Alignment of electronic energy levels at electrochemical interfaces.
The position of electronic energy levels in a phase depends on the surface potentials at its boundaries. Bringing two phases in contact at an interface will alter the surface potentials shifting the energy levels relative to each other. Calculating such shifts for electrochemical interfaces requires a combination of methods from computational surface science and physical chemistry. The problem is closely related to the computation of potentials of electrochemically inactive electrodes. These so-called ideally polarizable interfaces are impossible to cross for electrons. In this perspective we review two density functional theory based methods that have been developed for this purpose, the workfunction method and the hydrogen insertion method. The key expressions of the two methods are derived from the formal theory of absolute electrode potentials. As an illustration of the workfunction method we review the computation of the potential of zero charge of the Pt(111)-water interface as recently published by a number of groups. The example of the hydrogen insertion method is from our own work on the rutile TiO(2)(110)-water interface at the point of zero proton charge. The calculations are summarized in level diagrams aligning the electronic energy levels of the solid electrode (Fermi level of the metal, valence band maximum and conduction band minimum of the semiconductor) to the band edges of liquid water and the standard potential for the reduction of the hydroxyl radical. All potentials are calculated at the same level of density functional theory using the standard hydrogen electrode as common energy reference. Comparison to experiment identifies the treatment of the valence band of water as a potentially dangerous source of error for application to electrocatalysis and photocatalysis.


Assisted Fluid Management Software Guidance for Intraoperative Fluid Administration.
Excessive or inadequate fluid administration causes complications, but despite this, fluid administration during noncardiac surgery is highly variable. Goal-directed management helps optimize the amount and timing of fluid administration; however, implementation is difficult because algorithms are complex. The authors therefore tested the performance of the Acumen Assisted Fluid Management software (Edwards Lifesciences, USA), which is designed to guide optimal intravenous fluid administration during surgery. In this multicenter, prospective, single-arm cohort evaluation, the authors enrolled 330 adults scheduled for moderate- to high-risk noncardiac surgery that required arterial catheter insertion and mechanical ventilation. Clinicians chose a fluid strategy based on a desired 10%, 15%, or 20% increase in stroke volume (SV) in response to a fluid bolus. Dedicated fluid management software prompted "test" or "recommended" boluses, and clinicians were free to initiate a "user" bolus of 100 to 500 ml of crystalloid or colloid. Clinicians were free to accept or decline the software prompts. The authors primarily compared the fraction of software-recommended boluses that produced suitable increases in SV to a 30% reference rate. On an exploratory basis, we compared responses to software-recommended and clinician-initiated boluses. Four hundred twenty-four of 479 (89%) software-recommended fluid boluses and 508 of 592 (86%) clinician-initiated fluid boluses were analyzed per protocol. Of those, 66% (95% CI, 62 to 70%) of delivered fluid boluses recommended by the software resulted in desired increases in SV, compared with the 30% reference rate, whereas only 41% (95% CI, 38 to 44%) of clinician-initiated boluses did (P < 0.0001). The mean ± SD increase in SV after boluses recommended by the software was 14.2 ± 13.9% versus 8.3 ± 12.1% (P < 0.0001) for those initiated by clinicians. Fluid boluses recommended by the software resulted in desired SV increases more often, and with greater absolute SV increase, than clinician-initiated boluses. Automated assessment of fluid responsiveness may help clinicians optimize intraoperative fluid management during noncardiac surgery.


Long-term single cell analysis of S. pombe on a microfluidic microchemostat array.
Although Schyzosaccharomyces pombe is one of the principal model organisms for studying the cell cycle, surprisingly few methods have characterized S. pombe growth on the single cell level, and no methods exist capable of analyzing thousands of cells and tens of thousands of cell division events. We developed an automated microfluidic platform permitting S. pombe to be grown on-chip for several days under defined and changeable conditions. We developed an image processing pipeline to extract and quantitate several physiological parameters including cell length, time to division, and elongation rate without requiring synchronization of the culture. Over a period of 50 hours our platform analyzed over 100000 cell division events and reconstructed single cell lineages up to 10 generations in length. We characterized cell lengths and division times in a temperature shift experiment in which cells were initially grown at 30°C and transitioned to 25°C. Although cell length was identical at both temperatures at steady-state, we observed transient changes in cell length if the temperature shift took place during a critical phase of the cell cycle. We further show that cells born with normal length do divide over a wide range of cell lengths and that cell length appears to be controlled in the second generation, were large newly born cells have a tendency to divide more rapidly and thus at a normalized cell size. The platform is thus applicable to measure fine-details in cell cycle dynamics, should be a useful tool to decipher the molecular mechanism underlying size homeostasis, and will be generally applicable to study processes on the single cell level that require large numbers of precision measurements and single cell lineages.


Adherence to quality indicators and survival in patients with breast cancer.
International initiatives increasingly advocate physician adherence to clinical protocols that have been shown to improve outcomes, yet the process-outcome relationship for adhering to breast cancer care protocol is unknown. This study explores whether 100% adherence to a set of quality indicators applied to individuals with breast cancer is associated with better survival. Ten quality indicators (4 diagnosis-related and 6 treatment-related indicators) were used to measure the quality of care in 1378 breast cancer patients treated from 1995 to 2001. Adherence to each indicator was based on the number of procedures performed divided by the number of patients eligible for that procedure. The main analysis of adherence was dichotomous (ie, 100% adherence vs. <100% adherence). The outcome measures studied were 5-year overall survival and progression-free survival, calculated using the Kaplan-Meier method. The Cox's proportional hazard regression model was used for univariate and multivariate analyses. Most patients received care that demonstrated good adherence to the quality indicators. Multivariate analysis revealed that 100% adherence to entire set of quality indicators was significantly associated with better overall survival [hazard ratio (HR): 0.46; 95% confidence interval (CI): 0.33-0.63] and progression-free survival (HR 0.51; 95% CI, 0.39-0.67). One hundred percent adherence to treatment indicators alone was also associated with statistically significant improvements in overall and progression-free survivals. Our study strongly supports that 100% adherence to evidence supported quality-of-care indicators is associated with better survival rates for breast cancer patients and should be a priority for practitioners.


Effects of blood pressure lowering on cardiovascular risk according to baseline body-mass index: a meta-analysis of randomised trials.
The cardiovascular benefits of blood pressure lowering in obese people compared with people of normal weight might depend on choice of drug. We compared the effects of blood pressure-lowering regimens on cardiovascular risk in groups of patients categorised by baseline body-mass index (BMI). We used individual patient data from trials included in the Blood Pressure Lowering Treatment Trialists' Collaboration to compare the effects of different classes of blood pressure-lowering regimens for the primary outcome of total major cardiovascular events (stroke, coronary heart disease, heart failure, and cardiovascular death). We used meta-analyses and meta-regressions to assess interactions between treatment and BMI when fitted as either a categorical variable (<25 kg/m(2), 25 to <30 kg/m(2), and ≥30 kg/m(2)) or a continuous variable. Analyses were based on 135,715 individuals from 22 trials who had 14,353 major cardiovascular events. None of the six primary comparisons showed evidence that protection varied by drug class across the three BMI groups (all p for trend >0·20). When analysed as a continuous variable, angiotensin-converting-enzyme inhibitors gave slightly greater protection for each 5 kg/m(2) higher BMI than did calcium antagonists (hazard ratio 0·93, 95% CI 0·89-0·98; p=0·004) or diuretics (0·93, 0·89-0·98; p=0·002). The meta-regressions showed no relation between BMI category and the risk reduction for a given fall in systolic blood pressure. By contrast with a previous report, we noted no relation between BMI and the efficacy of calcium antagonists compared with diuretics. We found little evidence that selection of a particular class of blood pressure-lowering drug will lead to substantially different outcomes for individuals who are obese compared with those who are lean. None.


Predicting Short-term MCI-to-AD Progression Using Imaging, CSF, Genetic Factors, Cognitive Resilience, and Demographics.
In the Alzheimer's disease (AD) continuum, the prodromal state of mild cognitive impairment (MCI) precedes AD dementia and identifying MCI individuals at risk of progression is important for clinical management. Our goal was to develop generalizable multivariate models that integrate high-dimensional data (multimodal neuroimaging and cerebrospinal fluid biomarkers, genetic factors, and measures of cognitive resilience) for identification of MCI individuals who progress to AD within 3 years. Our main findings were i) we were able to build generalizable models with clinically relevant accuracy (~93%) for identifying MCI individuals who progress to AD within 3 years; ii) markers of AD pathophysiology (amyloid, tau, neuronal injury) accounted for large shares of the variance in predicting progression; iii) our methodology allowed us to discover that expression of CR1 (complement receptor 1), an AD susceptibility gene involved in immune pathways, uniquely added independent predictive value. This work highlights the value of optimized machine learning approaches for analyzing multimodal patient information for making predictive assessments.


Association between Ia antigens and the Fc receptors of certain T lymphocytes.
The Fc receptors of thymic and splenic T lymphocytes were detected using indirect immunofluorescence and soluble antigen-antibody complexes. 10-20% of thymocytes and 40-50% of Thy-1-positive splenic lymphocytes bound antigen-complexed Ig. The binding to thymocytes was partially inhibited (45-74%) by antibodies against antigens determined by the I region of the H-2 complex, but not by antibodies against K- or D-region antigens or Thy-1 antigen. The inhibition did not require the Fc portion of the inhibiting antibody. These results provide evidence that Ia antigens and the Fc receptors of some T lymphocytes are associated, and that the populations of T cells which bear these moieties at least partially overlap.


Autoimmunity to insulin receptor and hypoglycaemia in patient with Hodgkin's disease.
A 76-year-old man with fasting hypoglycaemia had impaired in-vitro binding of insulin to erythrocyte receptors. The immunoglobulin fraction of his plasma inhibited binding of insulin to normal donor erythrocytes in vitro. Autoantibodies may have stimulated the insulin receptor and produced hypoglycaemia. Hodgkin's disease developed and may have induced the autoimmunity. The hypoglycaemia did not respond to plasmapheresis or azathioprine alone, but it remitted after the addition of prednisolone, and the erythrocyte receptor binding of insulin became normal.


