and lung cancer had the highest concentrations (48.9 and 33.0 pg/ml, p = 0.009 and p < 0.001, respectively). IL-22 concentration did not correlate with systemic inflammation. IL-22 concentrations did not relate to any of the analysed cell types in BL indicating a potential mixed contribution of different cell populations to IL-22 production. Lavage IL-22 concentrations are high in patients with lung cancer but do not correlate with systemic inflammation, thus suggesting that lavage IL-22 may be related to the underlying malignancy. Our results suggest that lavage may represent a distinct compartment where the role of IL-22 in thoracic malignancies can be studied.


Development of an antibiotic spectrum score based on veterans affairs culture and susceptibility data for the purpose of measuring antibiotic de-escalation: a modified Delphi approach.
Development of a numerical score to measure the microbial spectrum of antibiotic regimens (spectrum score) and method to identify antibiotic de-escalation events based on application of the score. Web-based modified Delphi method. Physician and pharmacist antimicrobial stewards practicing in the United States recruited through infectious diseases-focused listservs. Three Delphi rounds investigated: organisms and antibiotics to include in the spectrum score, operationalization of rules for the score, and de-escalation measurement. A 4-point ordinal scale was used to score antibiotic susceptibility for organism-antibiotic domain pairs. Antibiotic regimen scores, which represented combined activity of antibiotics in a regimen across all organism domains, were used to compare antibiotic spectrum administered early (day 2) and later (day 4) in therapy. Changes in spectrum score were calculated and compared with Delphi participants' judgments on de-escalation with 20 antibiotic regimen vignettes and with non-Delphi steward judgments on de-escalation of 300 pneumonia regimen vignettes. Method sensitivity and specificity to predict expert de-escalation status were calculated. Twenty-four participants completed all Delphi rounds. Expert support for concepts utilized in metric development was identified. For vignettes presented in the Delphi, the sign of change in score correctly classified de-escalation in all vignettes except those involving substitution of oral antibiotics. The sensitivity and specificity of the method to identify de-escalation events as judged by non-Delphi stewards were 86.3% and 96.0%, respectively. Identification of de-escalation events based on an algorithm that measures microbial spectrum of antibiotic regimens generally agreed with steward judgments of de-escalation status.


THE RELATIONSHIP OF YELLOW FEVER OF THE WESTERN HEMISPHERE TO THAT OF AFRICA AND TO LEPTOSPIRAL JAUNDICE.
1. The yellow fever now in South America, the present yellow fever of Africa and the historic yellow fever of Panama and other American countries are the same disease. This conclusion is based on cross immunity tests in monkeys with strains of yellow fever virus from Africa and Brazil and on tests of sera from 25 persons, who had recovered from yellow fever in various places and at various times, for the power to protect monkeys against African or Brazilian virus strains. 2. Cases of leptospiral jaundice (Weil's disease) were present among those diagnosed as yellow fever in the recent epidemic in Rio de Janeiro. This is shown by the isolation of cultures of leptospirae from the blood of two patients by H. R. Muller and E. B. Tilden of The Rockefeller Institute, and by the demonstration by us of protective power against leptospirae and absence of protective power against yellow fever virus in the sera from two persons after recovery. The isolation of leptospirae by Noguchi and other investigators from the blood of occasional patients in past epidemics of yellow fever in a number of American countries indicates that leptospiral jaundice was present then as well and was diagnosed clinically as yellow fever. 3. The absence of protective power against leptospirae shown by the Brazilian sera which protected against yellow fever virus and the absence of protective power against yellow fever virus in the sera that protected against leptospirae point to the probability that American yellow fever is not the combined effect of leptospirae and yellow fever virus. The position of L. icteroides, isolated by Noguchi during yellow fever epidemics, now appears to be not that of a secondary invading microorganism in cases of virus yellow fever, but that of the incitant of a form of infectious jaundice, sometimes fatal, often coincident in its appearance with typical yellow fever and apparently indistinguishable from it clinically. This leptospiral disease has not hitherto been separated from true yellow fever. Noguchi's discoveries become; therefore, of the greatest significance in respect to the epidemiology and causation of yellow fever and of infectious jaundice, previously confused one with the other. In all outbreaks of supposed yellow fever hereafter the existence of the two kinds of jaundice, one due to yellow fever virus and the other to leptospirae will have to be taken into account. Only the former probably is spread by mosquitoes and requires anti-mosquito measures for its control. 4. The only difference observed by us between the American and African strains of yellow fever virus was a pronounced difference in virulence for monkeys. The virulence of the two African strains studied was very high while that of the one American strain was highly variable and usually low.


[Quality of data on myocardial infarction deaths, Brazil].
To evaluate the quality of data on acute myocardial infarction deaths from mortality information systems. Data on in-hospital acute myocardial infarction mortality collected from database of the Mortality Information System (SIM) and Hospital Information System (SIH), in 2000, were analyzed. Then data collected from medical records from two hospitals affiliated to the Unified Health System (SUS) in Rio de Janeiro, Brazil, were also analyzed. Medical records, death certificates, and hospital admission forms (AIH) were compared using the World Health Organization criteria of acute myocardial infarction diagnosis. Agreement among different sources was analyzed using Cohen's Kappa statistics and intraclass correlation coefficient. In-hospital death registries in SIM are much larger than in SIH/SUS. There were identified three mechanisms that could explain most of the observed discrepancy: missing hospital admission forms (32.9%), different main diagnosis registered in SIH/SUS (19.2%), and under reporting of deaths in hospital admission forms (3.3%). The medical records review could confirm the diagnoses of acute myocardial infarction in 67.1% of all deaths reported in death certificates. The sensitivity of data on acute myocardial infarction deaths in death certificates was about 90% for both health information systems analyzed. There is a need for actions to improve the quality of data registered in SIH/SUS such as standardization of criteria for issuing hospital admission forms during hospital emergencies and training local staff on registration systems.


Atopic dermatitis and asthma: parallels in the evolution of treatment.
To review epidemiologic correlations between asthma and atopic dermatitis (AD), identify common features in disease pathophysiology, and review steps involved in the development of asthma therapy guidelines to assess the appropriateness of a similar process and approach for AD. A 7-member panel representing specialists in dermatology, allergy, asthma, immunology, and pediatrics from around the United States convened to review the current literature and evolving data on AD. Participants presented reviews to the panel on the epidemiology of asthma and AD, the genetic predisposition to allergic disease, the current understanding of the immunopathophysiology of AD, interrelationships between the pathologic pathways of asthma and AD, evolving treatment concepts and options in AD, and the applicability of the asthma treatment model and how it may be adapted for guideline development for AD. Commentary and criticism were recorded for use in document preparation. There are clear epidemiologic parallels in asthma and AD. Importantly, AD frequently is the first manifestation of an atopic diathesis, which occurs in genetically predisposed individuals and also includes asthma and allergic rhinitis. Up to 80% of children with AD will eventually develop allergic rhinitis or asthma later in childhood. This classic "atopic triad" has numerous pathophysiologic elements in common, including cyclic nucleotide regulatory abnormalities, immune cell alterations, and inflammatory mediators and allergic triggers. New therapeutic options that target underlying immune mechanisms are available, and their place among treatments for AD is becoming established. Guidelines of care have been developed for asthma. The panel noted that the National Institutes of Health/National Heart, Lung, and Blood Institute guidelines for diagnosis and management of asthma, first issued in 1991, had a tremendous positive impact on many aspects of asthma treatment. It not only created a heightened awareness that asthma is a disease of chronic inflammation, but it also provided unified approaches for therapy and opened new areas of basic science and clinical research. In addition, the guidelines spurred interactions among physicians of various specialties and stimulated a great quantity of research in asthma therapy. It is anticipated that AD therapy guidelines would have similar positive outcomes. The panel concluded that, on the basis of current information and evolving therapeutic options, a clear rationale exists to support AD guideline development. The many parallels between AD and asthma suggest that processes and approaches used for the asthma therapy guidelines would be appropriate for AD.


