Comparative and reliability studies of neuromechanical leg muscle performances of volleyball athletes in different divisions.
This study compared neural profiles of the leg muscles of volleyball athletes playing in different divisions of Taiwan's national league to analyse the reliability and correlations between their profiles and biomechanical performances. Twenty-nine athletes including 12 and 17 from the first and second divisions of the league, respectively, were recruited. The outcome measures were compared between the divisions, including soleus H-reflex, first volitional (V) wave, normalised rate of electromyography (EMG) rise (RER) in the triceps surae muscles, and RER ratio for the tibialis anterior and soleus muscles, normalised root mean square (RMS) EMG in the triceps surae muscles, antagonist co-activation of the tibialis anterior muscle, rate of force development (RFD), and maximal plantar flexion torque and jump height. Compared to the results of the second division, the neural profiles of the first division showed greater normalised V waves, normalised RER in the lateral gastrocnemius, and normalised RMS EMG of the soleus and lateral gastrocnemius muscles with less antagonist co-activation of the tibialis anterior. First division volleyball athletes showed greater maximal torque, jump height, absolute RFD at 0-30, 0-100, and 0-200 ms, and less in the normalised RFD at 0-200 ms of plantar flexion when compared to the results of those in the second division. Neural profiles correlated to fast or maximal muscle strength or jump height. There are differences in the descending neural drive and activation strategies in leg muscles during contractions between volleyball athletes competing at different levels. These measures are reliable and correlate to biomechanical performances.


Microdissected pancreatic cancer proteomes reveal tumor heterogeneity and therapeutic targets.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a relative paucity of cancer cells that are surrounded by an abundance of nontumor cells and extracellular matrix, known as stroma. The interaction between stroma and cancer cells contributes to poor outcome, but how proteins from these individual compartments drive aggressive tumor behavior is not known. Here, we report the proteomic analysis of laser-capture microdissected (LCM) PDAC samples. We isolated stroma, tumor, and bulk samples from a cohort with long- and short-term survivors. Compartment-specific proteins were measured by mass spectrometry, yielding what we believe to be the largest PDAC proteome landscape to date. These analyses revealed that, in bulk analysis, tumor-derived proteins were typically masked and that LCM was required to reveal biology and prognostic markers. We validated tumor CALB2 and stromal COL11A1 expression as compartment-specific prognostic markers. We identified and functionally addressed the contributions of the tumor cell receptor EPHA2 to tumor cell viability and motility, underscoring the value of compartment-specific protein analysis in PDAC.


Dipturus amphispinus sp. nov., a new longsnout skate (Rajoidei: Rajidae) from the Philippines.
A new long-snouted skate, Dipturus amphispinus sp. nov., is formally described based on material caught in the Sulu Sea and later acquired from fish markets of the central and southern Philippines. It differs from its congeners in the western North Pacific, apart from D. wuhanlingi (East and South China Seas), in having a variably-defined, parallel row of posterolaterally directed lumbar thorns, and well-developed scapular thorns on each side of the disc. However, the paired rows of lumbar thorns are better defined in Dipturus amphispinus sp. nov. than in D. wuhanlingi, and these species also differ in some aspects of their morphometrics, meristics and squamation. Dipturus amphispinus sp. nov. displays marked sexual dimorphism with adult males having a relatively broader mouth, much longer teeth, a relatively shorter snout, head and disc, a taller first dorsal fin, and a proportionally longer posterior pelvic-fin lobe and tail, than adult-sized females.


Comparative study of vertebral fractures and luxations in dogs and cats.
The purpose of this retrospective study was to compare patterns of vertebral fractures and luxations in 42 cats and 47 dogs, and to evaluate the impact of species-related differences on clinical outcome. Data regarding aetiology, neurological status, radiographic appearance and follow-up were compared between the groups. The thoracolumbar (Th3-L3) area was the most commonly affected location in both cats (49%) and dogs (58%). No lesions were observed in the cervical vertebral segments in cats, and none of the cats showed any signs of a Schiff-Sherrington syndrome. Vertebral luxations were significantly more frequent in dogs (20%) than in cats (6%), whereas combined fracture-luxations occurred significantly more often in cats (65%) than in dogs (37%). Caudal vertebral segment displacement was mostly dorsal in cats and ventral in dogs, with a significant difference in direction between cats and large dogs. The clinical outcome did not differ significantly between the two populations, and was poor in most cases (cats: 61%; dogs: 56%). The degree of dislocation and axis deviation were both significantly associated with a worse outcome in dogs, but not in cats. Although several differences in vertebral fractures and luxation patterns exist between cats and dogs, these generally do not seem to affect outcome.


Synthesis, beta-adrenergic blocking activity and beta-receptor binding affinities of 1-substituted-3-(2-isopropyl-5-methyl-phenoxy)-propan-2-ol oxalates.
The compounds 1-isopropylamino-3-(2-isopropyl-5-methyl-phenoxy)-propan-2-ol oxalate (5) and 1-tert-butylamino-3-(2-isopropyl-5-methyl-phenoxy)-propan-2-ol oxalate (6) were synthesized from thymol (1), a naturally occurring agent in Thymus vulgaris L. Pharmacological evaluation of 5 and 6 were carried out using mouse ECG and isolated rat uterus models. Pretreatment of 5 (100 microg/kg, i.v.) and 6 (50 microg/kg, i.v.) antagonized isoprenaline (2 microg/kg, i.v.) induced tachycardia, similar to that of atenolol (CAS 29122-68-7, 20 microg/kg, i.v.) pretreatment in mouse ECG experiments as measured by R-R interval. Pretreatment of 5 and 6 blocked isoprenaline and adrenaline induced relaxation of isolated rat uterus (unprimed). Also the compounds 5 and 6 were subjected to in vitro beta1- and beta2-adrenergic receptor binding assay using turkey erythrocyte membrane (beta1) and lung homogenate of rats (beta2). Both 5 and 6 showed beta-adrenergic receptor affinity comparable with that of propranolol (propranolol hydrochloride, CAS 318-98-9) with out selectivity to any one beta-adrenergic receptor. These results suggest that both the compounds possess non-selective beta-adrenergic blocking activity, with the tert-butyl derivative 6 being more active than the isopropyl derivative 5.