Role of granulocyte-macrophage colony-stimulating factor in preventing apoptosis and improving functional outcome in experimental spinal cord contusion injury.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a potent hemopoietic cytokine that stimulates stem cell proliferation in the bone marrow and inhibits apoptotic cell death in leukocytes. Its effects in the central nervous system, however, are still unclear. The present study was undertaken to determine if GM-CSF can rescue neuronal cells from apoptosis and improve neurological function in a spinal cord injury (SCI) model. To study the effect of GM-CSF on apoptotic neuronal death, the authors used a staurosporine-induced neuronal death model in an N2A cell line (in vitro) and in a rat SCI model (in vivo). The N2A cells were preincubated with GM-CSF for 60 minutes before being exposed to staurosporine for 24 hours. To inhibit GM-CSF, N2A cells were pretreated with antibodies against the GM-CSF receptor for 60 minutes. Clip compression was,used to induce SCI. Animals were treated with daily doses of GM-CSF (20 microg/day) for 5 days. The number of apoptotic cells in the spinal cord and neurological improvements were assessed. Pretreatment with GM-CSF was found to protect N2A cells significantly from apoptosis, and neutralizing antibodies for the GM-CSF receptors inhibited the rescuing effect of GM-CSF on apoptosis. In the rat SCI model, neurological function improved significantly in the GM-CSF-treated group compared with controls treated with phosphate-buffered saline. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining showed that GM-CSF administration reduced apoptosis in the injured spinal cord. Treatment of SCI with GM-CSF showed beneficial effects. Neuronal protection against apoptosis is viewed as a likely mechanism underlying the therapeutic effect of GM-CSF in SCI.


Does postoperative cognitive decline after coronary bypass affect quality of life?
This study aimed to explore the influence of coronary artery bypass grafting (CABG) on both postoperative cognitive dysfunction and quality of life (QoL) and the association between the two patient-related outcomes. In a prospective, observational cohort study, patients with elective, isolated CABG were included. Cognitive function was assessed using the Cogstate computerised cognitive test battery preoperatively, 3 days and 6 months after surgery. QoL was measured preoperatively and at 6 months using the RAND-36 questionnaire including the Physical Component Score (PCS) and the Mental Component Score (MCS). Regression analysis, with adjustment for confounders, was used to evaluate the association between postoperative cognitive dysfunction and QoL. A total of 142 patients were included in the study. Evidence of persistent cognitive dysfunction was observed in 33% of patients after 6 months. At 6 months, the PCS had improved in 59% and decreased in 21% of patients, and the MCS increased in 49% and decreased in 29%. Postoperative cognitive changes were not associated with QoL scores. Postoperative cognitive dysfunction and decreased QoL are common 6 months after surgery, although cognitive function and QoL were found to have improved in many patients at 6 months of follow-up. Impaired cognitive function is not associated with impaired QoL at 6 months. NCT03774342.


Rainfall-induced removal of copper-based spray residues from vines.
The continuous use of copper against fungal diseases and off-target effects causes major environmental and agronomic problems. However, the rain-induced removal of Cu-based residues is known only for a limited number of crops. We present the results of rain-induced removal of fungicides from two monitored vineyard plots which were sprayed with two widely used Cu-based formulations: copper-oxychloride (CO) and Bordeaux mixture (BM), respectively. Cu removal per growing season was 0.60±0.12kgha(-1) (30% of the applied fungicide) for CO and 0.80±0.10kgha(-1) for BM (70% of the applied fungicide). Fractioning the Cu in soluble (CuS) and particulate fractions (CuP) showed that most of the Cu was removed as CuP, but CuS concentrations found in throughfall collectors exceeded the regulatory threshold for toxicity in surface waters. The first few millimeters of rain caused most of the Cu removal. Our findings agreed with the data reported in the scientific literature, in which a significant fraction of the Cu-based formulation is loosely attached to the plant surfaces. In addition, we found that rainfall energy had a minor influence on the removal.


Eradication therapy for peptic ulcer disease in Helicobacter pylori-positive people.
Peptic ulcer disease is the cause of dyspepsia in about 10% of people. Ninety-five percent of duodenal and 70% of gastric ulcers are associated with Helicobacter pylori. Eradication of H. pylori reduces the relapse rate of ulcers but the magnitude of this effect is uncertain. This is an update of Ford AC, Delaney B, Forman D, Moayyedi P. Eradication therapy for peptic ulcer disease in Helicobacter pylori-positive patients. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD003840. DOI: 10.1002/14651858.CD003840.pub4. To assess the proportion of peptic ulcers healed and the proportion of participants who remained free from relapse with eradication therapy against placebo or other pharmacological therapies in H. pylori-positive people.To assess the proportion of participants that achieved complete relief of symptoms and improvement in quality of life scores.To compare the incidence of adverse effects/drop-outs (total number for each drug) associated with the different treatments.To assess the proportion of participants in whom successful eradication was achieved. In this update, we identified trials by searching the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (1950 to March 2016) and Ovid EMBASE (1980 to March 2016). To identify further relevant trials, we handsearched reference lists from trials selected by electronic searching, and published abstracts from conference proceedings from the United European Gastroenterology Week (published in Gut) and Digestive Disease Week (published in Gastroenterology). The search was last updated in March 2016. We contacted members of Cochrane Upper GI and Pancreatic Diseases, and experts in the field and asked them to provide details of outstanding clinical trials and any relevant unpublished materials. We analysed randomised controlled trials of short- and long-term treatment of peptic ulcer disease in H. pylori-positive adults. Participants received at least one week of H. pylori eradication compared with ulcer healing drug, placebo or no treatment. Trials were included if they reported assessment from two weeks onwards. We collected data on ulcer healing, recurrence, relief of symptoms and adverse effects. We calculated the risk ratio (RR) with 95% confidence intervals (CI) using both fixed-effect and random-effects models with Review Manager software (RevMan 5.3) based on intention-to-treat analysis as far as possible. A total of 55 trials were included for one or more outcomes for this review.In duodenal ulcer healing, eradication therapy was superior to ulcer healing drug (UHD) (34 trials, 3910 participants, RR of ulcer persisting = 0.66, 95% confidence interval (CI) 0.58 to 0.76; 381/2286 (adjusted proportion: 12.4%) in eradication therapy plus UHD versus 304/1624 (18.7%) in UHD; low quality evidence) and no treatment (two trials, 207 participants, RR 0.37, 95% CI 0.26 to 0.53; 30/125 (adjusted proportion: 21.7%) in eradication therapy versus 48/82 (58.5%) in no treatment; low quality evidence).In gastric ulcer healing, the differences were imprecise between eradication therapy and UHD (15 trials, 1974 participants, RR 1.23, 95% CI 0.90 to 1.68; 220/1192 (adjusted proportion: 16.0%) in eradication therapy plus UHD versus 102/782 (13.0%) in UHD; very low quality evidence). In preventing duodenal ulcer recurrence the differences were imprecise between maintenance therapy with H.pylori eradication therapy and maintenance therapy with UHD (four trials, 319 participants, RR of ulcer recurring 0.73; 95% CI 0.42 to 1.25; 19/159 (adjusted proportion: 11.9%) in eradication therapy versus 26/160 (16.3%) in UHD; very low quality evidence), but eradication therapy was superior to no treatment (27 trials 2509 participants, RR 0.20, 95% CI 0.15 to 0.26; 215/1501 (adjusted proportion: 12.9%) in eradication therapy versus 649/1008 (64.4%) in no treatment; very low quality evidence).In preventing gastric ulcer recurrence, eradication therapy was superior to no treatment (12 trials, 1476 participants, RR 0.31, 95% CI 0.22 to 0.45; 116/697 (adjusted proportion: 16.3%) in eradication therapy versus 356/679 (52.4%) in no treatment; very low quality evidence). None of the trials reported proportion of people with gastric ulcer not healed after initial therapy between H.pylori eradication therapy and no active treatment or the proportion of people with recurrent gastric ulcer or peptic ulcers during maintenance therapy between H.pylori eradication therapy and ulcer healing drug therapy. Adding a one to two-week course of H. pylori eradication therapy is an effective treatment for people with H. pylori-positive duodenal ulcer when compared to ulcer healing drugs alone and no treatment. H. pylori eradication therapy is also effective in preventing recurrence of duodenal and gastric ulcer compared to no treatment. There is currently no evidence that H. pylori eradication therapy is an effective treatment in people with gastric ulcer or that it is effective in preventing recurrence of duodenal ulcer compared to ulcer healing drug. However, confidence intervals were wide and significant benefits or harms of H. pylori eradication therapy in acute ulcer healing of gastric ulcers compared to no treatment, and in preventing recurrence of duodenal ulcers compared to ulcer healing drugs cannot be ruled out.


Microfibres from apparel and home textiles: Prospects for including microplastics in environmental sustainability assessment.
Textiles release fibres to the environment during production, use, and at end-of-life disposal. Approximately two-thirds of all textile items are now synthetic, dominated by petroleum-based organic polymers such as polyester, polyamide and acrylic. Plastic microfibres (<5 mm) and nanofibres (<100 nm) have been identified in ecosystems in all regions of the globe and have been estimated to comprise up to 35% of primary microplastics in marine environments, a major proportion of microplastics on coastal shorelines and to persist for decades in soils treated with sludge from waste water treatment plants. In this paper we present a critical review of factors affecting the release from fabrics of microfibres, and of the risks for impacts on ecological systems and potentially on human health. This review is used as a basis for exploring the potential to include a metric for microplastic pollution in tools that have been developed to quantify the environmental performance of apparel and home textiles. We conclude that the simple metric of mass or number of microfibres released combined with data on their persistence in the environment, could provide a useful interim mid-point indicator in sustainability assessment tools to support monitoring and mitigation strategies for microplastic pollution. Identified priority research areas include: (1) Standardised analytical methods for textile microfibres and nanofibres; (2) Ecotoxicological studies using environmentally realistic concentrations; (3) Studies tracking the fate of microplastics in complex food webs; and (4) Refined indicators for microfibre impacts in apparel and home textile sustainability assessment tools.