Angiotensin II type 1 receptor blockade suppresses light-induced neural damage in the mouse retina.
Exposure to light contributes to the development and progression of retinal degenerative diseases. However, the mechanisms underlying light-induced tissue damage are not fully understood. Here, we examined the role of angiotensin II type 1 receptor (AT1R) signaling, which is part of the renin-angiotensin system, in light-induced retinal damage. Light-exposed Balb/c mice that were treated with the AT1R blockers (angiotensin II receptor blockers; ARBs) valsartan, losartan, and candesartan before and after the light exposure exhibited attenuated visual function impairment, compared to vehicle-treated mice. This effect was dose-dependent and observed across the ARB class of inhibitors. Further evaluation of valsartan showed that it suppressed a number of light-induced retinal effects, including thinning of the photoreceptor cell layer caused by apoptosis, shortening of the photoreceptor cell outer segment, and increased levels of reactive oxygen species (ROS). The role of ROS in retinal pathogenesis was investigated further using the antioxidant N-acetyl-l-cysteine (NAC). Treatment of light-exposed mice with NAC before the light exposure suppressed the visual function impairment and photoreceptor cell histological changes due to apoptosis. Moreover, treatment with valsartan or NAC suppressed the induction of c-fos (a component of the AP-1 transcription factor) and the upregulation of fasl (a proapoptotic molecule whose transcript is regulated downstream of AP-1). Our results suggest that AT1R signaling mediates light-induced apoptosis, by increasing the levels of ROS and proapoptotic molecules in the retina. Thus, AT1R blockade may represent a new therapeutic approach for preventing light-induced retinal neural tissue damage.


Distinctive emotional responses of clinicians to suicide-attempting patients--a comparative study.
Clinician responses to patients have been recognized as an important factor in treatment outcome. Clinician responses to suicidal patients have received little attention in the literature however, and no quantitative studies have been published. Further, although patients with high versus low lethality suicidal behaviors have been speculated to represent two distinct populations, clinicians' emotional responses to them have not been examined. Clinicians' responses to their patients when last seeing them prior to patients' suicide attempt or death were assessed retrospectively with the Therapist Response/Countertransference Questionnaire, administered anonymously via an Internet survey service. Scores on individual items and subscale scores were compared between groups, and linear discriminant analysis was applied to determine the combination of items that best discriminated between groups. Clinicians reported on patients who completed suicide, made high-lethality attempts, low-lethality attempts, or died unexpected non-suicidal deaths in a total of 82 cases. We found that clinicians treating imminently suicidal patients had less positive feelings towards these patients than for non-suicidal patients, but had higher hopes for their treatment, while finding themselves notably more overwhelmed, distressed by, and to some degree avoidant of them. Further, we found that the specific paradoxical combination of hopefulness and distress/avoidance was a significant discriminator between suicidal patients and those who died unexpected non-suicidal deaths with 90% sensitivity and 56% specificity. In addition, we identified one questionnaire item that discriminated significantly between high- and low-lethality suicide patients. Clinicians' emotional responses to patients at risk versus not at risk for imminent suicide attempt may be distinct in ways consistent with responses theorized by Maltsberger and Buie in 1974. Prospective replication is needed to confirm these results, however. Our findings demonstrate the feasibility of using quantitative self-report methodologies for investigation of the relationship between clinicians' emotional responses to suicidal patients and suicide risk.


Effects of poplar buds as an alternative to propolis on postharvest diseases control of strawberry fruits.
Botrytis cinerea and Rhizopus stolonifer, two main postharvest pathogens, cause great loss of strawberry fruits. Here, the effects of poplar buds extracts, a main plant source for Chinese propolis, on disease control were investigated in vitro and in vivo. The HPLC profile of poplar buds ethanol extract (PBEE) was almost identical to that of propolis ethanol extract (PEE), with the active flavonoids identified as pinocembrin, chrysin and galangin. PBEE exhibited similar inhibitory activities on spore germination of both pathogens compared with PEE, and PBEE also strongly inhibited the mycelial growth of the pathogens. In vivo, PBEE could effectively reduce decay of strawberry fruits stored at 13 °C. Although the weight loss was slightly increased, the contents of total soluble solid, titritable acid, vitamin C and total anthocyanins were significantly higher in PBEE treated fruits than those of the control. PBEE had the similar antifungal activity with propolis and had great potential as an alternative to propolis to control strawberry fruits diseases.


Distinction of 3D Objects and Scenes via Classification Network and Markov Random Field.
An importance measure of 3D objects inspired by human perception has a range of applications since people want computers to behave like humans in many tasks. This paper revisits a well-defined measure, distinction of 3D surface mesh, which indicates how important a region of a mesh is with respect to classification. We develop a method to compute it based on a classification network and a Markov Random Field (MRF). The classification network learns view-based distinction by handling multiple views of a 3D object. Using a classification network has an advantage of avoiding the training data problem which has become a major obstacle of applying deep learning to 3D object understanding tasks. The MRF estimates the parameters of a linear model for combining the view-based distinction maps. The experiments using several publicly accessible datasets show that the distinctive regions detected by our method are not just significantly different from those detected by methods based on handcrafted features, but more consistent with human perception. We also compare it with other perceptual measures and quantitatively evaluate its performance in the context of two applications. Furthermore, due to the view-based nature of our method, we are able to easily extend mesh distinction to 3D scenes containing multiple objects.


The prevalence and clinical characteristics of esophageal involvement in patients with Behçet's disease: a single center experience in Korea.
While a significant amount of clinical information has been reported concerning intestinal involvement in Behçet's disease (BD), esophageal involvement in BD has not yet been studied extensively. The aim of this study was to evaluate the prevalence of esophageal involvement in BD and its clinical characteristics. We retrospectively reviewed the medical records of 842 patients diagnosed with BD at a single tertiary institution in Korea between January 1990 and June 2006. Of the 842 patients with BD, 129 patients (15.3%) experienced upper gastrointestinal symptoms that required inspection through esophagogastroduodenoscopy. Esophageal involvement was found in 6 (4.7%) of the 129 patients. The activity index of Behçet's disease did not differ among patients with or without esophageal involvement. All patients with esophageal involvement responded well to medical treatment and no one experienced serious complications. The results of our study demonstrate that the prevalence of esophageal involvement in BD is very low and that most patients with such involvement face few complications and respond well to medical treatment.


Comparative STM studies of mixed ligand monolayers on gold nanoparticles in air and in 1-phenyloctane.
Scanning tunnelling microscopy (STM) studies have found stripe-like domains on gold nanoparticles (NPs) coated with certain binary mixtures of ligand molecules. The majority of these NPs' properties have been investigated for particles in solvents. Yet, most STM studies are for NPs in a dry state. Images of the same particles in air and liquid have not been obtained yet. In this work, a judicious choice of ligand molecules led to NPs with close-to-ideal STM imaging conditions in air and in 1-phenyloctane (PO). Large datasets under both conditions were acquired and rapidly evaluated through power spectral density (PSD) analysis. The result is a quantitative comparison of stripe-like domains in air and PO on the same NPs. PSD analysis determines a characteristic length-scale for these domains of ~1.0 nm in air and in PO showing persistence of striped domains in these two media. A length scale of ~0.7 nm for homoligand NPs was found.


Tele-surgery simulation with a patient organ model for robotic surgery training.
Robotic systems are increasingly being incorporated into general laparoscopic and thoracoscopic surgery to perform procedures such as cholecystectomy and prostatectomy. Robotic assisted surgery allows the surgeon to conduct minimally invasive surgery with increased accuracy and with potential benefits for patients. However, current robotic systems have their limitations. These include the narrow operative field of view, which can make instrument manipulation difficult. Current robotic applications are also tailored to specific surgical procedures. For these reasons, there is an increasing demand on surgeons to master the skills of instrument manipulation and their surgical application within a controlled environment. This study describes the development of a surgical simulator for training and mastering procedures performed with the da Vinci surgical system. The development of a tele-surgery simulator and the construction of a training center are also described, which will enable surgeons to simulate surgery from or in remote places, to collaborate over long distances, and for off-site expert assistance.