Revealing common disease mechanisms shared by tumors of different tissues of origin through semantic representation of genomic alterations and topic modeling.
Cancer is a complex disease driven by somatic genomic alterations (SGAs) that perturb signaling pathways and consequently cellular function. Identifying patterns of pathway perturbations would provide insights into common disease mechanisms shared among tumors, which is important for guiding treatment and predicting outcome. However, identifying perturbed pathways is challenging, because different tumors can have the same perturbed pathways that are perturbed by different SGAs. Here, we designed novel semantic representations that capture the functional similarity of distinct SGAs perturbing a common pathway in different tumors. Combining this representation with topic modeling would allow us to identify patterns in altered signaling pathways. We represented each gene with a vector of words describing its function, and we represented the SGAs of a tumor as a text document by pooling the words representing individual SGAs. We applied the nested hierarchical Dirichlet process (nHDP) model to a collection of tumors of 5 cancer types from TCGA. We identified topics (consisting of co-occurring words) representing the common functional themes of different SGAs. Tumors were clustered based on their topic associations, such that each cluster consists of tumors sharing common functional themes. The resulting clusters contained mixtures of cancer types, which indicates that different cancer types can share disease mechanisms. Survival analysis based on the clusters revealed significant differences in survival among the tumors of the same cancer type that were assigned to different clusters. The results indicate that applying topic modeling to semantic representations of tumors identifies patterns in the combinations of altered functional pathways in cancer.


Human TERT Promoter Mutations in Atypical and Anaplastic Meningiomas.
The role of telomerase reverse transcriptase (TERT) gene promoter mutations (pTERT) in atypical and anaplastic meningiomas remains controversial. This study aimed to evaluate their impact on the histologic diagnosis and prognosis in a retrospective series of 74 patients with atypical and anaplastic meningioma, including disease progression and relapse. A supplementary panel of 21 benign tumours was used as a control cohort. The mutation rate of the pTERT gene was assessed by Sanger sequencing. ATRX protein expression was detected by immunohistochemistry. The phenotypic and genotypic intra-tumour heterogeneity was studied in a sub-group of 12 cases using a Molecular Machines & Industries (MMI) CellCut laser microdissection (LMD) system. pTERT mutations were detected in 12/74 (17.6%) malignant meningiomas. The mutation rate was significantly higher in anaplastic meningiomas (7/23, 30.4%) compared to atypical tumours (5/48, 10.4%) (p = 0.0443). In contrast, the mutation rate was < 5% in benign tumours. All pTERT mutant cases retained nuclear ATRX immunoreactivity. pTERT mutations were significantly associated with the histologic grade (p = 0.0443) and were adverse prognostic factors for anaplastic tumours (p = 0.06). We reported on the pTERT mutation spectrum in malignant meningiomas, supporting their use in the prognostic classification.


Why would plant species become extinct locally if growing conditions improve?
Two assumptions underlie current models of the geographical ranges of perennial plant species: 1. current ranges are in equilibrium with the prevailing climate, and 2. changes are attributable to changes in macroclimatic factors, including tolerance of winter cold, the duration of the growing season, and water stress during the growing season, rather than to biotic interactions. These assumptions allow model parameters to be estimated from current species ranges. Deterioration of growing conditions due to climate change, e.g. more severe drought, will cause local extinction. However, for many plant species, the predicted climate change of higher minimum temperatures and longer growing seasons means, improved growing conditions. Biogeographical models may under some circumstances predict that a species will become locally extinct, despite improved growing conditions, because they are based on an assumption of equilibrium and this forces the species range to match the species-specific macroclimatic thresholds. We argue that such model predictions should be rejected unless there is evidence either that competition influences the position of the range margins or that a certain physiological mechanism associated with the apparent improvement in growing conditions negatively affects the species performance. We illustrate how a process-based vegetation model can be used to ascertain whether such a physiological cause exists. To avoid potential modelling errors of this type, we propose a method that constrains the scenario predictions of the envelope models by changing the geographical distribution of the dominant plant functional type. Consistent modelling results are very important for evaluating how changes in species areas affect local functional trait diversity and hence ecosystem functioning and resilience, and for inferring the implications for conservation management in the face of climate change.


Direct Comparison of 2 Rule-Out Strategies for Acute Myocardial Infarction: 2-h Accelerated Diagnostic Protocol vs 2-h Algorithm.
We compared 2 high-sensitivity cardiac troponin (hs-cTn)-based 2-h strategies in patients presenting with suspected acute myocardial infarction (AMI) to the emergency department (ED): the 2-h accelerated diagnostic protocol (2h-ADP) combining hs-cTn, electrocardiogram, and a risk score, and the 2-h algorithm exclusively based on hs-cTn concentrations and their absolute changes. Analyses were performed in 2 independent diagnostic cohorts [European Advantageous Predictors of Acute Coronary Syndrome Evaluation (APACE) study, Australian-New Zealand 2-h Accelerated Diagnostic Protocol to Assess patients with chest Pain symptoms using contemporary Troponins as the only biomarker (ADAPT) study] employing hs-cTnT (Elecsys) and hs-cTnI (Architect). The final diagnosis was adjudicated by 2 independent cardiologists. AMI was the final diagnosis in 16.5% (95% CI, 14.6%-18.6%) of the 1372 patients in APACE, and 12.6% (95% CI, 10.7%-14.7%) of 1153 patients in ADAPT. The negative predictive value (NPV) and sensitivity for AMI were very high and comparable with both strategies using either hs-cTnT or hs-cTnI in both cohorts (all statistical comparisons nonsignificant). The percentage of patients triaged toward rule-out was significantly lower with the 2h-ADP (36%-43%) vs the 2-h algorithm (55%-68%) with both assays and in both cohorts (P < 0.001). The sensitivity of the 2h-ADP was higher for 30-day major adverse cardiovascular events. Both algorithms provided very high and comparable safety as quantified by the NPV and sensitivity for AMI and major adverse cardiac events (MACE) at 30 days in patients triaged toward rule-out, although sensitivity for MACE at 30 days was lower with both algorithms in cohort 2. Although the 2-h algorithm was more efficacious, not all patients ruled out for AMI by this algorithm were appropriate candidates for early discharge. The 2h-ADP seems superior in the selection of patients for early discharge from the ED. APACE: http://clinicaltrials.gov/show/NCT00470587ADAPT: Australia-New Zealand Clinical Trials Registry ACTRN12611001069943.