The Impact of Racial and Ethnic Health Disparities in Diabetes Management on Clinical Outcomes: A Reinforcement Learning Analysis of Health Inequity Among Youth and Young Adults in the SEARCH for Diabetes in Youth Study.
To estimate difference in population-level glycemic control and the emergence of diabetes complications given a theoretical scenario in which non-White youth and young adults (YYA) with type 1 diabetes (T1D) receive and follow an equivalent distribution of diabetes treatment regimens as non-Hispanic White YYA. Longitudinal data from YYA diagnosed 2002-2005 in the SEARCH for Diabetes in Youth Study were analyzed. Based on self-reported race/ethnicity, YYA were classified as non-White race or Hispanic ethnicity (non-White subgroup) versus non-Hispanic White race (White subgroup). In the White versus non-White subgroups, the propensity score models estimated treatment regimens, including patterns of insulin modality, self-monitored glucose frequency, and continuous glucose monitoring use. An analysis based on policy evaluation techniques in reinforcement learning estimated the effect of each treatment regimen on mean hemoglobin A1c (HbA1c) and the prevalence of diabetes complications for non-White YYA. The study included 978 YYA. The sample was 47.5% female and 77.5% non-Hispanic White, with a mean age of 12.8 ± 2.4 years at diagnosis. The estimated population mean of longitudinal average HbA1c over visits was 9.2% and 8.2% for the non-White and White subgroup, respectively (difference of 0.9%). Within the non-White subgroup, mean HbA1c across visits was estimated to decrease by 0.33% (95% CI -0.45, -0.21) if these YYA received the distribution of diabetes treatment regimens of the White subgroup, explaining ∼35% of the estimated difference between the two subgroups. The non-White subgroup was also estimated to have a lower risk of developing diabetic retinopathy, diabetic kidney disease, and peripheral neuropathy with the White youth treatment regimen distribution (P < 0.05), although the low proportion of YYA who developed complications limited statistical power for risk estimations. Mathematically modeling an equalized distribution of T1D self-management tools and technology accounted for part of but not all disparities in glycemic control between non-White and White YYA, underscoring the complexity of race and ethnicity-based health inequity.


Decrypting bacterial polyphenol metabolism in an anoxic wetland soil.
Microorganisms play vital roles in modulating organic matter decomposition and nutrient cycling in soil ecosystems. The enzyme latch paradigm posits microbial degradation of polyphenols is hindered in anoxic peat leading to polyphenol accumulation, and consequently diminished microbial activity. This model assumes that polyphenols are microbially unavailable under anoxia, a supposition that has not been thoroughly investigated in any soil type. Here, we use anoxic soil reactors amended with and without a chemically defined polyphenol to test this hypothesis, employing metabolomics and genome-resolved metaproteomics to interrogate soil microbial polyphenol metabolism. Challenging the idea that polyphenols are not bioavailable under anoxia, we provide metabolite evidence that polyphenols are depolymerized, resulting in monomer accumulation, followed by the generation of small phenolic degradation products. Further, we show that soil microbiome function is maintained, and possibly enhanced, with polyphenol addition. In summary, this study provides chemical and enzymatic evidence that some soil microbiota can degrade polyphenols under anoxia and subvert the assumed polyphenol lock on soil microbial metabolism.


Aldehyde-alcohol dehydrogenase and/or thiolase overexpression coupled with CoA transferase downregulation lead to higher alcohol titers and selectivity in Clostridium acetobutylicum fermentations.
Metabolic engineering (ME) of Clostridium acetobutylicum has led to increased solvent (butanol, acetone, and ethanol) production and solvent tolerance, thus demonstrating that further efforts have the potential to create strains of industrial importance. With recently developed ME tools, it is now possible to combine genetic modifications and thus implement more advanced ME strategies. We have previously shown that antisense RNA (asRNA)-based downregulation of CoA transferase (CoAT, the first enzyme in the acetone-formation pathway) results in increased butanol to acetone selectivity, but overall reduced butanol yields and titers. In this study the alcohol/aldehyde dehydrogenase (aad) gene (encoding the bifunctional protein AAD responsible for butanol and ethanol production from butyryl-CoA and acetyl-CoA, respectively) was expressed from the phosphotransbutyrylase (ptb) promoter to enhance butanol formation and selectivity, while CoAT downregulation was used to minimize acetone production. This led to early production of high alcohol (butanol plus ethanol) titers, overall solvent titers of 30 g/L, and a higher alcohol/acetone ratio. Metabolic flux analysis revealed the likely depletion of butyryl-CoA. In order to increase then the flux towards butyryl-CoA, we examined the impact of thiolase (THL, thl) overexpression. THL converts acetyl-CoA to acetoacetyl-CoA, the first step of the pathway from acetyl-CoA to butyryl-CoA, and thus, combining thl overexpression with aad overexpression decreased, as expected, acetate and ethanol production while increasing acetone and butyrate formation. thl overexpression in strains with asRNA CoAT downregulation did not significantly alter product formation thus suggesting that a more complex metabolic engineering strategy is necessary to enhance the intracellular butyryl-CoA pool and reduce the acetyl-CoA pool in order to achieve improved butanol titers and selectivity.


Households as hotspots of Lassa fever? Assessing the spatial distribution of Lassa virus-infected rodents in rural villages of Guinea.
The Natal multimammate mouse (Mastomys natalensis) is the reservoir host of Lassa virus (LASV), an arenavirus that causes Lassa haemorrhagic fever in humans in West Africa. While previous studies suggest that spillover risk is focal within rural villages due to the spatial behaviour of the rodents, the level of clustering was never specifically assessed. Nevertheless, detailed information on the spatial distribution of infected rodents would be highly valuable to optimize LASV-control campaigns, which are limited to rodent control or interrupting human-rodent contact considering that a human vaccine is not available. Here, we analysed data from a four-year field experiment to investigate whether LASV-infected rodents cluster in households in six rural villages in Guinea. Our analyses were based on the infection status (antibody or PCR) and geolocation of rodents (n = 864), and complemented with a phylogenetic analysis of LASV sequences (n = 119). We observed that the majority of infected rodents were trapped in a few houses (20%) and most houses were rodent-free at a specific point in time (60%). We also found that LASV strains circulating in a specific village were polyphyletic with respect to neighbouring villages, although most strains grouped together at the sub-village level and persisted over time. In conclusion, our results suggest that: (i) LASV spillover risk is heterogeneously distributed within villages in Guinea; (ii) viral elimination in one particular village is unlikely if rodents are not controlled in neighbouring villages. Such spatial information should be incorporated into eco-epidemiological models that assess the cost-efficiency of LASV control strategies.


ATP competes with PIP2 for binding to gelsolin.
Gelsolin is a severing and capping protein that targets filamentous actin and regulates filament lengths near plasma membranes, contributing to cell movement and plasma membrane morphology. Gelsolin binds to the plasma membrane via phosphatidylinositol 4,5-bisphosphate (PIP2) in a state that cannot cap F-actin, and gelsolin-capped actin filaments are uncapped by PIP2 leading to filament elongation. The process by which gelsolin is removed from PIP2 at the plasma membrane is currently unknown. Gelsolin also binds ATP with unknown function. Here we characterize the role of ATP on PIP2-gelsolin complex dynamics. Fluorophore-labeled PIP2 and ATP were used to study their interactions with gelsolin using steady-state fluorescence anisotropy, and Alexa488-labeled gelsolin was utilized to reconstitute the regulation of gelsolin binding to PIP2-containing phospholipid vesicles by ATP. Under physiological salt conditions ATP competes with PIP2 for binding to gelsolin, while calcium causes the release of ATP from gelsolin. These data suggest a cycle for gelsolin activity. Firstly, calcium activates ATP-bound gelsolin allowing it to sever and cap F-actin. Secondly, PIP2-binding removes the gelsolin cap from F-actin at low calcium levels, leading to filament elongation. Finally, ATP competes with PIP2 to release the calcium-free ATP-bound gelsolin, allowing it to undergo a further round of severing.


Mediterranean diet of Crete: foods and nutrient content.
To describe the traditional diet of Crete and evaluate the nutrient composition of 3 types of diet common in Crete by means of chemical analyses of composite food samples. To compare results with dietary analyses from a nutrient database developed at the University of Crete, Greece. Three composite diet samples were obtained based on 7-day weighed food records representing the traditional Cretan Mediterranean diet (diet A), typical diet of present-day Greek adolescents (diet B), and fasting diet of the Eastern Orthodox church (diet C). Analyses were performed chemically and using a nutrient database. Chemical analyses provided a definitive measure, for the first time, of the nutrient composition of the complete Greek diet as it was in the early 1960s. In comparing chemical analyses with nutrient database analyses, differences greater than 15% of the analyzed value were found in all 3 diets for cholesterol and some vitamins. The differences between analyzed and calculated values in total fat and saturated fat content were less than 15% in all diets. The present study provides 2 practical examples of the Mediterranean diet, which although widely publicized has rarely been analyzed chemically. Diet A has been shown to be related to the lowest rates for coronary heart disease and cancer mortality compared with the diets of the other populations of the Seven Countries study. As such, it could be recommended for health promotion and prevention of disease. Diet C contains even lower amounts of saturated fatty acids and would be excellent for patients with hypercholesterolemia. The high antioxidants in diet C probably maintain very low levels of low-density lipoprotein cholesterol. Dietary analyses of the Greek diet could be based on an operational database such as ours if further chemical analyses are performed on specific foods. These would result in improved precision of the database and possible extension into national food composition tables and a national dietary database.


Welcome to Automated Experimentation: a new open access journal.
Modern experimental science provides more opportunities for yet larger series of experiments. Demand for experimental results also has become more diverse, requiring results that have direct connections to systems outside the laboratory. With this has come an ability to automate many areas of experimental science, not only the experiments themselves but also the larger processes that contribute to experimentation and analysis more broadly. As automated experimentation becomes more widely used and understood, we launch this journal to provide a proper publication channel for this new breed of interdisciplinary research as well as a bridge to all significant groundwork research that would facilitate possible automated experimentation. With this in mind, we are interested in publishing all kinds of research into scientific experimentation, including research where the potential for automation is at proof or concept or early deployment stage.