Genome-wide association study of 107 phenotypes in Arabidopsis thaliana inbred lines.
Although pioneered by human geneticists as a potential solution to the challenging problem of finding the genetic basis of common human diseases, genome-wide association (GWA) studies have, owing to advances in genotyping and sequencing technology, become an obvious general approach for studying the genetics of natural variation and traits of agricultural importance. They are particularly useful when inbred lines are available, because once these lines have been genotyped they can be phenotyped multiple times, making it possible (as well as extremely cost effective) to study many different traits in many different environments, while replicating the phenotypic measurements to reduce environmental noise. Here we demonstrate the power of this approach by carrying out a GWA study of 107 phenotypes in Arabidopsis thaliana, a widely distributed, predominantly self-fertilizing model plant known to harbour considerable genetic variation for many adaptively important traits. Our results are dramatically different from those of human GWA studies, in that we identify many common alleles of major effect, but they are also, in many cases, harder to interpret because confounding by complex genetics and population structure make it difficult to distinguish true associations from false. However, a-priori candidates are significantly over-represented among these associations as well, making many of them excellent candidates for follow-up experiments. Our study demonstrates the feasibility of GWA studies in A. thaliana and suggests that the approach will be appropriate for many other organisms.


Expression of p27(KIP1) and cyclin D1, and cell proliferation in human pterygium.
The pterygium is a growth onto the cornea of fibrovascular tissue that is continuous with the conjunctiva, whereas the mechanisms of cell proliferation in pterygium epithelium are unknown. To analyse the histopathology and the expression of cell cycle-related molecules in pterygium tissues. Seven pterygia were surgically removed using the bare-sclera procedure, and three normal bulbar conjunctivas were also obtained. Formalin-fixed, paraffin-wax-embedded tissues were analysed by immunohistochemistry with anti-p27(KIP1), cyclin D1 and Ki-67 antibodies. Conjunctival epithelium consisted of several layers of round cells with a few goblet cells. Nuclear immunoreactivity for p27(KIP1) was noted in many normal epithelial cells, where cyclin D1 and Ki-67-positive nuclei were intermingled. A variety of goblet cells were located in the superficial layer of the pterygium head as well as those of the body epithelia. Several pterygium epithelial cells were p27(KIP1) positive, whereas nuclear immunoreactivity for cyclin D1 and Ki-67 was detected in many epithelial cells. By contrast, immunoreactivity for p27(KIP1), cyclin D1 and Ki-67 was hardly detected in the pterygium stroma. It is suggested that pterygium growth and development are associated with the proliferation of epithelium, which is possibly involved in the expression of cell cycle-related molecules.


Champions for evidence-based practice: a critical role for advanced practice nurses.
Evidence-based practice is emerging as a widely accepted paradigm for contemporary professional nursing practice. Institutions and providers of healthcare services are adopting this framework to guide the structure, process, and outcomes of patient care delivery. Advanced practice nurses are ideally prepared and positioned within healthcare delivery systems to champion the integration of this practice as a model for evidence-based patient care. This article highlights opportunities and suggests strategies for advanced practice nurses to serve as catalysts for optimizing patient care through evidence-based practice.


Motility precedes egress of malaria parasites from oocysts.
Malaria is transmitted when an infected Anopheles mosquito deposits Plasmodium sporozoites in the skin during a bite. Sporozoites are formed within oocysts at the mosquito midgut wall and are released into the hemolymph, from where they invade the salivary glands and are subsequently transmitted to the vertebrate host. We found that a thrombospondin-repeat containing sporozoite-specific protein named thrombospondin-releated protein 1 (TRP1) is important for oocyst egress and salivary gland invasion, and hence for the transmission of malaria. We imaged the release of sporozoites from oocysts in situ, which was preceded by active motility. Parasites lacking TRP1 failed to migrate within oocysts and did not egress, suggesting that TRP1 is a vital component of the events that precede intra-oocyst motility and subsequently sporozoite egress and salivary gland invasion.


Revision of MELD to include serum albumin improves prediction of mortality on the liver transplant waiting list.
Allocation of donor livers for transplantation in most regions is based on the Model for End-Stage Liver Disease (MELD) or MELD-sodium (MELDNa). Our objective was to assess revisions to MELD and MELDNa that include serum albumin for predicting waiting list mortality. Adults registered for liver transplantation in the United States (2002-2007) were identified from the United Network for Organ Sharing (UNOS) database. Cox regression was used to determine the association between serum albumin and 3-month mortality, and to derive revised MELD and MELDNa scores incorporating albumin ('MELD-albumin' and '5-variable MELD [5vMELD]'). Among 40,393 patients, 9% died and 24% underwent transplantation within 3 months of listing. For serum albumin concentrations between 1.0 and 4.0 g/dL, a linear, inverse relationship was observed between albumin and 3-month mortality (adjusted hazard ratio per 1 g/dL reduction in albumin: 1.44; 95% CI 1.35-1.54). The c-statistics for 3-month mortality of MELD-albumin and MELD were 0.913 and 0.896, respectively (P<0.001); 5vMELD was superior to MELDNa (c-statistics 0.922 vs. 0.912, P<0.001). The potential benefit of 5vMELD was greatest in patients with low MELD (<15). Among low MELD patients who died, 27% would have gained ≥10 points with 5vMELD over MELD versus only 4-7% among low MELD survivors and high MELD (≥15) candidates (P<0.0005). Modification of MELD and MELDNa to include serum albumin is associated with improved prediction of waiting list mortality. If validated and shown to be associated with reduced mortality, adoption of 5vMELD as the basis for liver allograft allocation may improve outcomes on the liver transplant waiting list.


Neural correlates of beauty.
We have used the technique of functional MRI to address the question of whether there are brain areas that are specifically engaged when subjects view paintings that they consider to be beautiful, regardless of the category of painting (that is whether it is a portrait, a landscape, a still life, or an abstract composition). Prior to scanning, each subject viewed a large number of paintings and classified them into beautiful, neutral, or ugly. They then viewed the same paintings in the scanner. The results show that the perception of different categories of paintings are associated with distinct and specialized visual areas of the brain, that the orbito-frontal cortex is differentially engaged during the perception of beautiful and ugly stimuli, regardless of the category of painting, and that the perception of stimuli as beautiful or ugly mobilizes the motor cortex differentially.


Transport-reaction model of mural thrombogenesis: comparisons of mathematical model predictions and results from baboon models.
Thrombogenesis depends on biochemical reactions affected by blood flow dynamics. While mathematical models of mural thrombogenesis provide a means of understanding how blood flow affects thrombus growth, comparisons to experimental data are needed to validate the models and enable prediction of thrombus growth under diverse conditions. In this paper, we present mathematical models of mural thrombogenesis under flow and validation of the models with experimental data collected from a thrombogenic vascular graft segment. The grafts were placed in exteriorized high-flow arteriovenous (AV) shunts in baboons. Radiolabeled platelet deposition onto the thrombogenic segment, a marker of thrombus size, and plasma thrombin-antithrombin (TAT) concentration downstream of the graft, a marker of local thrombin generation, were monitored over time. The mathematical model of mural thrombogenesis consisted of transport-reaction equations in which platelets and thrombin were explicitly considered. We found that the transport-reaction model captured the order of magnitude of TAT sampled levels, while calculated rates of platelet deposition agreed well with radioimaging results. Analysis of experimental and modeling data indicates that, at least during part of thrombus growth progression, thrombin generation is in excess and platelet adhesion rates would be sustained even at lower local thrombin concentrations.


Sequential treatment for bulimia nervosa incorporating a self-care manual.
The aim of this study was to evaluate the effectiveness of a stepped care approach to the treatment of bulimia nervosa: a self-care manual followed, if necessary, by a course of attenuated cognitive behavioural treatment (CBT) in comparison with standard CBT. One hundred and ten patients, presenting at a tertiary referral centre with ICD-10 bulimia nervosa or atypical bulimia nervosa, were randomly assigned to one of two treatment conditions; a) a sequential treatment group: 8 weeks with a self-care manual followed by up to eight sessions of CBT (if still symptomatic) or b) 16 sessions of CBT. Bulimic symptoms improved significantly in both groups with no significant differences between the two groups on any of the measures at the end of treatment or at 18 months follow-up. At end of treatment 30% (95% CI: 18-46%) of the sequential group and 30% (95% CI: 17-47%) of the standard treatment group were free from all bulimic symptoms. Sixteen of those in the sequential group improved significantly with self-care and did not require additional treatment. The median number of sessions taken by the sequential group was three (95% CI: 0-6). At 18 months follow-up 40% (95% CI: 23-59%) of the sequential group and 41% (95% CI: 25-59%) of the CBT group were symptom free. A sequential approach to the treatment of bulimia may be as effective as standard CBT and can considerably reduce the amount of therapist contact required.