Use of alendronate sodium (Fosamax) to ameliorate osteoporosis in renal transplant patients: a case-control study.
Renal transplant patients often have severe bone and mineral deficiencies. While the clinical effects of immunosuppressive agents like calcineurin inhibitors (CIs) and sirolimus on bone turnover are unclear, bisphosphonates are effective in bone recovery in these patients. Gender is significantly associated with osteoporosis and affects bone turnover, which is different in women and men. The effective gender-related site of action of bisphosphonates is unknown. Initially, we enrolled 84 kidney recipients who had received their transplants at least 5 months ago; of these, 8 were excluded and 76 were finally included in the study. First bone mineral density (BMD) at the lumbar spine, hip, and femoral neck was determined using dual-energy X-ray absorptiometry (DXA) between September 2008 and March 2009. These 76 patients underwent a repeat procedure after a mean period 14 months. Immunosuppressive agents, bisphosphonates, patients' characteristics, and biochemical factors were analyzed on the basis of the BMD determined using DXA. After the 14-month period, the BMD of lumbar spine increased significantly (from 0.9 g/cm(2) to 0.92 g/cm(2), p<0.001), whereas that of the hip and femoral neck did not. Ordinal logistic regression analysis was used to show that Fosamax improved bone condition, as defined by WHO (p = 0.007). The use of immunosuppressive agents did not affect bone turnover (p>0.05). Moreover, in subgroup analysis, Fosamax increased the BMD at the lumbar spine and the hipbone in males (p = 0.028 and 0.03, respectively) but only at the lumbar spine in females (p = 0.022). After a long periods after renal transplantation, the detrimental effects of steroid and immunosuppressive agents on bone condition diminished. Short-term Fosamax administration effectively improves BMD in these patients. The efficacy of Fosamax differed between male and female renal transplant patients.


Epitope engineering and molecular metrics of immunogenicity: a computational approach to VLP-based vaccine design.
Developing antiviral vaccines is increasingly challenging due to associated time and cost of production as well as emerging drug-resistant strains. A computer-aided vaccine design strategy is presented that could greatly accelerate the discovery process and yield vaccines with high immunogenicity and thermal stability. Our strategy is based on foreign viral epitopes engineered onto well-established virus-like particles (VLPs) and demonstrates that such constructs present similar affinity for antibodies as does a native virus. This binding affinity serves as one molecular metric of immunogenicity. As a demonstration, we engineered a preS1 epitope of hepatitis B virus (HBV) onto the EF loop of human papillomavirus VLP (HPV-VLP). HBV-associated HzKR127 antibody displayed binding affinity for this structure at distances and strengths similar to those for the complex of the antibody with the full HBV (PDBID: 2EH8). This antibody binding affinity assessment, along with other molecular immunogenicity metrics, could be a key component of a computer-aided vaccine design strategy.


Host-pathogen interplay at primary infection sites in pigs challenged with Actinobacillus pleuropneumoniae.
Actinobacillus (A.) pleuropneumoniae is the causative agent of porcine pleuropneumonia and causes significant losses in the pig industry worldwide. Early host immune response is crucial for further progression of the disease. A. pleuropneumoniae is either rapidly eliminated by the immune system or switches to a long-term persistent form. To gain insight into the host-pathogen interaction during the early stages of infection, pigs were inoculated intratracheally with A. pleuropneumoniae serotype 2 and humanely euthanized eight hours after infection. Gene expression studies of inflammatory cytokines and the acute phase proteins haptoglobin, serum amyloid A and C-reactive protein were carried out by RT-qPCR from the lung, liver, tonsils and salivary gland. In addition, the concentration of cytokines and acute phase proteins were measured by quantitative immunoassays in bronchoalveolar lavage fluid, serum and saliva. In parallel to the analyses of host response, the impact of the host on the bacterial pathogen was assessed on a metabolic level. For the latter, Fourier-Transform Infrared (FTIR-) spectroscopy was employed. Significant cytokine and acute phase protein gene expression was detected in the lung and the salivary gland however this was not observed in the tonsils. In parallel to the analyses of host response, the impact of the host on the bacterial pathogen was assessed on a metabolic level. For the latter investigations, Fourier-Transform Infrared (FTIR-) spectroscopy was employed. The bacteria isolated from the upper and lower respiratory tract showed distinct IR spectral patterns reflecting the organ-specific acute phase response of the host. In summary, this study implies a metabolic adaptation of A. pleuropneumoniae to the porcine upper respiratory tract already during early infection, which might indicate a first step towards the persistence of A. pleuropneumoniae. Not only in lung, but also in the salivary gland an increased inflammatory gene expression was detectable during the acute stage of infection.


HIV-1 drug resistance in variants from the female genital tract and plasma.
Human immunodeficiency virus type 1 (HIV-1) drug-resistance mutations may arise in a fraction of viral variants, and these variants may differ between compartments, including the genital tract and blood. We studied 14 women with detectable HIV-1 in both the genital tract and plasma despite antiretroviral treatment. We obtained HIV-1 RNA sequences from 280 unique viral variants and then determined the resistance genotype and the predicted phenotype (Virtual Phenotype; Virco BVBA) of each variant. Eight patients (57%) displayed mutations conferring high-level HIV-1 drug resistance. Although we observed differences in specific mutations among viral variants, 13 of the 14 women showed highly concordant HIV-1 genotypic and predicted phenotypic resistance patterns in the 2 compartments. In 1 patient, resistance mutations appeared only in plasma; all variants in her genital tract, which displayed a low viral load, were susceptible. These data suggest that, for the majority of women, determination of HIV-1 drug resistance in the plasma will approximate the drug-resistance pattern in the genital tract. Analysis of individual variants enabled us to identify minority species bearing distinctive linked mutations, which may serve as a source of novel resistance genotypes. These data are relevant to clinical management and the evolution of drug resistance.