A Novel Folic Acid Receptor-Targeted Drug Delivery System Based on Curcumin-Loaded β-Cyclodextrin Nanoparticles for Cancer Treatment.
A novel folate receptor-targeted β-cyclodextrin (β-CD) drug delivery vehicle was constructed to improve the bioavailability, biosafety, and drug loading capacity of curcumin. Controlled release and targeted delivery was achieved by modifying the nanoparticles with folic acid (FA). Folate-conjugated β-CD-polycaprolactone block copolymers were synthesized and characterized. Curcumin-loaded nanoparticles (FA-Cur-NPs) were structured by self-assembly. The physicochemical properties, stability, release behavior and tumor-targeting ability of the fabricated nanoparticles were studied. The average particle size and drug loading of FA-Cur-NPs was 151.8 nm and 20.27%, respectively. Moreover, the FA-Cur-NPs exhibited good stability in vitro for 72 h. The drug release profiles showed that curcumin from FA-Cur-NPs was released significantly faster in a pH 6.4 phosphate buffered solution (PBS) than in pH 7.4, indicating that curcumin can be enriched around the tumor site compared with normal cells. Additionally, the internalization of FA-Cur-NPs was aided by FA receptor-mediated endocytosis, and its cytotoxicity was proportional to the cellular uptake efficiency. Furthermore, in vivo studies confirmed that FA-Cur-NPs exhibited marked accumulation in the tumor site and excellent antitumor activity. These findings suggest that FA-Cur-NPs are a promising approach for improving cancer therapy through active targeting and controllable release.


The effect of green-coffee extract supplementation on obesity: A systematic review and dose-response meta-analysis of randomized controlled trials.
Given that the most recent systematic review investigating Green-Coffee Extract (GCE) as a weight loss facilitator was nearly a decade ago and that the authors reported there no consensus on the effect of GCE/CGA (Chlorogenic acids) on body composition indices, a comprehensive systematic review and dose-response meta-analysis of all available randomized controlled trial (RCTs) was undertaken to examine the effect of GCE and CGA intervention on body weight (BW), body mass index (BMI) and waist circumference (WC) in adults. We conducted a systematic search of all available randomized controlled trials (RCTs) performed up to June 2019 in the following electronic databases: PubMed, Scopus and Google Scholar. RCTs that investigated the effect GCE/CGA Supplementation on BW, BMI and WC in adults were included for final analysis. The pooled weight mean difference (WMD) of included studies was estimated using a random-effects model. A total of 13 articles with 16 RCTs were included in the meta-analysis. Results revealed significant reduction in BMI (WMD: -0.403 kg/m2, 95% CI: -0.800, -0.005, p = 0.047) and no significant change in BW (WMD: -0.585 kg, 95% CI: -1.498, 0.329, p = 0.210) and WC (WMD: -0.847 cm, 95% CI: -1.764, 0.071, p = 0.070). In the subgroup analysis, studies that were conducted on baseline BMI ≥25 kg/m2 revealed a significant greater reduction in body weight and BMI than those performed on baseline BMI <25 kg/m2. Moreover, short supplementation periods of less than 4 weeks had no effect. The results of current meta-analysis study support the use of GCE supplementation for the improvement of obesity indices, with sub-group analysis highlighting greater improvements in individuals with a starting BMI ≥25 kg/m2.


Does drought stress modify the effects of plant-growth promoting rhizobacteria on an aboveground chewing herbivore?
Soil microbes have important effects on the interactions of plants with their environment, by promoting plant growth, inducing resistance to pests or by conferring tolerance to abiotic stress. However, their effects are variable and the factors responsible for this variation are mainly unknown. Our aim was to assess how drought stress modifies the effect of the nonpathogenic rhizobacterium Pseudomonas simiae WCS417r on plant growth and resistance against the generalist leaf-chewing caterpillar Mamestra brassicae. We studied Arabidopsis thaliana Col-0 plants, as well as mutants altered in the biosynthesis of the phytohormones jasmonic acid (JA) and abscisic acid (ABA). Caterpillars did not prefer rhizobacteria-treated plants, independently of drought stress. Rhizobacteria colonization had a variable effect on caterpillar performance, which ranged from positive in one experiment to neutral in a second one. Drought had a consistent negative effect on herbivore performance; however, it did not modify the effect of rhizobacteria on herbivore performance. The effect of drought on herbivore performance was JA-mediated (confirmed with the use of the dde2-2 mutant), but it was still present in the ABA-deficient mutant aba2-1. Plant biomass was reduced by both drought and herbivory but it was enhanced by rhizobacterial colonization. Pseudomonas simiae WCS417r is able to promote plant growth even when plants are suffering herbivory. Nevertheless, the microbial effect on the herbivore is variable, independently of drought stress. To get the best possible outcome from the rhizobacteria-plant mutualism it is important to understand which other factors may be responsible for its context-dependency.


Role of the animal model on the pharmacokinetics of equine-derived antivenoms.
Antivenom pharmacokinetics has been studied in heterologous models in which the animal species used as immunoglobulin source is different from that used as recipient. In these models, after intravenous administration of antivenom, the plasma concentration of immunoglobulins shows a rapid initial declining-phase followed by a slower terminal-phase, which has been associated with antivenom distribution and elimination, respectively. We have compared pharmacokinetic parameters for equine-derived antivenom in homologous (horse) and heterologous (cow) models. It was found that the maximum concentration is lower in cows than in horses. Additionally, the steady-state distribution volume is higher in cows as compared to horses. On the other hand, models were not different in the time required to reach the maximum concentration, the area under the concentration/time curve, the half-life of decay during the slowest phase, the systemic clearance and the mean residence time. Similar results were obtained in a rabbit model, in which the pharmacokinetics was also affected by passive immunization of rabbits with anti-equine IgG. We conclude that, in addition to other physiological differences (e.g. cardiac frequency, plasmatic volume, glomerular filtration rate, etc.) between animal models, the ability to remove foreign immunoglobulins might influence the way in which the plasma concentration of antivenom decreases over time, thereby distorting the pharmacokinetic predictions based on non-compartmental models.


Prenatal music stimulation facilitates the postnatal functional development of the auditory as well as visual system in chicks (Gallus domesticus).
Rhythmic sound or music is known to improve cognition in animals and humans. We wanted to evaluate the effects of prenatal repetitive music stimulation on the remodelling of the auditory cortex and visual Wulst in chicks. Fertilized eggs (0 day) of white leghorn chicken (Gallus domesticus) during incubation were exposed either to music or no sound from embryonic day 10 until hatching. Auditory and visual perceptual learning and synaptic plasticity, as evident by synaptophysin and PSD-95 expression, were done at posthatch days (PH) 1, 2 and 3. The number of responders was significantly higher in the music stimulated group as compared to controls at PH1 in both auditory and visual preference tests. The stimulated chicks took significantly lesser time to enter and spent more time in the maternal area in both preference tests. A significantly higher expression of synaptophysin and PSD-95 was observed in the stimulated group in comparison to control at PH1-3 both in the auditory cortex and visual Wulst. A significant inter-hemispheric and gender-based difference in expression was also found in all groups. These results suggest facilitation of postnatal perceptual behaviour and synaptic plasticity in both auditory and visual systems following prenatal stimulation with complex rhythmic music.


Proteome profiling in murine models of multiple sclerosis: identification of stage specific markers and culprits for tissue damage.
The identification of new biomarkers is of high interest for the prediction of the disease course and also for the identification of pathomechanisms in multiple sclerosis (MS). To specify markers of the chronic disease phase, we performed proteome profiling during the later phase of myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis (MOG-EAE, day 35 after immunization) as a model disease mimicking many aspects of secondary progressive MS. In comparison to healthy controls, high resolution 2 dimensional gel electrophoresis revealed a number of regulated proteins, among them glial fibrilary acidic protein (GFAP). Phase specific up-regulation of GFAP in chronic EAE was confirmed by western blotting and immunohistochemistry. Protein levels of GFAP were also increased in the cerebrospinal fluid of MS patients with specificity for the secondary progressive disease phase. In a next step, proteome profiling of an EAE model with enhanced degenerative mechanisms revealed regulation of alpha-internexin, syntaxin binding protein 1, annexin V and glutamate decarboxylase in the ciliary neurotrophic factor (CNTF) knockout mouse. The identification of these proteins implicate an increased apoptosis and enhanced axonal disintegration and correlate well the described pattern of tissue injury in CNTF -/- mice which involve oligodendrocyte (OL) apoptosis and axonal injury.In summary, our findings underscore the value of proteome analyses as screening method for stage specific biomarkers and for the identification of new culprits for tissue damage in chronic autoimmune demyelination.


A detailed phenomenological comparison of complex visual hallucinations in dementia with Lewy bodies and Alzheimer's disease.
Visual hallucinations (VH) are a core feature of dementia with Lewy bodies (DLB), but little is known about their phenomenology. A total of 73 dementia patients (42 DLB, 30 Alzheimer's disease [AD], 1 undiagnosed) in contact with clinical services were assessed with a detailed standardized inventory. DLB was diagnosed according to the criteria of McKeith and colleagues, AD was diagnosed using the NINCDS-ADRDA criteria. Autopsy confirmation has been obtained when possible. VH were defined using the definition of Burns and colleagues. Detailed descriptions of hallucinatory experiences were recorded. Annual follow-up interviews were undertaken. The clinical diagnosis has been confirmed in 18 of the 19 cases that have come to autopsy. A total of 93% of DLB patients and 27% of AD patients experienced VH. DLB patients were significantly more likely to experience multiple VH that persisted over follow-up. They were significantly more likely to hear their VH speak but there were no significant differences in the other phenomenological characteristics including whether the hallucinations moved, the time of day that they were experienced, their size, the degree of insight, and whether they were complete. VH may be more likely to be multiple, to speak, and to be persistent in DLB patients. These characteristics could potentially aid accurate diagnosis.


rsfMRI effects of KB220Z™ on neural pathways in reward circuitry of abstinent genotyped heroin addicts.
Recently, Willuhn et al. reported that cocaine use and even non-substance-related addictive behavior increases as dopaminergic function is reduced. Chronic cocaine exposure has been associated with decreases in D2/D3 receptors and was also associated with lower activation of cues in occipital cortex and cerebellum, in a recent PET study by Volkow's et al. Therefore, treatment strategies, like dopamine agonist therapy, that might conserve dopamine function may be an interesting approach to relapse prevention in psychoactive drug and behavioral addictions. To this aim, we evaluated the effect of KB220Z™ on reward circuitry of 10 heroin addicts undergoing protracted abstinence (average 16.9 months). In a randomized placebo-controlled crossover study of KB220Z, five subjects completed a triple-blinded experiment in which the subject, the person administering the treatment, and the person evaluating the response to treatment were blinded to the treatment that any particular subject was receiving. In addition, nine subjects were genotyped utilizing the GARSDX™ test. We preliminarily report that KB220Z induced an increase in BOLD activation in caudate-accumbens-dopaminergic pathways compared to placebo following 1-hour acute administration. Furthermore, KB220Z also reduced resting-state activity in the putamen of abstinent heroin addicts. In the second phase of this pilot study of all 10 abstinent heroin-dependent subjects, we observed that three brain regions of interest were significantly activated from resting state by KB220Z compared to placebo (p < 0.05). Increased functional connectivity was observed in a putative network that included the dorsal anterior cingulate, medial frontal gyrus, nucleus accumbens, posterior cingulate, occipital cortical areas, and cerebellum. These results and other quantitative electroencephalogy (qEEG) study results suggest a putative anti-craving/anti-relapse role of KB220Z in addiction by direct or indirect dopaminergic interaction. Due to small sample size, we caution definitive interpretation of these preliminary results, and confirmation with additional research and ongoing rodent and human studies of KB220Z is required.