The association of meningitis with postoperative cerebrospinal fluid fistula.
Objective To determine the risk factors for and the clinical course of postoperative meningitis following lateral skull base surgery and to determine its relationship to cerebrospinal fluid (CSF) fistula. Patients Patients undergoing lateral skull base surgery between July 1999 and February 2010 at an academic tertiary referral center. All subjects had culture-proven meningitis or suspected bacterial meningitis in the postoperative period. Medical records were compared with the lateral skull base patients who did not develop meningitis. Results Of 508 procedures, 16 patients developed meningitis (3.1%). The most common diagnosis was acoustic neuroma in 81.3%; 68.8% of patients had a CSF leak prior to onset of meningitis, and 50% received a lumbar drain. The median time from surgery to the onset of meningitis was 12 days with a range of 2 to 880 days. The relative risk of developing meningitis in the setting of postoperative CSF fistula is 10.2 (p < 0.0001). No meningitis-associated mortality was observed. Conclusions Postoperative meningitis occurred in a small number of patients undergoing lateral skull base surgery. A postoperative CSF fistula leads to an increased risk of meningitis by a factor of 10.2.


Should the DSM V drop Asperger syndrome?
The DSM IV defines Asperger syndrome (AS) as a pervasive developmental (autistic spectrum) disorder characterized by social deficits and rigid focused interests in the absence of language impairment and cognitive delay. Since its inclusion in the DSM-IV, there has been a dramatic increase in its recognition both in children and adults. However, because studies have generally failed to demonstrate a clear distinction between AS and autism, some researchers have called for its elimination from the forthcoming DSM V. This report argues for a modification of its diagnostic criteria and its continued retention in the diagnostic manual.


Evaluation of California's Armed and Prohibited Persons System: study protocol for a cluster-randomised trial.
Too little is known about the effectiveness of efforts to prevent firearm violence. Our objective is to evaluate California's Armed and Prohibited Persons System (APPS), a law enforcement intervention that seeks to recover firearms from individuals who purchased them legally but subsequently became prohibited from having access to firearms. Prohibitions usually arise from events suggesting an increased risk for future violence. This group-randomised trial involves approximately 20 000 APPS-eligible individuals in 1041 communities. Randomisation was performed at the community level, to early or later intervention (Group 1 and Group 2, respectively) with stratification by region, population and violent crime rate. APPS is being implemented by the California Department of Justice. The principal outcome measure is the incidence of arrest for a firearm-related or violent crime. Primary analysis will be on an intention-to-treat basis, comparing individuals in Group 1 and Group 2 communities. Analyses will focus on time to event, using proportional hazards regression with adjustment for the clustered nature of the data and incorporating individual- and community-level characteristics. Secondary analyses will examine the effect of the intervention on an as treated basis, effects on subgroups, and effects on community-wide measures such as crime rates. APPS may have a significant impact on risk for future violence among members of its target population. The findings of this study will likely be generalisable and have clear implications for violence prevention policy and practice. NCT02318732.


Serum Neopterin and Procalcitonin Levels in Relationship with Pediatric Burn Wound Infections.
Infection and septic complications in burn patients can be monitored by procalcitonin (PCT) and neopterin plasma values. The aim of the study was to investigate serum neopterin and PCT levels with WBC (white blood cell) and CRP (C-reactive protein) levels in patient group (PG) and healthy control group (HCG) and to investigate the relationship of these markers with burn wound infections (BWI). As the PG, 23 patients between 0-12 ages and up to 30% Total Body Surface Area (TBSA) burned and 15 HCG were included. PCT, neopterin, WBC, and CRP results on the first, the seventh, the fourteenth and the 21st day have been compared. During the follow-up period, 11 patients with BWI and 12 patients without BWI were classified as infected and non-infected patients, respectively. PCT and neopterin levels were detected higher in patients with BWI but no significant difference were present. Also, PCT and neopterin levels within the first 24 hours following the burn were detected higher in PG than HCG. CRP and WBC levels were detected high due to burn trauma. PCT and neopterin levels were increased in patients with BWI. PCT levels were increased during the pre-infectious period, while neopterin levels increased during the post-infectious period.


A spike-train probability model.
Poisson processes usually provide adequate descriptions of the irregularity in neuron spike times after pooling the data across large numbers of trials, as is done in constructing the peristimulus time histogram. When probabilities are needed to describe the behavior of neurons within individual trials, however, Poisson process models are often inadequate. In principle, an explicit formula gives the probability density of a single spike train in great generality, but without additional assumptions, the firing-rate intensity function appearing in that formula cannot be estimated. We propose a simple solution to this problem, which is to assume that the time at which a neuron fires is determined probabilistically by, and only by, two quantities: the experimental clock time and the elapsed time since the previous spike. We show that this model can be fitted with standard methods and software and that it may used successfully to fit neuronal data.


Complete Genome Sequence of the Arcobacter bivalviorum Type Strain LMG 26154.
Arcobacters are routinely recovered from marine environments, and multiple Arcobacter species have been isolated from shellfish. Arcobacter bivalviorum was recovered from mussels collected in the Ebro Delta in northeastern Spain. This report describes the complete whole-genome sequence of the A. bivalviorum type strain LMG 26154 (= F4T = CECT 7835T).


Complexation of Ln(3+) Ions with Cyclam Dipicolinates: A Small Bridge that Makes Huge Differences in Structure, Equilibrium, and Kinetic Properties.
The coordination properties toward the lanthanide ions of two macrocyclic ligands based on a cyclam platform containing picolinate pendant arms have been investigated. The synthesis of the ligands was achieved by using the well-known bis-aminal chemistry. One of the cyclam derivatives (cb-tedpa(2-)) is reinforced with a cross-bridge unit, which results in exceptionally inert [Ln(cb-tedpa)](+) complexes. The X-ray structures of the [La(cb-tedpa)Cl], [Gd(cb-tedpa)](+), and [Lu(Me2tedpa)](+) complexes indicate octadentate binding of the ligands to the metal ions. The analysis of the Yb(3+)-induced shifts in [Yb(Me2tedpa)](+) indicates that this complex presents a solution structure very similar to that observed in the solid state for the Lu(3+) analogue. The X-ray structures of [La(H2Me2tedpa)2](3+) and [Yb(H2Me2tedpa)2](3+) complexes confirm the exocyclic coordination of the metal ions, which gives rise to coordination polymers with the metal coordination environment being fulfilled by oxygen atoms of the picolinate groups and water molecules. The X-ray structure of [Gd(Hcb-tedpa)2](+) also indicates exocyclic coordination that in this case results in a discrete structure with an eight-coordinated metal ion. The nonreinforced complexes [Ln(Me2tedpa)](+) were prepared and isolated as chloride salts in nonaqueous media. However, these complexes were found to undergo dissociation in aqueous solution, except in the case of the complexes with the smallest Ln(3+) ions (Ln(3+) = Yb(3+) and Lu(3+)). A DFT investigation shows that the increased stability of the [Ln(Me2tedpa)](+) complexes in solution across the lanthanide series is the result of an increased binding energy of the ligand due to the increased charge density of the Ln(3+) ion.


Drug-induced hair colour changes.
Hair colour modifications comprise lightening/greying, darkening, or even a complete hair colour change, which may involve the scalp and/or all body hair. Systemic medications may cause hair loss or hypertrichosis, while hair colour change is an uncommon adverse effect. The rapidly increasing use of new target therapies will make the observation of these side effects more frequent. A clear relationship between drug intake and hair colour modification may be difficult to demonstrate and the underlying mechanisms of hair changes are often unknown. To assess whether a side effect is determined by a specific drug, different algorithms or scores (e.g. Naranjo, Karch, Kramer, and Begaud) have been developed. The knowledge of previous similar reports on drug reactions is a key point of most algorithms, therefore all adverse events should be recognised and reported to the scientific community. Furthermore, even if hair colour change is not a life-threatening side effect, it is of deep concern for patient's quality of life and adherence to treatment. We performed a review of the literature on systemic drugs which may induce changes in hair colour.