Radiation-induced cerebellar-cerebral functional connectivity alterations in nasopharyngeal carcinoma patients.
The current study aimed to investigate the altered cerebellar-cerebral functional connectivity (FC) induced by radiotherapy to nasopharyngeal carcinoma (NPC) patients. Twenty-four NPC patients without treatment, and 35 NPC patients receiving radiotherapy underwent functional MRI scanning. Montreal cognitive assessment (MoCA) was performed to evaluate the cognitive status of all participants. FC between 10 predefined cerebellar seeds, which were demonstrated to be involved in different brain functional networks, and all brain voxels was obtained for each participant. Using a second-level two-sample t-test, three significantly different FCs between the two patient groups were found, including the connections between the left lobule VIII and the right medial frontal gyrus, the left lobule VIII and the right crus I, and the right lobule VIIb and the right fusiform gyrus. The altered cerebellar-cerebral FCs were also significantly correlated to the MoCA score, as well as the attention score, one of the seven subscores in MoCA. We suggested that the altered cerebellar-cerebral FCs may underlie the radiation-induced cognitive deficits in NPC patients, especially in the domain of attention. Furthermore, considering the functional networks in which the altered connections involved, the anticorrelation between the default network and dorsal attention network may be impaired, and the mediating function of the frontoparietal network to dorsal attention network may be disrupted. The significantly altered cerebellar-cerebral FC may serve as the potential biomarker in revealing the radiation-induced functional abnormalities and may help in the early intervention to the cognitive impairment.


Atmospheric warming and the amplification of precipitation extremes.
Climate models suggest that extreme precipitation events will become more common in an anthropogenically warmed climate. However, observational limitations have hindered a direct evaluation of model-projected changes in extreme precipitation. We used satellite observations and model simulations to examine the response of tropical precipitation events to naturally driven changes in surface temperature and atmospheric moisture content. These observations reveal a distinct link between rainfall extremes and temperature, with heavy rain events increasing during warm periods and decreasing during cold periods. Furthermore, the observed amplification of rainfall extremes is found to be larger than that predicted by models, implying that projections of future changes in rainfall extremes in response to anthropogenic global warming may be underestimated.


ReportingTools: an automated result processing and presentation toolkit for high-throughput genomic analyses.
It is common for computational analyses to generate large amounts of complex data that are difficult to process and share with collaborators. Standard methods are needed to transform such data into a more useful and intuitive format. We present ReportingTools, a Bioconductor package, that automatically recognizes and transforms the output of many common Bioconductor packages into rich, interactive, HTML-based reports. Reports are not generic, but have been individually designed to reflect content specific to the result type detected. Tabular output included in reports is sortable, filterable and searchable and contains context-relevant hyperlinks to external databases. Additionally, in-line graphics have been developed for specific analysis types and are embedded by default within table rows, providing a useful visual summary of underlying raw data. ReportingTools is highly flexible and reports can be easily customized for specific applications using the well-defined API. The ReportingTools package is implemented in R and available from Bioconductor (version ≥ 2.11) at the URL: http://bioconductor.org/packages/release/bioc/html/ReportingTools.html. Installation instructions and usage documentation can also be found at the above URL.


Comparing the effectiveness and cost-effectiveness of self-management interventions in four high-priority chronic conditions in Europe (COMPAR-EU): a research protocol.
Population ageing and increasing chronic illness burden have sparked interest in innovative care models. While self-management interventions (SMIs) are drawing increasing attention, evidence of their efficacy is mostly based on pairwise meta-analysis, generally derived from randomised controlled trials comparing interventions versus a control or no intervention. As such, relevant efficacy data for comparisons among different SMIs that can be applied to specific chronic conditions are missing. Therefore, the relevance of the available evidence for decision-making at clinical, organisational and policy levels is limited. To identify, compare and rank the most effective and cost-effective SMIs for adults with four high-priority chronic conditions: type 2 diabetes, obesity, chronic obstructive pulmonary disease,and heart failure. All activities will be conducted as part of the cost-effectiveness of self-management interventions in four high-priority chronic conditions in Europe(COMPAR-EU, Comparing effectiveness of self-management interventions in 4 high priority chronic diseases inEurope) Project, an European Union (EU)-funded project designed to bridge the gap between current knowledge and practice on SMIs. In the first phase of the project, we will develop and validate a taxonomy, and a Core Outcome Set for each condition. These activities will inform a series of systematic review and network meta-analysis about the effectiveness of SMIs. We will also perform a cost-effectiveness analysis of the most effective SMIs and an evaluation of contextual factors. We will finally develop tailored decision-making tools for the different relevant stakeholders. Ethical approval was obtained from the local ethics committee (University Institute for Primary Care Research - IDIAP Jordi Gol). All patients and other stakeholders will provide informed consent prior to participation. This project has been funded by the EU Horizon 2020 research and innovation programme (grant agreement no. 754936). Results will be of interest to relevant stakeholder groups (patients, professionals, managers, policymakers and industry), and will be disseminated in a tailored multi-pronged approach that will include deployment of an interactive platform.


Tropical dung beetle morphological traits predict functional traits and show intraspecific differences across land uses.
Functional traits and functional diversity measures are increasingly being used to examine land use effects on biodiversity and community assembly rules. Morphological traits are often used directly as functional traits. However, behavioral characteristics are more difficult to measure. Establishing methods to derive behavioral traits from morphological measurements is necessary to facilitate their inclusion in functional diversity analyses. We collected morphometric data from over 1,700 individuals of 12 species of dung beetle to establish whether morphological measurements can be used as predictors of behavioral traits. We also compared morphology among individuals collected from different land uses (primary forest, logged forest, and oil palm plantation) to identify whether intraspecific differences in morphology vary among land use types. We show that leg and eye measurements can be used to predict dung beetle nesting behavior and period of activity and we used this information to confirm the previously unresolved nesting behavior for Synapsis ritsemae. We found intraspecific differences in morphological traits across different land use types. Phenotypic plasticity was found for traits associated with dispersal (wing aspect ratio and wing loading) and reproductive capacity (abdomen size). The ability to predict behavioral functional traits from morphology is useful where the behavior of individuals cannot be directly observed, especially in tropical environments where the ecology of many species is poorly understood. In addition, we provide evidence that land use change can cause phenotypic plasticity in tropical dung beetle species. Our results reinforce recent calls for intraspecific variation in traits to receive more attention within community ecology.