State of the "art": a taxonomy of artistic stylization techniques for images and video.
This paper surveys the field of nonphotorealistic rendering (NPR), focusing on techniques for transforming 2D input (images and video) into artistically stylized renderings. We first present a taxonomy of the 2D NPR algorithms developed over the past two decades, structured according to the design characteristics and behavior of each technique. We then describe a chronology of development from the semiautomatic paint systems of the early nineties, through to the automated painterly rendering systems of the late nineties driven by image gradient analysis. Two complementary trends in the NPR literature are then addressed, with reference to our taxonomy. First, the fusion of higher level computer vision and NPR, illustrating the trends toward scene analysis to drive artistic abstraction and diversity of style. Second, the evolution of local processing approaches toward edge-aware filtering for real-time stylization of images and video. The survey then concludes with a discussion of open challenges for 2D NPR identified in recent NPR symposia, including topics such as user and aesthetic evaluation.


Proposed declassification of disease categories related to sexual orientation in the International Statistical Classification of Diseases and Related Health Problems (ICD-11).
The World Health Organization is developing the 11th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-11), planned for publication in 2017. The Working Group on the Classification of Sexual Disorders and Sexual Health was charged with reviewing and making recommendations on disease categories related to sexuality in the chapter on mental and behavioural disorders in the 10th revision (ICD-10), published in 1990. This chapter includes categories for diagnoses based primarily on sexual orientation even though ICD-10 states that sexual orientation alone is not a disorder. This article reviews the scientific evidence and clinical rationale for continuing to include these categories in the ICD. A review of the evidence published since 1990 found little scientific interest in these categories. In addition, the Working Group found no evidence that they are clinically useful: they neither contribute to health service delivery or treatment selection nor provide essential information for public health surveillance. Moreover, use of these categories may create unnecessary harm by delaying accurate diagnosis and treatment. The Working Group recommends that these categories be deleted entirely from ICD-11. Health concerns related to sexual orientation can be better addressed using other ICD categories.


Exercise neuroprotection in a rat model of binge alcohol consumption.
Excessive alcohol intake produces structural and functional deficits in corticolimbic pathways that are thought to underlie cognitive deficits in the alcohol use disorders (AUDs). Animal models of binge alcohol administration support the direct link of high levels of alcohol consumption and neurotoxicity in the hippocampus and surrounding cortex. In contrast, voluntary wheel running enhances hippocampal neurogenesis and generally promotes the health of neurons. We investigated whether voluntary exercise prior to binge alcohol exposure could protect against alcohol-induced cell loss. Female Long-Evans rats exercised voluntarily for 14 days before undergoing 4 days of binge alcohol consumption. Brains were harvested immediately after the last dose of alcohol and examined for various histological markers of neurodegeneration, including both cell death (FluoroJade B) and cell birth (Ki67) markers. Rats that exercised prior to binge exposure were significantly less behaviorally intoxicated, which was not a result of enhanced hepatic metabolism. Rats that exercised prior to binge alcohol consumption had reduced loss of dentate gyrus granule cells and fewer FluoroJade B positive cells in the dentate gyrus and associated entorhinal-perirhinal cortex compared to nonexercisers. However, exercise did not protect against cell death in the piriform cortex nor protect against alcohol-induced decreases in cell proliferation, evidenced by a similar alcohol-induced reduction in Ki67 labeled cells between exercise and sedentary rats. We conclude that exercise can reduce behavioral sensitivity to ethanol intoxication and protect vulnerable brain areas from alcohol-induced cell death. Exercise neuroprotection of alcohol-induced brain damage has important implications in understanding the neurobiology of the AUDs as well as in developing novel treatment strategies.


Rhythmic brushstrokes distinguish van Gogh from his contemporaries: findings via automated brushstroke extraction.
Art historians have long observed the highly characteristic brushstroke styles of Vincent van Gogh and have relied on discerning these styles for authenticating and dating his works. In our work, we compared van Gogh with his contemporaries by statistically analyzing a massive set of automatically extracted brushstrokes. A novel extraction method is developed by exploiting an integration of edge detection and clustering-based segmentation. Evidence substantiates that van Gogh's brushstrokes are strongly rhythmic. That is, regularly shaped brushstrokes are tightly arranged, creating a repetitive and patterned impression. We also found that the traits that distinguish van Gogh's paintings in different time periods of his development are all different from those distinguishing van Gogh from his peers. This study confirms that the combined brushwork features identified as special to van Gogh are consistently held throughout his French periods of production (1886-1890).


Exploring sensory integrative dysfunction in process schizophrenia.
During a 6-week period, the effects of sensory integrative activities on a group of seven chronic nonparanoid schizophrenic adults were compared to the effects of sedentary activities in a control group of seven similar subjects. The effects of each therapeutic approach were evaluated by measuring the patients' performance in several areas using the Nurses Observation Scale of Inpatient Evaluation-30 (NOSIE-30), The Object Manipulation Speed Test, a gait analysis, and grip strength. The results indicated general improvement in the experimental group. Behaviors measured by the NOSIE-30 showed the most significant improvements. The control group showed isolated improvements in grooming (measured by the NOSIE-30) and in right-hand use (measured by The Object Manipulation Speed Test). These findings suggest that 6 weeks of sensory integrative activities can improve the overall functioning of chronic nonparanoid schizophrenic patients, facilitate their adaptive responses, and enable them to participate more fully in other areas of therapeutic intervention.


Trial frame refraction versus autorefraction among new patients in a low-vision clinic.
To determine the relationship between refractive error as measured by autorefraction and that measured by trial frame refraction among a sample of adults with vision impairment seen in a university-based low-vision clinic and to determine if autorefraction might be a suitable replacement for trial frame refraction. A retrospective chart review of all new patients 19 years or older seen over an 18-month period was conducted and the following data collected: age, sex, primary ocular diagnosis, entering distance visual acuity, habitual correction, trial frame refraction, autorefraction, and distance visual acuity measured after trial frame refraction. Trial frame refraction and autorefraction were compared using paired t-tests, intraclass correlations, and Bland-Altman plots. Final analyses included 440 patients for whom both trial frame refraction and autorefraction data were available for the better eye. Participants were mostly female (59%) with a mean age of 68 years (SD = 20). Age-related macular degeneration was the most common etiology for vision impairment (44%). Values for autorefraction and trial frame refraction were statistically different, but highly correlated for the spherical equivalent power (r = 0.92), the cylinder power (r = 0.80) and overall blurring strength (0.89). Although the values of the cross-cylinders J(0) and J(45) were similar, they were poorly correlated (0.08 and 0.15, respectively). The range of differences in spherical equivalent power was large (-8.6 to 4.9). Autorefraction is highly correlated with trial frame refraction. Differences are sometimes substantial, making autorefraction an unsuitable substitute for trial frame refraction.


Using Observational Data to Estimate the Effect of Hand Washing and Clean Delivery Kit Use by Birth Attendants on Maternal Deaths after Home Deliveries in Rural Bangladesh, India and Nepal.
Globally, puerperal sepsis accounts for an estimated 8-12% of maternal deaths, but evidence is lacking on the extent to which clean delivery practices could improve maternal survival. We used data from the control arms of four cluster-randomised controlled trials conducted in rural India, Bangladesh and Nepal, to examine associations between clean delivery kit use and hand washing by the birth attendant with maternal mortality among home deliveries. We tested associations between clean delivery practices and maternal deaths, using a pooled dataset for 40,602 home births across sites in the three countries. Cross-sectional data were analysed by fitting logistic regression models with and without multiple imputation, and confounders were selected a priori using causal directed acyclic graphs. The robustness of estimates was investigated through sensitivity analyses. Hand washing was associated with a 49% reduction in the odds of maternal mortality after adjusting for confounding factors (adjusted odds ratio (AOR) 0.51, 95% CI 0.28-0.93). The sensitivity analysis testing the missing at random assumption for the multiple imputation, as well as the sensitivity analysis accounting for possible misclassification bias in the use of clean delivery practices, indicated that the association between hand washing and maternal death had been over estimated. Clean delivery kit use was not associated with a maternal death (AOR 1.26, 95% CI 0.62-2.56). Our evidence suggests that hand washing in delivery is critical for maternal survival among home deliveries in rural South Asia, although the exact magnitude of this effect is uncertain due to inherent biases associated with observational data from low resource settings. Our findings indicating kit use does not improve maternal survival, suggests that the soap is not being used in all instances that kit use is being reported.