Genetic variation in DNA-repair pathways and response to radiochemotherapy in esophageal adenocarcinoma: a retrospective cohort study of the Eastern Cooperative Oncology Group.
Recent data in esophageal cancer suggests the variant allele of a single-nucleotide polymorphism (SNP) in XRCC1 may be associated with resistance to radiochemotherapy. However, this SNP has not been assessed in a histologically homogeneous clinical trial cohort that has been treated with a uniform approach. In addition, whether germline DNA may serve as a surrogate for tumor genotype at this locus is unknown in this disease. Our objective was to assess this SNP in relation to the pathologic complete response (pCR) rate in subjects with esophageal adenocarcinoma who received cisplatin-based preoperative radiochemotherapy in a multicenter clinical trial (Eastern Cooperative Oncology Group 1201). As a secondary aim, we investigated the rate of allelic imbalance between germline and tumor DNA. Eighty-one eligible treatment-naïve subjects with newly diagnosed resectable esophageal adenocarcinoma received radiotherapy (45 Gy) concurrent with cisplatin-based chemotherapy, with planned subsequent surgical resection. The primary endpoint was pCR, defined as complete absence of tumor in the surgical specimen after radiochemotherapy. Using germline DNA from 60 subjects, we examined the base-excision repair SNP, XRCC1 Arg399Gln, and 4 other SNPs in nucleotide excision (XPD Lys751Gln and Asp312Asn, ERCC1 3' flank) and double-stranded break (XRCC2 5' flank) repair pathways, and correlated genotype with pCR rate. Paired tumor tissue was used to estimate the frequency of allelic imbalance at the XRCC1 SNP. The variant allele of the XRCC1 SNP (399Gln) was detected in 52% of subjects. Only 6% of subjects with the variant allele experienced a pCR, compared to 28% of subjects without the variant allele (odds ratio 5.37 for failing to achieve pCR, p = 0.062). Allelic imbalance at this locus was found in only 10% of informative subjects, suggesting that germline genotype may reflect tumor genotype at this locus. No significant association with pCR was noted for other SNPs. Assessed for the first time in a prospective, interventional trial cohort of esophageal adenocarcinoma, XRCC1 399Gln was associated with resistance to radiochemotherapy. Further investigation of this genetic variation is warranted in larger cohorts. In addition, these data indicate that germline genotype may serve as a surrogate for tumor genotype at this locus.


Prestin-Dependence of Outer Hair Cell Survival and Partial Rescue of Outer Hair Cell Loss in PrestinV499G/Y501H Knockin Mice.
A knockin (KI) mouse expressing mutated prestinV499G/Y501H (499 prestin) was created to study cochlear amplification. Recordings from isolated outer hair cells (OHC) in this mutant showed vastly reduced electromotility and, as a consequence, reduced hearing sensitivity. Although 499 prestin OHCs were normal in stiffness and longer than OHCs lacking prestin, accelerated OHC death was unexpectedly observed relative to that documented in prestin knockout (KO) mice. These observations imply an additional role of prestin in OHC maintenance besides its known requirement for mammalian cochlear amplification. In order to gain mechanistic insights into prestin-associated OHC loss, we implemented several interventions to improve survival. First, 499 prestin KI's were backcrossed to Bak KO mice, which lack the mitochondrial pro-apoptotic gene Bak. Because oxidative stress is implicated in OHC death, another group of 499 prestin KI mice was fed the antioxidant diet, Protandim. 499 KI mice were also backcrossed onto the FVB murine strain, which retains excellent high-frequency hearing well into adulthood, to reduce the compounding effect of age-related hearing loss associated with the original 499 prestin KIs. Finally, a compound heterozygous (chet) mouse expressing one copy of 499 prestin and one copy of KO prestin was also created to reduce quantities of 499 prestin protein. Results show reduction in OHC death in chets, and in 499 prestin KIs on the FVB background, but only a slight improvement in OHC survival for mice receiving Protandim. We also report that improved OHC survival in 499 prestin KIs had little effect on hearing phenotype, reaffirming the original contention about the essential role of prestin's motor function in cochlear amplification.


Two Decades of Genetically Encoded Biosensors Based on Förster Resonance Energy Transfer.
Two decades have passed since the development of the first calcium indicator based on the green fluorescent protein (GFP) and the principle of Förster resonance energy transfer (FRET). During this period, researchers have advanced many novel ideas for the improvement of such genetically encoded FRET biosensors, which have allowed them to expand their targets from small molecules to signaling proteins and physicochemical properties. Although the merits of "genetically encoded" FRET biosensors became clear once various cell lines were established and several transgenic organisms were generated, the road to these developments was not necessarily a smooth one. Moreover, even today the development of new FRET biosensors remains a very labor-intensive, trial-and-error process. Therefore, at this junction, it may be worthwhile to summarize the progress of the FRET biosensor and discuss the future direction of its development and application.Key words: FRET, biosensor, fluorescent protein.


Health-Related Quality of Life, Subjective Health Complaints, Psychological Distress and Coping in Pakistani Immigrant Women With and Without the Metabolic Syndrome : The InnvaDiab-DEPLAN Study on Pakistani Immigrant Women Living in Oslo, Norway.
The increasingly high number of immigrants from South-East Asia with The Metabolic Syndrome (MetS) is an important challenge for the public health sector. Impaired glucose is essential in MetS. The blood glucose concentration is not only governed by diet and physical activity, but also by psychological distress which could contribute to the development of MetS. The aim of this study is to describe health-related quality of life, subjective health complaints (SHC), psychological distress, and coping in Pakistani immigrant women, with and without MetS. As a part of an randomized controlled intervention study in Oslo, Norway, female Pakistani immigrants (n = 198) answered questionnaires regarding health related quality of life, SHC, psychological distress, and coping. Blood variables were determined and a standardized oral glucose tolerance test was performed. The participants had a high score on SHC and psychological distress. About 40% of the participants had MetS, and this group showed significantly lower general health, lower physical function, and more bodily pain, than those without MetS. Those with MetS also had more SHC, depressive symptoms, higher levels of somatisation, and scored significantly lower on the coping strategy of active problem solving. Pakistani immigrant women seem to have a high prevalence of SHC and psychological distress, especially those with MetS.


Neuroradiologic aspects of cerebral disseminated intravascular coagulation.
Six patients with neurovascular disseminated intravascular coagulation (DIC) illustrate the diversity of neuroradiologic changes in that condition. Emphasis is placed on the involvement of large cerebral vessels, especially as reflected by cerebral vein or sinus occlusions. The latter occurred in four of the six cases reported; deep or superficial veins, larger lobar draining veins such as the superficial middle cerebral vein, or large bore vessels such as the superior sagittal sinus or jugular bulb were involved. Radionuclide sinography or computed tomography (CT) was useful in revealing large vessel occlusions or their sequelae; in two cases CT showed focal hemorrhage in an unusual location. Although DIC has classically been envisioned as occurring within the arterial microcirculation, these cases attest to the occurrence of large vessel, especially venous, involvement in neurovascular DIC.


Regulation of cyclin D-dependent kinase 4 (cdk4) by cdk4-activating kinase.
The accumulation of assembled holoenzymes composed of regulatory D-type cyclins and their catalytic partner, cyclin-dependent kinase 4 (cdk4), is rate limiting for progression through the G1 phase of the cell cycle in mammalian fibroblasts. Both the synthesis and assembly of D-type cyclins and cdk4 depend upon serum stimulation, but even when both subunits are ectopically overproduced, they do not assemble into complexes in serum-deprived cells. When coexpressed from baculoviral vectors in intact Sf9 insect cells, cdk4 assembles with D-type cyclins to form active protein kinases. In contrast, recombinant D-type cyclin and cdk4 subunits produced in insect cells or in bacteria do not assemble as efficiently into functional holoenzymes when combined in vitro but can be activated in the presence of lysates obtained from proliferating mammalian cells. Assembly of cyclin D-cdk4 complexes in coinfected Sf9 cells facilitates phosphorylation of cdk4 on threonine 172 by a cdk-activating kinase (CAK). Assembly can proceed in the absence of this modification, but cdk4 mutants which cannot be phosphorylated by CAK remain catalytically inactive. Therefore, formation of the cyclin D-cdk4 complex and phosphorylation of the bound catalytic subunit are independently regulated, and in addition to the requirement for CAK activity, serum stimulation is required to promote assembly of the complexes in mammalian cells.