Revised European Scleroderma Trials and Research Group Activity Index is the best predictor of short-term severity accrual.
The European Scleroderma Trials and Research Group (EUSTAR) recently developed a preliminarily revised activity index (AI) that performed better than the European Scleroderma Study Group Activity Index (EScSG-AI) in systemic sclerosis (SSc). To assess the predictive value for short-term disease severity accrual of the EUSTAR-AI, as compared with those of the EScSG-AI and of known adverse prognostic factors. Patients with SSc from the EUSTAR database with a disease duration from the onset of the first non-Raynaud sign/symptom ≤5 years and a baseline visit between 2003 and 2014 were first extracted. To capture the disease activity variations over time, EUSTAR-AI and EScSG-AI adjusted means were calculated. The primary outcome was disease progression defined as a Δ≥1 in the Medsger's severity score and in distinct items at the 2-year follow-up visit. Logistic regression analysis was carried out to identify predictive factors. 549 patients were enrolled. At multivariate analysis, the EUSTAR-AI adjusted mean was the only predictor of any severity accrual and of that of lung and heart, skin and peripheral vascular disease over 2 years. The adjusted mean EUSTAR-AI has the best predictive value for disease progression and development of severe organ involvement over time in SSc.


Pediatric patients on ketogenic diet undergoing general anesthesia-a medical record review.
To identify guidelines for anesthesia management and determine whether general anesthesia is safe for pediatric patients on ketogenic diet (KD). Retrospective medical record review. Postoperative recovery area. All pediatric patients who underwent general anesthesia while on KD between 2009 and 2014 were reviewed. We identified 24 patients who underwent a total of 33 procedures. All children were on KD due to intractable epilepsy. The age of patients ranged from 1 to 15 years. General anesthesia for the scheduled procedures. Patients' demographics, seizure history, type of procedure; perioperative blood chemistry, medications including the anesthesia administered, and postoperative complications. Twenty-four patients underwent a total of 33 procedures. The duration of KD treatment at the time of general anesthesia ranged from 4 days to 8 years. Among the 33 procedures, 3 patients had complications that could be attributable to KD and general anesthesia. A 9-year-old patient experienced increased seizures on postoperative day 0. An 8-year-old patient with hydropcephalus developed metabolic acidosis on postoperative day 1, and a 7-year-old patient's procedure was complicated by respiratory distress and increased seizure activity in the postanesthesia care unit. This study showed that it is relatively safe for children on KD to undergo general anesthesia. The 3 complications attributable to general anesthesia were mild, and the increased seizure frequencies in 2 patients returned back to baseline in 24 hours. Although normal saline is considered more beneficial than lactated Ringer's solution in patients on KD, normal saline should also be administered carefully because of the risk of exacerbating patients' metabolic acidosis. One should be aware of the potential change of the ketogenic status due to drugs given intraoperatively.


Do health care providers give sufficient information and good counseling during ante-natal care in Lao PDR?: an observational study.
It is increasingly recognized that improving the quality of maternal health care delivery is of utmost importance in many countries. In Laos, the quality of antenatal care (ANC) service remains inadequate, but it has never been assessed thoroughly. This study aims to determine the ANC quality at the urban and rural public health facilities in Laos and provides suggestions to improve health education and counseling in addition to other routine care in public ANC services. This health-facility based, cross-sectional observation study included both health providers (n = 77) and pregnant women (n = 421) from purposively selected health facilities (n = 16). Information on the mothers' current pregnancies, previous visits and their last children was collected. The time spent for each ANC session as well as ANC services provided were recorded. Descriptive and inferential statistics were applied to analyze the data. Overall performance of ANC services by health care providers was poor in both urban and rural areas. Insufficient provision of information on danger signs during pregnancy, nutrition, breast feeding and iron supplements was revealed. Generally the communication skills, behavior and attitude of health providers were very poor. Less than a quarter of pregnant women were treated with kindness and respect. Only 4% of the observed ANC session took privacy into consideration. Less than 10% of available information materials were used during each ANC session. None of the health providers in both rural and urban areas performed specific counseling. Overall mean (SD) time-spent for each ANC session was 16.21 (4.28) minutes. A positive correlation was identified between the length of working experience of health providers and their physical performance scores (adjusted R square = 0.017). The overall performance of ANC services by health care providers was inadequate in both urban and rural areas. Insufficient provision of health education and poor communication skills of health care providers were revealed. Existing IEC materials were scarcely used. Taking action to improve the quality of ANC services by training and providing specific guidelines, creating dedicated rooms, and providing sufficient and effective materials for counseling are all greatly needed in public health facilities in Laos.


Effect of nosocomial vancomycin-resistant enterococcal bacteremia on mortality, length of stay, and costs.
To determine the impact of vancomycin-resistant enterococcal bacteremia on patient outcomes and costs by assessing mortality, excess length of stay, and charges attributable to it. A population-based, matched, historical cohort study. A 1,025-bed, university-based teaching facility and referral hospital. Two hundred seventy-seven vancomycin-resistant enterococcal bacteremia case-patients and 277 matched control-patients identified between 1993 and 2000. The crude mortality rate was 50.2% and 19.9% for case-patients and control-patients, respectively, yielding a mortality rate of 30.3% attributable to vancomycin-resistant enterococcal bacteremia. The excess length of hospital stay attributable to vancomycin-resistant enterococcal bacteremia was 17 days, of which 12 days were spent in intensive care units. On average, dollars 77,558 in extra charges was attributable to each vancomycin-resistant enterococcal bacteremia. To adjust for severity of illness, 159 pairs of case-patients and control-patients, who had the same severity of illness (All Patient Refined-Diagnosis Related Group complexity level), were further analyzed. When patients were stratified by severity of illness, the crude mortality rate was 50.3% among case-patients compared with 27.7% among control-patients, accounting for an attributable mortality rate of 22.6%. Attributable excess length of stay and charges were 17 days and dollars 81,208, respectively. Vancomycin-resistant enterococcal bacteremia contributes significantly to excess mortality and economic loss, once severity of illness is considered. Efforts to prevent these infections will likely be cost-effective.