Murine coronavirus requires lipid rafts for virus entry and cell-cell fusion but not for virus release.
Thorp and Gallagher first reported that depletion of cholesterol inhibited virus entry and cell-cell fusion of mouse hepatitis virus (MHV), suggesting the importance of lipid rafts in MHV replication (E. B. Thorp and T. M. Gallagher, J. Virol. 78:2682-2692, 2004). However, the MHV receptor is not present in lipid rafts, and anchoring of the MHV receptor to lipid rafts did not enhance MHV infection; thus, the mechanism of lipid rafts involvement is not clear. In this study, we defined the mechanism and extent of lipid raft involvement in MHV replication. We showed that cholesterol depletion by methyl beta-cyclodextrin or filipin did not affect virus binding but reduced virus entry. Furthermore, MHV spike protein bound to nonraftraft membrane at 4 degrees C but shifted to lipid rafts at 37 degrees C, indicating a redistribution of membrane following virus binding. Thus, the lipid raft involvement in MHV entry occurs at a step following virus binding. We also found that the viral spike protein in the plasma membrane of the infected cells was associated with lipid rafts, whereas that in the Golgi membrane, where MHV matures, was not. Moreover, the buoyant density of the virion was not changed when MHV was produced from the cholesterol-depleted cells, suggesting that MHV does not incorporate lipid rafts into the virion. These results indicate that MHV release does not involve lipid rafts. However, MHV spike protein has an inherent ability to associate with lipid rafts. Correspondingly, cell-cell fusion induced by MHV was retarded by cholesterol depletion, consistent with the association of the spike protein with lipid rafts in the plasma membrane. These findings suggest that MHV entry requires specific interactions between the spike protein and lipid rafts, probably during the virus internalization step.


Noninvasive assessment of coronary vasodilation using magnetic resonance angiography.
The purpose of this study was to investigate the use of coronary magnetic resonance angiography (MRA) for assessing human epicardial coronary artery vasodilation. Coronary vasodilation plays a vital role in the human coronary circulation. Previous studies of epicardial coronary vasodilation have used invasive coronary angiography. Coronary MRA may provide an alternative noninvasive method to directly assess changes in coronary size. Thirty-two subjects were studied: 12 patients (age 55 +/- 18 years) and 20 healthy subjects (age 34 +/- 4 years). High-resolution multi-slice spiral coronary MRA (in-plane resolution of 0.52 to 0.75 mm) was performed before and after sublingual nitroglycerin (NTG). Quantitative analysis of coronary vasodilation was performed on cross-sectional images of the right coronary artery (RCA). A time-course analysis of coronary vasodilation was performed in a subset of eight subjects for 30 min after NTG. Signal-to-noise ratio was also measured on the in-plane RCA images. Coronary MRA demonstrated a 23% increase in cross-sectional area after NTG (16.9 +/- 7.8 mm2 to 20.8 +/- 8.9 mm2, p <0.0001), with significant vasodilation between 3 and 15 min after NTG on time-course analysis. The MRA measurements had low interobserver variability (< or =5%) and good correlation with X-ray angiography (r=0.98). The magnitude of vasodilation correlated with baseline cross-sectional area (r=0.52, p=0.03) and age (r=0.40, p=0.019). Post-NTG images also demonstrated a 31% improvement in coronary signal-to-noise ratio (p = 0.002). Nitroglycerin-enhanced coronary MRA can noninvasively measure coronary artery vasodilation and is a promising noninvasive technique to study coronary vasomotor function.


Glucagon regulation of plasma ketone body concentration in human diabetes.
The present study was designed to test the hypothesis that physiological concentrations of glucagon may increase plasma ketone body concentration when sufficient free fatty acid substrate is available to support hepatic ketogenesis. Physiological elevations of plasma glucagon concentration were produced by a constant infusion of hormone, and increased plasma-free fatty acid availability was produced by simultaneous heparin injection to induce intravascular lipolysis. In the five insulin-dependent subjects studied, when plasma glucagon concentration remained at the normal basal level of 72+/-14 pg/ml during control saline infusion, the heparin-induced increase in free fatty acid availability resulted in approximately a 20% increase in plasma ketone body concentration. In contrast, when plasma glucagon concentration was elevated by hormone infusion to the physiological level of 215+/-35 pg/ml, the heparin-induced increases in free fatty acid availability resulted in approximately an 80% increase in plasma ketone body concentration. These results suggest that physiological elevations in plasma glucagon concentration may augment ketonemia in diabetic man when simultaneous elevations in plasma-free fatty acid arepresent.


Unique mechanistic insights into the beneficial effects of soluble epoxide hydrolase inhibitors in the prevention of cardiac fibrosis.
Tissue fibrosis represents one of the largest groups of diseases for which there are very few effective therapies. In the heart, myocardial infarction (MI) resulting in the loss of cardiac myocytes can culminate in adverse cardiac remodeling leading to eventual heart failure. Adverse cardiac remodeling includes myocyte hypertrophy, fibrosis, and electrical remodeling. We have previously demonstrated the beneficial effects of several potent soluble epoxide hydrolase inhibitors (sEHIs) in different models of cardiac hypertrophy and failure. Here, we directly determine the molecular mechanisms underlying the beneficial effects of sEHIs in cardiac remodeling post-MI. Treatment with a potent sEHI, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea (TPPU), which was started 1 wk post-MI in a murine model, results in a significant improvement in cardiac function. Importantly, treatment with TPPU results in a decrease in cardiac fibrosis as quantified using histological and immunostaining techniques. Moreover, single-cell-based assays demonstrate that treatment with TPPU results in a significant decrease not only in the percentages but also the proliferative capacity of different populations of cardiac fibroblasts as well as a reduction in the migration of fibroblasts into the heart from the bone marrow. Our study provides evidence for a possible unique therapeutic strategy to reduce cardiac fibrosis and improve cardiac function post-MI.


Early life exposure to maternal insulin resistance has persistent effects on hepatic NAFLD in juvenile nonhuman primates.
The origins of nonalcoholic fatty liver disease (NAFLD) may lie in early intrauterine exposures. Here we examined the maternal response to chronic maternal high-fat (HF) diet and the impact of postweaning healthy diet on mechanisms for NAFLD development in juvenile nonhuman primate (NHP) offspring at 1 year of age. Pregnant females on HF diet were segregated as insulin resistant (IR; HF+IR) or insulin sensitive (IS; HF+IS) compared with control (CON)-fed mothers. HF+IR mothers have increased body mass, higher triglycerides, and increased placental cytokines. At weaning, offspring were placed on a CON or HF diet. Only offspring from HF+IR mothers had increased liver triglycerides and upregulated pathways for hepatic de novo lipid synthesis and inflammation that was irreversible upon switching to a healthy diet. These juvenile livers also showed a combination of classical and alternatively activated hepatic macrophages and natural killer T cells, in the absence of obesity or insulin resistance. Our findings suggest that maternal insulin resistance, including elevated triglycerides, insulin, and weight gain, initiates dysregulation of the juvenile hepatic immune system and development of de novo lipogenic pathways that persist in vitro and may be an irreversible "first hit" in the pathogenesis of NAFLD in NHP.


Relationship of safety climate and safety performance in hospitals.
To examine the relationship between measures of hospital safety climate and hospital performance on selected Patient Safety Indicators (PSIs). Primary data from a 2004 survey of hospital personnel. Secondary data from the 2005 Medicare Provider Analysis and Review File and 2004 American Hospital Association's Annual Survey of Hospitals. A cross-sectional study of 91 hospitals. Negative binomial regressions used an unweighted, risk-adjusted PSI composite as dependent variable and safety climate scores and controls as independent variables. Some specifications included interpersonal, work unit, and organizational safety climate dimensions. Others included separate measures for senior managers and frontline personnel's safety climate perceptions. Hospitals with better safety climate overall had lower relative incidence of PSIs, as did hospitals with better scores on safety climate dimensions measuring interpersonal beliefs regarding shame and blame. Frontline personnel's perceptions of better safety climate predicted lower risk of experiencing PSIs, but senior manager perceptions did not. The results link hospital safety climate to indicators of potential safety events. Some aspects of safety climate are more closely related to safety events than others. Perceptions about safety climate among some groups, such as frontline staff, are more closely related than perceptions in other groups.


Threshold cascades with response heterogeneity in multiplex networks.
Threshold cascade models have been used to describe the spread of behavior in social networks and cascades of default in financial networks. In some cases, these networks may have multiple kinds of interactions, such as distinct types of social ties or distinct types of financial liabilities; furthermore, nodes may respond in different ways to influence from their neighbors of multiple types. To start to capture such settings in a stylized way, we generalize a threshold cascade model to a multiplex network in which nodes follow one of two response rules: some nodes activate when, in at least one layer, a large enough fraction of neighbors is active, while the other nodes activate when, in all layers, a large enough fraction of neighbors is active. Varying the fractions of nodes following either rule facilitates or inhibits cascades. Near the inhibition regime, global cascades appear discontinuously as the network density increases; however, the cascade grows more slowly over time. This behavior suggests a way in which various collective phenomena in the real world could appear abruptly yet slowly.


When helping hurts: miscarried helping in families of youth with chronic pain.
To examine "miscarried helping" as a maladaptive dyadic process in families of youth with chronic pain using the Actor-Partner Interdependence Model. 210 adolescents with chronic pain (mean = 14.23 years; 73.9% female) and their parents participating in a multicenter study completed measures assessing pain characteristics, miscarried helping, family functioning, parental protectiveness, and child depressive symptoms. Multilevel modeling revealed significant actor effects of miscarried helping on family functioning for both parents and teens, but not partner effects. Individual-level factors, including child pain characteristics, depressive symptoms, and parental protectiveness, uniquely contributed to miscarried helping. Higher perceptions of miscarried helping contribute to worse family functioning and may be a useful target for psychological intervention in parents of children with chronic pain. Parents who exhibit more protective responses to pain and youth with more depressive symptoms may be at increased risk for a miscarried helping process to develop.