A summary of mutations in the UV-sensitive disorders: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy.
The human diseases xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy are caused by mutations in a set of interacting gene products, which carry out the process of nucleotide excision repair. The majority of the genes have now been cloned and many mutations in the genes identified. The relationships between the distribution of mutations in the genes and the clinical presentations can be used for diagnosis and for understanding the functions and the modes of interaction among the gene products. The summary presented here represents currently known mutations that can be used as the basis for future studies of the structure, function, and biochemical properties of the proteins involved in this set of complex disorders, and may allow determination of the critical sites for mutations leading to different clinical manifestations. The summary indicates where more data are needed for some complementation groups that have few reported mutations, and for the groups for which the gene(s) are not yet cloned. These include the Xeroderma pigmentosum (XP) variant, the trichothiodystrophy group A (TTDA), and ultraviolet sensitive syndrome (UVs) groups. We also recommend that the XP-group E should be defined explicitly through molecular terms, because assignment by complementation in culture has been difficult. XP-E by this definition contains only those cell lines and patients that have mutations in the small subunit, DDB2, of a damage-specific DNA binding protein.


Conserved expression of Arabidopsis thaliana poly (A) binding protein 2 (PAB2) in distinct vegetative and reproductive tissues.
The poly(A) tails of eukaryotic mRNAs are complexed with poly(A) binding protein (PABP). The poly(A)-PABP complex is central to the efficient translation initiation and control of poly (A) tail length and is required in some pathways of mRNA decay. A large gene family encodes PABPs in Arabidopsis thaliana. In striking contrast to the floral and root specific expression of three previously reported Arabidopsis PABPs, we demonstrate that RNA and protein for one highly diverse member of this family, PAB2, are expressed in roots, stems, leaves, flowers, pollen and siliques of Arabidopsis. However, cell-type specific analysis of a PAB2 reporter gene fusion revealed that PAB2 is spatially and temporally regulated in each organ. For example, strong expression was detected only in the stele and meristem region of roots and a dramatic decrease in expression was observed upon fertilization of ovules. Furthermore, the PAB2-reporter construct gave a nearly identical expression pattern in transgenic tobacco, demonstrating that PAB2 expression is under strong selective constraint. The PAB2-reporter was also strongly expressed in the transmittal tissues of both Arabidopsis and tobacco, raising the possibility of its involvement in the pollination-dependent poly(A) tail shortening of transmittal tissue specific mRNAs previously reported in tobacco (Wang et al. 1996, Plant J. 9, 715-727). In view of its potential role in poly(A) tail shortening, we demonstrated the strong and distinct presence of PAB2 protein in transmittal tissues of Arabidopsis. The evolutionary and functional implications of the expression pattern of PAB2 and its possible functional roles in post-transcriptional regulation in transmittal tissues are discussed.


Does AMH Reflect Follicle Number Similarly in Women with and without PCOS?
Increased Anti-Mullerian Hormone in polycystic ovary syndrome, may be due to overactive follicles rather than reflect antral follicle count. Does Anti-Mullerian Hormone reflect antral follicle count similarly in women with or without polycystic ovary syndrome or polycystic ovarian morphology? Cross-sectional, case-control. Women who delivered preterm in 1999-2006. For each index woman, a woman with a term delivery was identified. Participation rate was 69%. Between 2006-2008, 262 women were included, and diagnosed to have polycystic ovary syndrome, polycystic ovarian morphology or to be normal controls. Blood tests, a clinical examination and vaginal ultrasound. Anti-Mullerian Hormone/antral follicle count-ratio, SHBG, androstenedione and insulin, to test potential influence on the Anti-Mullerian Hormone/antral follicle count -ratio. Mean Anti-Mullerian Hormone/antral follicle count ratio in women with polycystic ovary syndrome or polycystic ovarian morphology was similar to that of the controls (polycystic ovary syndrome: 1,2 p = 0,10 polycystic ovarian morphology: 1,2, p = 0,27 Controls 1,3). Anti-Mullerian Hormone showed a positive linear correlation to antral follicle count in all groups. Multivariate analysis did not change the results. We confirmed the positive correlation between AMH and follicle count. Anti-Mullerian Hormone seems to be a reliable predictor of antral follicle count, independent of polycystic ovary syndrome diagnosis or ovarian morphology.


Effects of CO2 enrichment on two microalgae species: A toxicity approach using consecutive generations.
As a result of the increasing pressure provoked by anthropogenic activities, the world climate is changing and oceans health is in danger. One of the most important factors affecting the marine environment is the well-known process called ocean acidification. Also, there are other natural or anthropogenic processes that produce an enrichment of CO2 in the marine environment (CO2 leakages from Carbon Capture and Storage technologies (CCS), organic matter diagenesis, volcanic vents, etc). Most of the studies related to acidification of the marine environment by enrichment of CO2 have been focused on short-term experiments. To evaluate the effects related to CO2 enrichment, laboratory-scale experiments were performed using the marine microalgae Tetraselmis chuii and Phaeodactylum tricornutum. Three different pH values (two treatments - pH 7.4 and 6.0 - and a control - pH 8.0) were tested on the selected species across four consecutive generations. Seawater was collected and exposed to different scenarios of CO2 enrichment by means of CO2 injection. The results showed different effects depending on the species and the generation used. Effects on T. chuii were shown on cell density, chlorophyll-a and metabolic activity, however, a slight adaptation across generations was found in this last parameter. P. tricornutum was more sensitive to acidification conditions through generations, with practically total growth inhibition in the fourth one. The conclusions obtained in this work are useful to address the potential ecological risk related to acidification by enrichment of CO2 on the marine ecosystem by using consecutive generations of microalgae.


Human chorionic gonadotrophin priming for fertility treatment with in vitro maturation.
In vitro maturation (IVM) is a fertility treatment that involves the transvaginal retrieval of immature oocytes, and their subsequent maturation and fertilisation. Although the live birth rate is lower than conventional in vitro fertilisation (IVF) with ovarian stimulation, it is a useful treatment, as it avoids the risk of ovarian hyperstimulation syndrome (OHSS). Women with polycystic ovaries (PCO) or polycystic ovarian syndrome (PCOS) are at an increased risk of OHSS. Thus, IVM may be a more useful treatment in this patient group.Strategies to maximise the maturation rates of the immature oocytes are important. This review focuses on the administration of human chorionic gonadotrophin (hCG) prior to immature oocyte retrieval. To determine the effectiveness and safety of hCG priming in subfertile women who are undergoing IVM treatment in the context of assisted reproduction. We searched the following electronic databases up to 29 August 2016: Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL, MEDLINE, Embase, PsycINFO, and CINAHL. We also searched the trial registries ClinicalTrials.gov and WHO ICTPR to identify ongoing and registered trials. We sought recently published papers not yet indexed in the major databases, and reviewed the reference lists of reviews and retrieved studies as sources of potentially relevant studies. There were no language restrictions. We included randomised controlled trials (RCTs) that compared hCG priming with placebo or no priming in women undergoing IVM. We also included RCTs that compared different doses of hCG, or the timing of oocyte retrieval. The primary outcomes were live birth rate and miscarriage rate per woman randomised. Two review authors independently selected studies for inclusion, and with a third author, assessed risk of bias and extracted data. We contacted the original authors where data were missing. For dichotomous outcomes, we used the Mantel-Haenszel method to calculate odds ratios (OR). For continuous outcomes, we calculated the mean differences (MD) between treatment groups. We assessed statistical heterogeneity using the I² statistic. We assessed the overall quality of the evidence using GRADE methods. We included four studies, with a total of 522 women, in the review. One of these studies did not report outcomes per woman randomised, and so was not included in formal analysis. Three studies investigated 10,000 units hCG priming compared to no priming. One study investigated 20,000 units hCG compared to 10,000 units hCG priming. Three studies only included women with PCOS (N = 122), while this was an exclusion criteria in the fourth study (N = 400).We rated all four studies as having an unclear risk of bias in more than one of the seven domains assessed. The quality of the evidence was low, the main limitations being lack of blinding and imprecision.When 10,000 units hCG priming was compared to no priming, we found no evidence of a difference in the live birth rates per woman randomised (OR 0.65, 95% confidence intervals (CI) 0.24 to 1.74; one RCT; N = 82; low quality evidence); miscarriage rate (OR 0.60, 95% CI 0.21 to 1.72; two RCTs; N = 282; I² statistic = 21%; low quality evidence), or clinical pregnancy rate (OR 0.52, 95% CI 0.26 to 1.03; two RCTs, N = 282, I² statistic = 0%, low quality evidence). Though inconclusive, our findings suggested that hCG may be associated with a reduction in clinical pregnancy rates; 22% of women who received no priming achieved pregnancy, while between 7% and 23% of women who received hCG priming did so.The study comparing 20,000 units hCG with 10,000 units hCG did not report sufficient data to enable us to calculate odds ratios.No studies reported on adverse events (other than miscarriage) or drug reactions. This review found no conclusive evidence that hCG priming had an effect on live birth, pregnancy, or miscarriage rates in IVM. There was low quality evidence that suggested that hCG priming may reduce clinical pregnancy rates, however, these findings were limited by the small number of data included. As no data were available on adverse events (other than miscarriage) or on drug reactions, we could not adequately assess the safety of hCG priming. We need further evidence from well-designed RCTs before we can come to definitive conclusions about the role of hCG priming, and the optimal dose and timing.