Stygiolobus rod-shaped virus and the interplay of crenarchaeal rudiviruses with the CRISPR antiviral system.
A newly characterized archaeal rudivirus Stygiolobus rod-shaped virus (SRV), which infects a hyperthermophilic Stygiolobus species, was isolated from a hot spring in the Azores, Portugal. Its virions are rod-shaped, 702 (+/- 50) by 22 (+/- 3) nm in size, and nonenveloped and carry three tail fibers at each terminus. The linear double-stranded DNA genome contains 28,096 bp and an inverted terminal repeat of 1,030 bp. The SRV shows morphological and genomic similarities to the other characterized rudiviruses Sulfolobus rod-shaped virus 1 (SIRV1), SIRV2, and Acidianus rod-shaped virus 1, isolated from hot acidic springs of Iceland and Italy. The single major rudiviral structural protein is shown to generate long tubular structures in vitro of similar dimensions to those of the virion, and we estimate that the virion constitutes a single, superhelical, double-stranded DNA embedded into such a protein structure. Three additional minor conserved structural proteins are also identified. Ubiquitous rudiviral proteins with assigned functions include glycosyl transferases and a S-adenosylmethionine-dependent methyltransferase, as well as a Holliday junction resolvase, a transcriptionally coupled helicase and nuclease implicated in DNA replication. Analysis of matches between known crenarchaeal chromosomal CRISPR spacer sequences, implicated in a viral defense system, and rudiviral genomes revealed that about 10% of the 3,042 unique acidothermophile spacers yield significant matches to rudiviral genomes, with a bias to highly conserved protein genes, consistent with the widespread presence of rudiviruses in hot acidophilic environments. We propose that the 12-bp indels which are commonly found in conserved rudiviral protein genes may be generated as a reaction to the presence of the host CRISPR defense system.


Cytotoxin production by Helicobacter pylori from patients with upper gastrointestinal tract diseases.
A cytotoxin produced by some Helicobacter pylori strains has recently been identified. The cytotoxin induces intracellular vacuolization of cultured cells. The aim of the present study was to examine the frequency of occurrence of cytotoxin-producing strains of H. pylori from subjects with upper gastrointestinal disease including nonulcer dyspepsia, gastric and duodenal ulcer disease, gastroesophageal reflux disease, and gastric cancer. Broth culture filtrates of clinical isolates of H. pylori recovered from 175 patients were used to inoculate Vero and HeLa cell monolayers for the detection of vacuolating cytotoxin activity. The results obtained demonstrated that the highest percentage of strains producing cytotoxin were found in subjects with peptic ulcer disease (gastric ulcer, 65%; duodenal ulcer, 66%; P < 0.01 compared with nonulcer dyspepsia, 38%). Of the 11 patients with gastroesophageal reflux disease, 4 of 5 patients in this group who had esophageal ulcers, were found to be infected with strains that produced cytotoxin. Three of the four patients with carcinoma of the stomach were also found to be infected with cytotoxic strains of H. pylori. With increasing severity of mucosal damage in subjects with a normal upper gastrointestinal tract, macroscopic gastritis, duodenitis, and peptic ulceration, there were corresponding increase in the proportion of strains producing cytotoxin; these increases were 32, 46, 50, and 66%, respectively. H. pylori strains from subjects with ulcer disease commonly produced vacuolating cytotoxin, suggesting that it may be a virulence factor in the pathogenesis of peptic ulcer disease.


HIV prevention advice for people with serious mental illness.
People with serious mental illness have rates of Human Immuno-deficiency Virus (HIV) infection higher than expected in the general population for the same demographic area. Despite this elevated prevalence, UK national strategies around sexual health and HIV prevention do not state that people with serious mental illness are a high risk group. However, a significant proportion in this group are sexually active and engage in HIV-risk behaviours including having multiple sexual partners, infrequent use of condoms and trading sex for money or drugs. Therefore we propose the provision of HIV prevention advice could enhance the physical and social well being of this population. To assess the effects of HIV prevention advice in reducing morbidity, mortality and preserving the quality of life in people with serious mental illness. We searched the Cochrane Schizophrenia Group's Trials Register (24 January, 2012), which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. There is no language, date, document type, or publication status limitations for inclusion of records in the register. We planned to include all randomised controlled trials focusing on HIV prevention advice versus standard care or comparing HIV prevention advice with other more focused methods of delivering care or information for people with serious mental illness. Review authors (NW, AC, AA, GT) independently screened search results and did not identify any studies that fulfilled the review's criteria. We did not identify any randomised studies that evaluated advice regarding HIV for people with serious mental illness. The excluded studies illustrate that randomisation of packages of care relevant to both people with serious mental illness and HIV risk are possible. Policy makers, clinicians, researchers and service users need to collaborate to produce guidance on how best to provide advice for people with serious mental illness in preventing the spread of HIV infection. It is entirely feasible that this could be within the context of a well-designed simple large randomised study.


Predicting mutually exclusive spliced exons based on exon length, splice site and reading frame conservation, and exon sequence homology.
Alternative splicing of pre-mature RNA is an important process eukaryotes utilize to increase their repertoire of different protein products. Several types of different alternative splice forms exist including exon skipping, differential splicing of exons at their 3'- or 5'-end, intron retention, and mutually exclusive splicing. The latter term is used for clusters of internal exons that are spliced in a mutually exclusive manner. We have implemented an extension to the WebScipio software to search for mutually exclusive exons. Here, the search is based on the precondition that mutually exclusive exons encode regions of the same structural part of the protein product. This precondition provides restrictions to the search for candidate exons concerning their length, splice site conservation and reading frame preservation, and overall homology. Mutually exclusive exons that are not homologous and not of about the same length will not be found. Using the new algorithm, mutually exclusive exons in several example genes, a dynein heavy chain, a muscle myosin heavy chain, and Dscam were correctly identified. In addition, the algorithm was applied to the whole Drosophila melanogaster X chromosome and the results were compared to the Flybase annotation and an ab initio prediction. Clusters of mutually exclusive exons might be subsequent to each other and might encode dozens of exons. This is the first implementation of an automatic search for mutually exclusive exons in eukaryotes. Exons are predicted and reconstructed in the same run providing the complete gene structure for the protein query of interest. WebScipio offers high quality gene structure figures with the clusters of mutually exclusive exons colour-coded, and several analysis tools for further manual inspection. The genome scale analysis of all genes of the Drosophila melanogaster X chromosome showed that WebScipio is able to find all but two of the 28 annotated mutually exclusive spliced exons and predicts 39 new candidate exons. Thus, WebScipio should be able to identify mutually exclusive spliced exons in any query sequence from any species with a very high probability. WebScipio is freely available to academics at http://www.webscipio.org.