Characterization of the L gene and 5' trailer region of Ebola virus.
The nucleotide sequences of the L gene and 5' trailer region of Ebola virus strain Mayinga (subtype Zaire) have been determined, thus completing the sequence of the Ebola virus genome. The putative transcription start signal of the L gene was identical to the determined 5' terminus of the L mRNA (5' GAGGAAGAUUAA) and showed a high degree of similarity to the corresponding regions of other Ebola virus genes. The 3' end of the L mRNA terminated with 5' AUUAUAAAAAA, a sequence which is distinct from the proposed transcription termination signals of other genes. The 5' trailer sequence of the Ebola virus genomic RNA consisted of 676 nt and revealed a self-complementary sequence at the extreme end which may play an important role in virus replication. The L gene contained a single ORF encoding a polypeptide of 2212 aa. The deduced amino acid sequence showed identities of about 73 and 44% to the L proteins of Ebola virus strain Maleo (subtype Sudan) and Marburg virus, respectively. Sequence comparison studies of the Ebola virus L proteins with several corresponding proteins of other non-segmented, negative-strand RNA viruses, including Marburg viruses, confirmed a close relationship between filoviruses and members of the Paramyxovirinae. The presence of several conserved linear domains commonly found within L proteins of other members of the order Mononegavirales identified this protein as the RNA-dependent RNA polymerase of Ebola virus.


DNA polymerase arrest by adducted trivalent chromium.
Carcinogenic chromium (Cr6+) enters cells via the sulfate transport system and undergoes intracellular reduction to trivalent chromium, which strongly adducts to DNA. In this study, the effect of adducted trivalent chromium on in vitro DNA synthesis was analyzed with a polymerase-arrest assay in which prematurely terminated replication products were separated on a DNA sequencing gel. A synthetic DNA replication template was treated with increasing concentrations of chromium(III) chloride. The two lowest chromium doses used resulted in biologically relevant adduct levels (6 and 21 adducts per 1,000 DNA nucleotides) comparable with those measured in nuclear matrix DNA from cells treated with a 50% cytotoxic dose of sodium chromate in vivo. In vitro replication of the chromium-treated template DNA using the Sequenase version 2.0 T7 DNA polymerase (United States Biochemical Corp., Cleveland, OH) resulted in dose-dependent polymerase arrest beginning at the lowest adduct levels analyzed. The pattern of polymerase arrest remained consistent as chromium adduct levels increased, with the most intense arrest sites occurring 1 base upstream of guanine residues on the template strand. Replication by the DNA polymerase I large (Klenow) fragment as well as by unmodified T7 DNA polymerase also resulted in similar chromium-induced polymerase arrest. Interstrand cross-linking between complementary strands was detected in template DNA containing 62, 111, and 223 chromium adducts per 1,000 DNA nucleotides but not in template containing 6 or 21 adducts per 1,000 DNA nucleotides, in which arrest nevertheless did occur. Low-level, dose-dependent interstrand cross-linking between primer and template DNA, however, was detectable even at the lowest chromium dose analyzed. Since only 9% of chromium adducts resulted in polymerase arrest in this system, we hypothesized that arrest occurred when the enzyme encountered chromium-mediated interstrand DNA-DNA cross-links between either the template and a separate DNA molecule or the template and its complementary strand in the same molecule. These results suggest that the obstruction of DNA replication by chromium-mediated DNA-DNA cross-links is a potential mechanism of chromium-induced genotoxicity in vivo.


Estimating the Unique Information of Continuous Variables.
The integration and transfer of information from multiple sources to multiple targets is a core motive of neural systems. The emerging field of partial information decomposition (PID) provides a novel information-theoretic lens into these mechanisms by identifying synergistic, redundant, and unique contributions to the mutual information between one and several variables. While many works have studied aspects of PID for Gaussian and discrete distributions, the case of general continuous distributions is still uncharted territory. In this work we present a method for estimating the unique information in continuous distributions, for the case of one versus two variables. Our method solves the associated optimization problem over the space of distributions with fixed bivariate marginals by combining copula decompositions and techniques developed to optimize variational autoencoders. We obtain excellent agreement with known analytic results for Gaussians, and illustrate the power of our new approach in several brain-inspired neural models. Our method is capable of recovering the effective connectivity of a chaotic network of rate neurons, and uncovers a complex trade-off between redundancy, synergy and unique information in recurrent networks trained to solve a generalized XOR task.


Spatial autocorrelation in uptake of antenatal care and relationship to individual, household and village-level factors: results from a community-based survey of pregnant women in six districts in western Kenya.
The majority of maternal deaths, stillbirths, and neonatal deaths are concentrated in a few countries, many of which have weak health systems, poor access to health services, and low coverage of key health interventions. Early and consistent antenatal care (ANC) attendance could significantly reduce maternal and neonatal morbidity and mortality. Despite this, most Kenyan mothers initiate ANC care late in pregnancy and attend fewer than the recommended visits. We used survey data from 6,200 pregnant women across six districts in western Kenya to understand demand-side factors related to use of ANC. Bayesian multi-level models were developed to explore the relative importance of individual, household and village-level factors in relation to ANC use. There is significant spatial autocorrelation of ANC attendance in three of the six districts and considerable heterogeneity in factors related to ANC use between districts. Working outside the home limited ANC attendance. Maternal age, the number of small children in the household, and ownership of livestock were important in some districts, but not all. Village proportions of pregnancy in women of child-bearing age was significantly correlated to ANC use in three of the six districts. Geographic distance to health facilities and the type of nearest facility was not correlated with ANC use. After incorporating individual, household and village-level covariates, no residual spatial autocorrelation remained in the outcome. ANC attendance was consistently low across all the districts, but factors related to poor attendance varied. This heterogeneity is expected for an outcome that is highly influenced by socio-cultural values and local context. Interventions to improve use of ANC must be tailored to local context and should include explicit approaches to reach women who work outside the home.


Global HIV-1 molecular epidemiology with special reference to genetic analysis of HIV-1 subtypes circulating in North India: functional and pathogenic implications of genetic variation.
HIV-1 displays extensive genetic diversity globally which poses challenge in designing a suitable antigen/immunogen to provoke desired protective immune response in host. HIV-1 mediated pathogenesis is complex and involves host genes, virus genes and other factors. A number of genetic subtypes have been identified based on sequence variations, largely in envelope region. Different genetic subtypes display variation in amino acid sequences with increasing incidence of subtype B, C, D and mosaic recombinants in India. They can potentially alter the functions of several proteins like Rev, Tat ,Vpr, Vif etc and thereby, influence HIV-1 mediated pathogenesis. Recent study has shown that LTR promoter region exhibits novel mosaic structures with segments from B/C Myanmar and India. This indicates rapid evolving nature of HIV-1 and causing epidemics due to existence of multiple subtypes in Indian region. These multiple subtypes show significant differences in various functions (gene activation, cell cycle arrest, RNA binding activities) compared to prototype subtype B genes. These differences may help in better understanding of unique features of HIV-1 epidemic in India.


Compositional analyses of the associations between sedentary time, different intensities of physical activity, and cardiometabolic biomarkers among children and youth from the United States.
Compositional data analysis is one appropriate method for co-dependent data, even when data are collected for a subdivision of the 24-hour period, such as the waking day. Objectives were to use compositional analyses to examine the combined and relative associations of sedentary time (ST), light-intensity physical activity (LPA), moderate-intensity physical activity (MPA), and vigorous-intensity physical activity (VPA) with cardiometabolic biomarkers in a representative sample of children and youth. This cross-sectional study included 2544 participants aged 6-17 years from the 2003-2006 United States National Health and Nutrition Examination Survey. ST (<100 counts per minute), LPA (100 counts per minute to <4 METs; Freedson age-specific equation), MPA (4 to <7 METs), and VPA (≥7 METs) were accelerometer-derived. Cardiometabolic biomarkers included waist circumference, body mass index (BMI) z-score, HDL-cholesterol, C-reactive protein, and blood pressure. Triglycerides, glucose, insulin, and LDL-cholesterol were measured in a fasting sub-sample of adolescents (n = 670). Compositional linear regression models were conducted. The composition of ST, LPA, MPA, and VPA was significantly associated with BMI z-score, log waist circumference, systolic and diastolic blood pressure, HDL-cholesterol, and log plasma glucose (variance explained: 1-29%). Relative to the other three behaviors, VPA was negatively associated with BMI z-score (γVPA = -0.206, p = 0.005) and waist circumference (γVPA = -0.03, p = 0.001). Conversely, ST was positively associated with waist circumference (γST = 0.029, p = 0.013). ST and VPA were also positively associated with diastolic blood pressure (γST = 2.700, p = 0.018; γVPA = 1.246, p = 0.038), relative to the other behaviors, whereas negative associations were observed for LPA (γLPA = -2.892, p = 0.026). Finally, VPA was positively associated with HDL-cholesterol, relative to other behaviors (γVPA = 0.058, p<0.001). The ST and physical activity composition appears important for many aspects of cardiometabolic health in children and youth. Compositions with more time in higher-intensity activities may be better for some aspects of cardiometabolic health.


Age-specific mortality and immunity patterns of SARS-CoV-2.
Estimating the size of the coronavirus disease 2019 (COVID-19) pandemic and the infection severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is made challenging by inconsistencies in the available data. The number of deaths associated with COVID-19 is often used as a key indicator for the size of the epidemic, but the observed number of deaths represents only a minority of all infections1,2. In addition, the heterogeneous burdens in nursing homes and the variable reporting of deaths of older individuals can hinder direct comparisons of mortality rates and the underlying levels of transmission across countries3. Here we use age-specific COVID-19-associated death data from 45 countries and the results of 22 seroprevalence studies to investigate the consistency of infection and fatality patterns across multiple countries. We find that the age distribution of deaths in younger age groups (less than 65 years of age) is very consistent across different settings and demonstrate how these data can provide robust estimates of the share of the population that has been infected. We estimate that the infection fatality ratio is lowest among 5-9-year-old children, with a log-linear increase by age among individuals older than 30 years. Population age structures and heterogeneous burdens in nursing homes explain some but not all of the heterogeneity between countries in infection fatality ratios. Among the 45 countries included in our analysis, we estimate that approximately 5% of these populations had been infected by 1 September 2020, and that much higher transmission rates have probably occurred in a number of Latin American countries. This simple modelling framework can help countries to assess the progression of the pandemic and can be applied in any scenario for which reliable age-specific death data are available.