Reasons for defaulting from drug-resistant tuberculosis treatment in Armenia: a quantitative and qualitative study.
Armenia, a country with a high prevalence of drug-resistant tuberculosis (DR-TB). To identify factors related to default from DR-TB treatment in Yerevan. Using a retrospective cohort design, we compared defaulters with patients who were cured, completed or failed treatment. Patients who initiated DR-TB treatment from 2005 to 2011 were included in the study. A qualitative survey was conducted including semi-structured interviews with defaulters and focus group discussions with care providers. Of 381 patients, 193 had achieved treatment success, 24 had died, 51 had failed treatment and 97 had defaulted. The number of drugs to which the patient was resistant at admission (aRR 1.16, 95%CI 1.05-1.27), the rate of treatment interruption based on patient's decision (aRR 1.03, 95%CI 1.02-1.05), the rate of side effects (aRR 1.18, 95%CI 1.09-1.27), and absence of culture conversion during the intensive phase (aRR 0.47, 95%CI 0.31-0.71) were independently associated with default from treatment. In the qualitative study, poor treatment tolerance, a perception that treatment was inefficient, lack of information, incorrect perception of being cured, working factors and behavioural problems were factors related to treatment default. In addition to economic reasons, poor tolerance of and poor response to treatment were the main factors associated with treatment default.


In Silico, In Vitro, and In Vivo Evaluation of Precipitation Inhibitors in Supersaturated Lipid-Based Formulations of Venetoclax.
The concept of using precipitation inhibitors (PIs) to sustain supersaturation is well established for amorphous formulations but less in the case of lipid-based formulations (LBF). This study applied a systematic in silico-in vitro-in vivo approach to assess the merits of incorporating PIs in supersaturated LBFs (sLBF) using the model drug venetoclax. sLBFs containing hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone (PVP), PVP-co-vinyl acetate (PVP/VA), Pluronic F108, and Eudragit EPO were assessed in silico calculating a drug-excipient mixing enthalpy, in vitro using a PI solvent shift test, and finally, bioavailability was assessed in vivo in landrace pigs. The estimation of pure interaction enthalpies of the drug and the excipient was deemed useful in determining the most promising PIs for venetoclax. The sLBF alone (i.e., no PI present) displayed a high initial drug concentration in the aqueous phase during in vitro screening. sLBF with Pluronic F108 displayed the highest venetoclax concentration in the aqueous phase and sLBF with Eudragit EPO the lowest. In vivo, the sLBF alone showed the highest bioavailability of 26.3 ± 14.2%. Interestingly, a trend toward a decreasing bioavailability was observed for sLBF containing PIs, with PVP/VA being significantly lower compared to sLBF alone. In conclusion, the ability of a sLBF to generate supersaturated concentrations of venetoclax in vitro was translated into increased absorption in vivo. While in silico and in vitro PI screening suggested benefits in terms of prolonged supersaturation, the addition of a PI did not increase in vivo bioavailability. The findings of this study are of particular relevance to pre-clinical drug development, where the high in vivo exposure of venetoclax was achieved using a sLBF approach, and despite the perceived risk of drug precipitation from a sLBF, including a PI may not be merited in all cases.


Grd19/Snx3p functions as a cargo-specific adapter for retromer-dependent endocytic recycling.
Amajor function of the endocytic system is the sorting of cargo to various organelles. Endocytic sorting of the yeast reductive iron transporter, which is composed of the Fet3 and Ftr1 proteins, is regulated by available iron. When iron is provided to iron-starved cells, Fet3p-Ftr1p is targeted to the lysosome-like vacuole and degraded. In contrast, when iron is not available, Fet3p-Ftr1p is maintained on the plasma membrane via an endocytic recycling pathway requiring the sorting nexin Grd19/Snx3p, the pentameric retromer complex, and the Ypt6p Golgi Rab GTPase module. A recycling signal in Ftr1p was identified and found to bind directly to Grd19/Snx3p. Retromer and Grd19/Snx3p partially colocalize to tubular endosomes, where they are physically associated. After export from the endosome, Fet3p-Ftr1p transits through the Golgi apparatus for resecretion. Thus, Grd19/Snx3p, functions as a cargo-specific adapter for the retromer complex, establishing a precedent for a mechanism by which sorting nexins expand the repertoire of retromer-dependent cargos.


The impact of dark chocolate intake on arterial elasticity in individuals with HIV/AIDS undergoing ART: a randomized, double-blind, crossover trial.
An increase in the frequency of cardiovascular diseases has been observed in the HIV/AIDS population. Studies involving healthy subjects or subjects with other diseases have shown benefits of chocolate supplementation on endothelial function and vasodilation. We evaluate the impact of chocolate consumption on arterial elasticity in people living with human immunodeficiency virus - PLHIV. A double-blind, crossover trial including 110 PLHIV (19 to 59 years) on antiretroviral therapy - ART for at least 6 months and with a viral load of <500 copies per mL was conducted. All subjects were randomly assigned to 15-d dietary supplements containing dark chocolate or placebo with a 15-d washout period. Each participant received one of the two sequences: A (dark chocolate, placebo chocolate); B (placebo chocolate, dark chocolate). Arterial elasticity was measured using the HDI/PulseWave™ CR-2000 CardioVascular Profiling System®. Body composition, lipid profile, C-reactive protein, and thiobarbituric acid reactive substances were also assessed. Analysis of variance (ANOVA) for repeated measures using the Stata 11.0® program was used for cross-over analysis. Most subjects were men (59.0%) and Caucasian (46.1%) and the mean age was 44.6 ± 7.1 years. The mean time since diagnosis of HIV infection was 13.7 ± 5.3 years and the mean duration of ART was 12.9 ± 4.2 years. Chocolate consumption resulted in significant alterations in the large artery elasticity index - LAEI (p = 0.049) and the mean concentration of HDL-c was higher after supplementation with dark chocolate (p = 0.045). This is the first study to evaluate the effect of chocolate on arterial elasticity in PLHIV. The results showed that dark chocolate consumption for 15 days improved the elastic properties of the LAEI in PLHIV. These findings, added to the noninvasive method used, may expand the knowledge of CVDs in this population.


Experimental evidence supports a sex-specific selective sieve in mitochondrial genome evolution.
Mitochondria are maternally transmitted; hence, their genome can only make a direct and adaptive response to selection through females, whereas males represent an evolutionary dead end. In theory, this creates a sex-specific selective sieve, enabling deleterious mutations to accumulate in mitochondrial genomes if they exert male-specific effects. We tested this hypothesis, expressing five mitochondrial variants alongside a standard nuclear genome in Drosophila melanogaster, and found striking sexual asymmetry in patterns of nuclear gene expression. Mitochondrial polymorphism had few effects on nuclear gene expression in females but major effects in males, modifying nearly 10% of transcripts. These were mostly male-biased in expression, with enrichment hotspots in the testes and accessory glands. Our results suggest an evolutionary mechanism that results in mitochondrial genomes harboring male-specific mutation loads.


Simple and efficient methods for the accurate evaluation of patterning effects in ultrafast photonic switches.
Although patterning effects (PEs) are known to be a limiting factor of ultrafast photonic switches based on semiconductor optical amplifiers (SOAs), a simple approach for their evaluation in numerical simulations and experiments is missing. In this work, we experimentally investigate and verify a theoretical prediction of the pseudo random binary sequence (PRBS) length needed to capture the full impact of PEs. A wide range of SOAs and operation conditions are investigated. The very simple form of the PRBS length condition highlights the role of two parameters, i.e. the recovery time of the SOAs as well as the operation bit rate. Furthermore, a simple and effective method for probing the maximum PEs is demonstrated, which may relieve the computational effort or the experimental difficulties associated with the use of long PRBSs for the simulation or characterization of SOA-based switches. Good agrement with conventional PRBS characterization is obtained. The method is suitable for quick and systematic estimation and optimization of the switching performance.