Acid anhydrides and asthma.
We have studied asthma caused by inhaled acid anhydrides as a model of hapten-induced airway hyperresponsiveness. Inhalation tests with the relevant anhydride in sensitised individuals reproducibly provoked a significant increase in non-specific airway responsiveness identifiable 3 h after the test and prior to the development of the late asthmatic reaction. Seven cases of asthma caused by tetrachlorophthalic anhydride (TCPA) had specific IgE in their serum to a TCPA-human serum albumin conjugate. RAST inhibition studies showed the anhydride to be involved in the antibody-combining site. Survey of the factory population where these 7 cases worked allowed investigation of the determinants of the specific IgE response: its presence was associated with intensity of exposure and current cigarette smoking; in addition smoking interacted with atopy to increase the prevalence of specific IgE. During a 5-year period of avoidance of exposure to TCPA specific IgE declined exponentially with a half-life of one year, suggesting continuing IgE secretion. Five years after avoidance of exposure, airway hyperresponsiveness remained increased in several cases.


In situ and space-based observations of the Kelud volcanic plume: The persistence of ash in the lower stratosphere.
Volcanic eruptions are important causes of natural variability in the climate system at all time scales. Assessments of the climate impact of volcanic eruptions by climate models almost universally assume that sulfate aerosol is the only radiatively active volcanic material. We report satellite observations from the Cloud-Aerosol Lidar with Orthogonal Polarization (CALIOP) on board the Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO) satellite after the eruption of Mount Kelud (Indonesia) on 13 February 2014 of volcanic materials in the lower stratosphere. Using these observations along with in situ measurements with the Compact Optical Backscatter AerosoL Detector (COBALD) backscatter sondes and optical particle counters (OPCs) made during a balloon field campaign in northern Australia, we find that fine ash particles with a radius below 0.3 µm likely represented between 20 and 28% of the total volcanic cloud aerosol optical depth 3 months after the eruption. A separation of 1.5-2 km between the ash and sulfate plumes is observed in the CALIOP extinction profiles as well as in the aerosol number concentration measurements of the OPC after 3 months. The settling velocity of fine ash with a radius of 0.3 µm in the tropical lower stratosphere is reduced by 50% due to the upward motion of the Brewer-Dobson circulation resulting a doubling of its lifetime. Three months after the eruption, we find a mean tropical clear-sky radiative forcing at the top of the atmosphere from the Kelud plume near -0.08 W/m2 after including the presence of ash; a value ~20% higher than if sulfate alone is considered. Thus, surface cooling following volcanic eruptions could be affected by the persistence of ash and should be considered in climate simulations.


Constitutive activation of chaperone-mediated autophagy in cells with impaired macroautophagy.
Three different types of autophagy-macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA)-contribute to degradation of intracellular components in lysosomes in mammalian cells. Although some level of basal macroautophagy and CMA activities has been described in different cell types and tissues, these two pathways are maximally activated under stress conditions. Activation of these two pathways is often sequential, suggesting the existence of some level of cross-talk between both stress-related autophagic pathways. In this work, we analyze the consequences of blockage of macroautophagy on CMA activity. Using mouse embryonic fibroblasts deficient in Atg5, an autophagy-related protein required for autophagosome formation, we have found that blockage of macroautophagy leads to up-regulation of CMA, even under basal conditions. Interestingly, different mechanisms contribute to the observed changes in CMA-related proteins and the consequent activation of CMA during basal and stress conditions in these macroautophagy-deficient cells. This work supports a direct cross-talk between these two forms of autophagy, and it identifies changes in the lysosomal compartment that underlie the basis for the communication between both autophagic pathways.


Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine.
Cerebrospinal fluid (CSF) S-adenosylmethionine (SAM) levels were significantly lower in severely depressed patients than in a neurological control group. The administration of SAM either intravenously or orally is associated with a significant rise of CSF SAM, indicating that it crosses the blood-brain barrier in humans. These observations provide a rational basis for the antidepressant effect of SAM, which has been confirmed in several countries. CSF SAM levels were low in a group of patients with Alzheimer's dementia suggesting a possible disturbance of methylation in such patients and the need for trials of SAM treatment.


Virological success of lopinavir/ritonavir salvage regimen is affected by an increasing number of lopinavir/ritonavir-related mutations.
We evaluated the virological outcome of lopinavir/ritonavir (LPV/RTV) in 224 HIV-1-infected and protease inhibitor (PI)-experienced patients showing virological failure to a highly active antiretroviral therapy (HAART) regimen and followed up for at least 3 months. At baseline, the median level of plasma viraemia was 4.61 log10 copies/ml (range 3-6.48) and the median CD4 cell count was 219 cells/mm3 (range 1-836). During a median follow-up of 272 days (range 92-635), we observed an increase in the number of CD4 cells (P=0.02) and a dramatic decrease in plasma viraemia levels (P=0.0001), which became undetectable in 122 patients (54.5%). The closely related predictive factors were baseline plasma viraemia levels and the number of mutations known to reduce susceptibility to LPV/RTV. Thirty-one patients (13.8%) discontinued LPV/RTV during the follow-up, and one AIDS event and three deaths were recorded. Of the 134 patients (59.8%) who underwent a baseline genotype resistance test, 22 (16.4%) had > or = 6 mutations known to reduce LPV/RTV susceptibility; plasma viraemia became undetectable in 76 patients (56.7%), only five of whom harboured > or = 6 mutations at baseline (P=0.0001). The independent predictive factors related to virological success were plasma viraemia levels and the number of mutations reducing susceptibility to LPV/RTV at baseline; each additional log10 copies/ml of HIV RNA reduced the probability of virological success by 34.0% and each extra mutation by 14.5%.