T-cell ageing in end-stage renal disease patients: Assessment and clinical relevance.
End-stage renal disease (ESRD) patients have a defective T-cell-mediated immune system which is related to excessive premature ageing of the T-cell compartment. This is likely to be caused by the uremia-associated pro-inflammatory milieu, created by loss of renal function. Therefore, ESRD patients are highly susceptible for infections, have an increased risk for virus-associated cancers, respond poorly to vaccination and have an increased risk for atherosclerotic diseases. Three ageing parameters can be used to assess an immunological T-cell age. First, thymic output can be determined by assessing the T-cell receptor excision circles-content together with CD31 expression within the naïve T cells. Second, the telomere length of T cells and third the T-cell differentiation status are also indicators of T-cell ageing. Analyses based on these parameters in ESRD patients revealed that the immunological T-cell age is increased by on average 20 years compared to the chronological age. After kidney transplantation (KTx) the aged T-cell phenotype persists although the pro-inflammatory milieu is diminished. This might be explained by epigenetic modifications at hematopoietic stem cells level. Assessment of an immunological T-cell age could be an important tool to identify KTx recipients who are at risk for allograft rejection or to prevent over-immunosuppression.


Aromatase inhibitor exemestane has antiproliferative effects on human mesothelioma cells.
The aim of this study was to investigate the expression and biological activity of aromatase (CYP19A1) in malignant mesothelioma (MM). We found CYP19A1 in five human MM cell lines using reverse transcription polymerase chain reaction and Western immunoblots and in a group of samples from patients with MM by immunohistochemistry. Aromatization activity was determined in MM cells by enzyme-linked immunosorbent assay as a measure of estradiol (E2) product, in basal condition and after addition of cytokine, prostaglandin-E2, and epidermal growth factor to MM cells. Treatment of MM cells with exemestane, a CYP19A1 inhibitor, was assessed by cell proliferation kit, cell cycle analysis, and Western blot for caspase, poly(ADP-ribose)polymerase, Bcl-xL, and v-akt murin thymoma viral oncogene homolog (Akt). Biological activity of CYP19A1, already present in basal condition, was increased in MPP89 and Ist-Mes1 cells after treatment with cytokine, in all MM cells on prostaglandin-E2 treatment, and in MPP89, Ist-Mes2, and Ist-Mes1 after addition of epidermal growth factor. Treatment of MM cells with exemestane led to significant reduction of tumor cell growth, perturbation of cell cycle, caspase activation, poly(ADP-ribose)polymerase cleavage, and down-regulation of phosphorylation of Akt and Bcl-xL. In tumor tissues, we found a cytoplasmic localization of CYP19A1. By univariate analysis, overall survival resulted to be strongly influenced by high CYP19A1 expression (p = 0.001). These findings show that CYP19A1 is present in MM and that cell growth can be down-regulated by exemestane. As Akt pathway and Bcl-xL are implicated in conferring resistance to conventional chemotherapy, exemestane could open new treatment strategies to be associated with standard therapy for patients afflicted with MM.


Physical therapy treatment of persistent genital arousal disorder during pregnancy: a case report.
Persistent genital arousal disorder (PGAD) is described as the spontaneous, intrusive, and unwanted genital arousal in the absence of sexual interest and desire. Whether the etiology of this disorder is essentially central or peripheral is unclear; however, a presenting symptom may be persistent engorgement of genital erectile and vascular tissue. To describe a case of a distressed 27 year old pregnant woman with symptoms consistent with PGAD, and the intervention leading to the resolution of symptoms. A patient with symptoms of PGAD was assessed. Information regarding this condition was offered. A manual therapy treatment was provided to decrease muscle hypertonus near the pudendal nerve, and a home intervention was suggested. Complete resolution of symptoms per patient's report 1 week later. Treatment with pelvic floor manual therapy directed at the pudendal nerve may provide safe and significant relief from PGAD symptoms in a pregnant woman patient.


The role of the teashirt gene in trunk segmental identity in Drosophila.
The phenotypes of different mutant combinations of teashirt (tsh) and homeotic genes together with their regulatory interactions are described in order to gain insight into tsh gene function. We show that when tsh, Scr, Antp and BX-C genes are missing, the ventral part of the trunk (or thorax and abdomen) is transformed to anterior head identity showing that tsh is a homeotic gene. These genes act synergistically to suppress the expression of the procephalic gene labial (lab) in subsets of cells in each segment of the trunk. Transcripts from the tsh gene always accumulate in segments destined to acquire trunk identities. tsh gene activity is required for the normal function of the Antp and BX-C genes, which modulate in part the expression of tsh. As a whole, our results suggest that tsh plays an essential dual role, during embryogenesis, for determining segmental identity of the trunk. First, tsh is required critically for the identity of the anterior prothorax. Second, tsh is required globally for segmental identity throughout the entire trunk whereas the "classical" homeotic genes have more specific roles. Our results are consistent with the idea that tsh is defining the ground state of the Drosophila trunk region seen in the absence of the Antp and BX-C genes.


An outbreak of Mayaro virus disease in Belterra, Brazil. II. Epidemiology.
Epidemiological investigations of an outbreak of Mayaro (MAY) virus which occurred inthe rural village of Belterra, Pará, Brazil are reported. Human cases were first recorded in December 1977 and continued through June 1978. Approximately 20% of the more than 4,000 persons resident in Belterra were infected, and a very high proportion of those infected suffered overt clinical illness. Cases were identified in all areas of Belterra and among all age groups; however, the greatest number of cases was seen among those who resided in close proximity to the forests. Yellow fever (YF) virus was also active in Belterra concurrently with the MAY virus outbreak. Six human cases of YF were identified, of which five were fatal. The YF outbreak ended following YF vaccination of the human population.


Conformational flexibility of the oncogenic protein LMO2 primes the formation of the multi-protein transcription complex.
LMO2 was discovered via chromosomal translocations in T-cell leukaemia and shown normally to be essential for haematopoiesis. LMO2 is made up of two LIM only domains (thus it is a LIM-only protein) and forms a bridge in a multi-protein complex. We have studied the mechanism of formation of this complex using a single domain antibody fragment that inhibits LMO2 by sequestering it in a non-functional form. The crystal structure of LMO2 with this antibody fragment has been solved revealing a conformational difference in the positioning and angle between the two LIM domains compared with its normal binding. This contortion occurs by bending at a central helical region of LMO2. This is a unique mechanism for inhibiting an intracellular protein function and the structural contusion implies a model in which newly synthesized, intrinsically disordered LMO2 binds to a partner protein nucleating further interactions and suggests approaches for therapeutic targeting of LMO2.


Using register data to deduce patterns of social exchange.
This paper presents a novel method for deducting propensities for social exchange between individuals based on the choices they make, and based on factors such as country of origin, sex, school grades and socioeconomic background. The objective here is to disentangle the effect of social ties from the other factors, in order to find patterns of social exchange. This is done through a control-treatment design on analysing available data, where the 'treatment' is similarity of choices between socially connected individuals, and the control is similarity of choices between non-connected individuals. Structural dependencies are controlled for and effects from different classes are pooled through a mix of methods from network and meta-analysis. The method is demonstrated and tested on Swedish register data on students at upper secondary school. The results show that having similar grades is a predictor of social exchange. Also, previous results from Norwegian data are replicated, showing that students cluster based on country of origin.


Hemispheric asymmetries in cognitive modeling: connectionist modeling of unilateral visual neglect.
Neglect is an acquired cognitive disorder characterized by a lack of processing of one side of a stimulus or representational space. There are hemispheric asymmetries in its cause and in its effects, but implemented computational models of neglect have tended not to incorporate this fact. The authors report a series of neural network simulations of the line-bisection task. They test the hypothesis that simple, neuroanatomically realistic principles of connectivity in the nervous system can produce emergent behaviors that capture a wide range of quantitative and qualitative data observed in neglect patients presenting with general visuospatial neglect. They demonstrate that exploring low-level architectural principles in implemented computational models is both a productive avenue of research and offers the most parsimonious explanations of behaviors observed in patients.


Impact of Orthognathic Correction of Class II Malocclusion on the Perception of Social Characteristics.
To evaluate the influence on the perception of social characteristics after orthognathic treatment for the correction of Class II malocclusion. A cross-sectional study was conducted with the participation of 240 observers who evaluated images of individuals before and after orthognathic surgery for the correction of malocclusion. Based on the images, two different questionnaires were applied containing 44 questions each for evaluating social competence, intellectual ability, psychological adjustment, and attractiveness. The mean scores for evaluations of the images were compared using the Mann-Whitney U test at 5% level of significance (α=0.05). Orthognathic treatment significantly (p<0.05) improved the evaluation of individuals in the requisites of the score attributed to the image (p=0.008), extroversion (p=0.026), happiness (p=0.006), self-confidence (p=0.046), and attractiveness (p=0.015). Orthognathic treatment for the correction of Class II malocclusions has a positive effect on the perception of social characteristics of individuals. The individuals subjected to orthognathic surgery were evaluated as being more attractive, intelligent, socially competent, and psychologically adjusted.


Ablation of Barrett's oesophagus: towards improved outcomes for oesophageal cancer?
Barrett's oesophagus is the major risk factor for the development of oesophageal adenocarcinoma. The management of Barrett's oesophagus entails treating reflux symptoms with acid-suppressing medication or surgery (fundoplication). However, neither form of anti-reflux therapy produces predictable regression, or prevents cancer development. Patients with Barrett's oesophagus usually undergo endoscopic surveillance, which aims to identify dysplastic changes or cancer at its earliest stage, when treatment outcomes should be better. Alternative endoscopic interventions are now available and are suggested for the treatment of early cancer and prevention of progression of Barrett's oesophagus to cancer. Such treatments could minimize the risks associated with oesophagectomy. The current status of these interventions is reviewed. Various endoscopic interventions have been described, but with long-term outcomes uncertain, they remain somewhat controversial. Radiofrequency ablation of dysplastic Barrett's oesophagus might reduce the risk of cancer progression, although cancer development has been reported after this treatment. Endoscopic mucosal resection (EMR) allows a 1.5-2 cm diameter piece of oesophageal mucosa to be removed. This provides better pathology for diagnosis and staging, and if the lesion is confined to the mucosa and fully excised, EMR can be curative. The combination of EMR and radiofrequency ablation has been used for multifocal lesions, but long-term outcomes are unknown. The new endoscopic interventions for Barrett's oesophagus and early oesophageal cancer have the potential to improve clinical outcomes, although evidence that confirms superiority over oesphagectomy is limited. Longer-term outcome data and data from larger cohorts are required to confirm the appropriateness of these procedures.