Benzene photolysis on ice: implications for the fate of organic contaminants in the winter.
The members of the important class of organic pollutants known as BTEX (benzene, toluene, ethylbenzene, and xylenes) do not undergo direct photolysis in natural waters, because their absorption spectra do not overlap that of the solar radiation which reaches the Earth's surface. Recent work has shown that aromatic compounds undergo significant red-shifts in their absorption spectra when they are present at air-ice interfaces, suggesting that BTEX components could undergo direct photolysis at ice surfaces. Using glancing-angle laser-induced fluorescence (LIF) as a probe, we measured benzene photodegradation at lambda > 295 nm having a rate constant of (3 +/- 1 x 10(-4) s(-1)) under our experimental conditions. We predict that the photolysis rate at environmental ice surfaces will be similar, based on the photon flux dependence we measured. This study presents the first report of direct benzene photolysis under environmentally relevant conditions. The results suggest that direct photolysis could be an important removal pathway for organic pollutants such as BTEX in snow-covered regions, for example, in polar or urban areas contaminated by oil spills or leaks.


Adenovirus platform enhances transduction efficiency of human mesenchymal stem cells: An opportunity for cellular carriers of targeted TRAIL-based TR3 biologics in ovarian cancer.
Clinical application of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based cancer therapeutics has not reached optimal potencies in part due to inadequate drug stability and inefficiencies in cancer-selective drug delivery. As such, innovative strategies regarding drug design and delivery are of utmost importance to achieve improved treatment results. With our current study, we aimed at exploring the groundwork for a two-stage targeting concept, which is based on the intrinsic tumor homing capacity of mesenchymal stem cells (MSCs) as cellular drug factories for the in situ production of our newly designed and biomarker-targeted TRAIL-based TR3 therapeutics. Since MSCs are primary cells, capable in vitro of only a limited number of cell divisions, identification of suitable strategies for their efficient genetic manipulation is of critical importance. We chose adenoviral (Ad) vectors as a transduction vehicle due to its ability to infect dividing and non-dividing cells and because of their limited restrictions regarding the packaging capacity of their genetic payload. In order to enhance the transduction efficacy of MSCs using Ad5 wild-type-based vectors, we tested a variety of fiber knob modifications on a panel of patient-derived MSC lines established from adipose tissue. We identified Ad5pK7, an Ad5 vector containing a polylysine fiber knob modification, exhibiting the highest transduction rates across a panel of 16 patient-derived MSC lines. We further demonstrated that MSCs could be efficiently transduced with an Ad5pK7 vector containing membrane-anchored and secreted TR3 expression units, including the MUC16 (CA125)-targeted variant Meso64-TR3. In both in vitro and in vivo experiments, MSC-derived Meso64-TR3 was far more potent on MUC16-expressing ovarian cancer compared to its non-targeted TR3 counterpart. Our findings thus provide the foundation to initiate further preclinical investigations on MSC-mediated treatment options in ovarian cancer using biomarker-targeted TR3-based biologics.


MicroRNAs: their discovery, biogenesis, function and potential use as biomarkers in non-invasive prenatal diagnostics.
MiRNAs are a widespread class of small non-coding RNAs that have the ability to silence gene expression through sequence complementarity to their targets. We describe their initial discovery in the nematode C.elegans and review what is currently known about their biogenesis. The regulation of expression and processing of miRNAs, and the mechanisms through which miRNAs locate their correct targets are not yet fully understood. MiRNAs are involved in a multitude of developmental and pathological processes leading to an explosion of research in disparate subject areas. In this review we draw attention to placentally expressed miRNAs that can be detected in the maternal plasma; and we discuss their potential use as biomarkers in non-invasive prenatal diagnostics.


Catalytic hydrogen evolution by Fe(II) carbonyls featuring a dithiolate and a chelating phosphine.
Two pentacoordinate mononuclear iron carbonyls of the form (bdt)Fe(CO)P2 [bdt = benzene-1,2-dithiolate; P2 = 1,1'-diphenylphosphinoferrocene (1) or methyl-2-{bis(diphenylphosphinomethyl)amino}acetate (2)] were prepared as functional, biomimetic models for the distal iron (Fe(d)) of the active site of [FeFe]-hydrogenase. X-ray crystal structures of the complexes reveal that, despite similar ν(CO) stretching band frequencies, the two complexes have different coordination geometries. In X-ray crystal structures, the iron center of 1 is in a distorted trigonal bipyramidal arrangement, and that of 2 is in a distorted square pyramidal geometry. Electrochemical investigation shows that both complexes catalyze electrochemical proton reduction from acetic acid at mild overpotential, 0.17 and 0.38 V for 1 and 2, respectively. Although coordinatively unsaturated, the complexes display only weak, reversible binding affinity toward CO (1 bar). However, ligand centered protonation by the strong acid, HBF4·OEt2, triggers quantitative CO uptake by 1 to form a dicarbonyl analogue [1(H)-CO](+) that can be reversibly converted back to 1 by deprotonation using NEt3. Both crystallographically determined distances within the bdt ligand and density functional theory calculations suggest that the iron centers in both 1 and 2 are partially reduced at the expense of partial oxidation of the bdt ligand. Ligand protonation interrupts this extensive electronic delocalization between the Fe and bdt making 1(H)(+) susceptible to external CO binding.


Cryo-electron tomographic structure of an immunodeficiency virus envelope complex in situ.
The envelope glycoprotein (Env) complexes of the human and simian immunodeficiency viruses (HIV and SIV, respectively) mediate viral entry and are a target for neutralizing antibodies. The receptor binding surfaces of Env are in large part sterically occluded or conformationally masked prior to receptor binding. Knowledge of the unliganded, trimeric Env structure is key for an understanding of viral entry and immune escape, and for the design of vaccines to elicit neutralizing antibodies. We have used cryo-electron tomography and averaging to obtain the structure of the SIV Env complex prior to fusion. Our result reveals novel details of Env organisation, including tight interaction between monomers in the gp41 trimer, associated with a three-lobed, membrane-distal gp120 trimer. A cavity exists at the gp41-gp120 trimer interface. Our model for the spike structure agrees with previously predicted interactions between gp41 monomers, and furthers our understanding of gp120 interactions within an intact spike.


Long-term straw decomposition in agro-ecosystems described by a unified three-exponentiation equation with thermal time.
Understanding drivers of straw decomposition is essential for adopting appropriate management practice to improve soil fertility and promote carbon (C) sequestration in agricultural systems. However, predicting straw decomposition and characteristics is difficult because of the interactions between many factors related to straw properties, soil properties, and climate, especially under future climate change conditions. This study investigated the driving factors of straw decomposition of six types of crop straw including wheat, maize, rice, soybean, rape, and other straw by synthesizing 1642 paired data from 98 published papers at spatial and temporal scales across China. All the data derived from the field experiments using little bags over twelve years. Overall, despite large differences in climatic and soil properties, the remaining straw carbon (C, %) could be accurately represented by a three-exponent equation with thermal time (accumulative temperature). The lignin/nitrogen and lignin/phosphorus ratios of straw can be used to define the size of labile, intermediate, and recalcitrant C pool. The remaining C for an individual type of straw in the mild-temperature zone was higher than that in the warm-temperature and subtropical zone within one calendar year. The remaining straw C after one thermal year was 40.28%, 37.97%, 37.77%, 34.71%, 30.87%, and 27.99% for rice, soybean, rape, wheat, maize, and other straw, respectively. Soil available nitrogen and phosphorus influenced the remaining straw C at different decomposition stages. For one calendar year, the total amount of remaining straw C was estimated to be 29.41 Tg and future temperature increase of 2 °C could reduce the remaining straw C by 1.78 Tg. These findings confirmed the long-term straw decomposition could be mainly driven by temperature and straw quality, and quantitatively predicted by thermal time with the three-exponent equation for a wide array of straw types at spatial and temporal scales in agro-ecosystems of China.