Ancestry-Dependent Enrichment of Deleterious Homozygotes in Runs of Homozygosity.
Runs of homozygosity (ROH) are important genomic features that manifest when an individual inherits two haplotypes that are identical by descent. Their length distributions are informative about population history, and their genomic locations are useful for mapping recessive loci contributing to both Mendelian and complex disease risk. We have previously shown that ROH, and especially long ROH that are likely the result of recent parental relatedness, are enriched for homozygous deleterious coding variation in a worldwide sample of outbred individuals. However, the distribution of ROH in admixed populations and their relationship to deleterious homozygous genotypes is understudied. Here we analyze whole-genome sequencing data from 1,441 unrelated individuals from self-identified African American, Puerto Rican, and Mexican American populations. These populations are three-way admixed between European, African, and Native American ancestries and provide an opportunity to study the distribution of deleterious alleles partitioned by local ancestry and ROH. We re-capitulate previous findings that long ROH are enriched for deleterious variation genome-wide. We then partition by local ancestry and show that deleterious homozygotes arise at a higher rate when ROH overlap African ancestry segments than when they overlap European or Native American ancestry segments of the genome. These results suggest that, while ROH on any haplotype background are associated with an inflation of deleterious homozygous variation, African haplotype backgrounds may play a particularly important role in the genetic architecture of complex diseases for admixed individuals, highlighting the need for further study of these populations.


Catalytic properties and inhibition of proline-specific dipeptidyl peptidases II, IV and VII.
There is currently intense interest in the emerging group of proline-specific dipeptidases, and their roles in the regulation of biological processes. Dipeptidyl peptidase IV (DPP-IV) is involved in glucose metabolism by contributing to the regulation of glucagon family peptides and has emerged as a potential target for the treatment of metabolic diseases. Two other proline-specific dipeptidases, DPP-VII (also known as quiescent cell proline dipeptidase) and DPP-II, have unknown functions and have recently been suggested to be identical proteases based on a sequence comparison of human DPP-VII and rat DPP-II (78% identity) [Araki, Li, Yamamoto, Haneda, Nishi, Kikkawa and Ohkubo (2001) J. Biochem. 129, 279-288; Fukasawa, Fukasawa, Higaki, Shiina, Ohno, Ito, Otogoto and Ota (2001) Biochem. J. 353, 283-290]. To facilitate the identification of selective substrates and inhibitors for these enzymes, a complete biochemical profile of these enzymes was obtained. The pH profiles, substrate specificities as determined by positional scanning, Michaelis-Menten constants and inhibition profiles for DPP-VII and DPP-II were shown to be virtually identical, strongly supporting the hypothesis that they are the same protease. In addition, substrate specificities, catalytic constants and IC(50) values were shown to be markedly different from those of DPP-IV. Selective DPP-IV and DPP-VII substrates were identified and they can be used to design selective inhibitors and probe further into the biology of these enzymes.


Mild cognitive impairment: directions for future research.
Mild cognitive impairment (MCI), an intermediate state between normal aging and dementia, is characterized by acquired cognitive deficits, without significant decline in functional activities of daily living. Studies conducted on MCI have introduced new concepts regarding the possible distinctions between normal and pathologic aging of the brain. Neuroimaging and genetic testing have aided in the identification of individuals at increased risk for dementia. The measurement of change in cognitive and functional status in MCI remains challenging, because it requires instruments that are more sensitive and specific than those considered adequate for research in dementia. The authors provide an overview of the many methods that have been used to study MCI and directions that may help achieve greater uniformity in methodology. Considerable heterogeneity exists in research methodology used to study the epidemiology, thresholds for cognitive and functional impairment, rate of progression, risk factors, and defining subtypes of MCI. This article emphasizes the need for uniformity in the use of 1) appropriate and sensitive neuropsychological and functional measures to diagnose MCI, 2) reliable methods to determine progression or improvement of cognitive impairment, and 3) instruments in epidemiologic studies to establish population estimates for diverse ethnic and cultural groups. Greater consensus is needed to standardize definitions and research methodology for MCI, so as to make future studies more comparable and more useful for designing effective treatment strategies.


Illuminant spectrum estimation at a pixel.
In this paper, an algorithm is proposed to estimate the spectral power distribution of a light source at a pixel. The first step of the algorithm is forming a two-dimensional illuminant invariant chromaticity space. In estimating the illuminant spectrum, generalized inverse estimation and Wiener estimation methods were applied. The chromaticity space was divided into small grids and a weight matrix was used to estimate the illuminant spectrum illuminating the pixels that fall within a grid. The algorithm was tested using a different number of sensor responses to determine the optimum number of sensors for accurate colorimetric and spectral reproduction. To investigate the performance of the algorithm realistically, the responses were multiplied with Gaussian noise and then quantized to 10 bits. The algorithm was tested with standard and measured data. Based on the results presented, the algorithm can be used with six sensors to obtain a colorimetrically good estimate of the illuminant spectrum at a pixel.


Maternal bisphenol A alters fetal endocrine system: Thyroid adipokine dysfunction.
Because bisphenol A (BPA) has been detected in animals, the aim of this study was to investigate the possible effects of maternal BPA exposure on the fetal endocrine system (thyroid-adipokine axis). BPA (20 or 40 μg/kg body weight) was orally administered to pregnant rats from gestation day (GD) 1-20. In both treated groups, the dams and their fetuses had lower serum thyroxine (T4) and triiodothyronine (T3) levels, and higher thyrotropin (TSH) level than control dams and fetuses at GD 20. Some histopathological changes in fetal thyroid glands were observed in both maternal BPA groups at embryonic day (ED) 20, including fibroblast proliferation, hyperplasia, luminal obliteration, oedema, and degeneration. These disorders resulted in the suppression of fetal serum growth hormone (GH), insulin growth factor-1 (IGF1) and adiponectin (ADP) levels, and the elevation of fetal serum leptin, insulin and tumor necrosis factor-alpha (TNFα) levels in both treated groups with respect to control. The depraved effects of both treated groups were associated with reduced maternal and fetal body weight compared to the control group. These alterations were dose dependent. Thus, BPA might penetrate the placental barrier and perturb the fetal thyroid adipokine axis to influence fat metabolism and the endocrine system.


The BH3-only protein Puma is both necessary and sufficient for neuronal apoptosis induced by DNA damage in sympathetic neurons.
DNA damage activates apoptosis in several neuronal populations and is an important component of neuropathological conditions. While it is well established that neuronal apoptosis, induced by DNA damage, is dependent on the key cell death regulators p53 and Bax, it is unknown which proteins link the p53 signal to Bax. Using rat sympathetic neurons as an in vitro model of neuronal apoptosis, we show that cytosine arabinoside is a DNA damaging drug that induces the expression of the BH3-only pro-apoptotic genes Noxa, Puma and Bim. Increased expression occurred after p53 activation, measured by its phosphorylation at serine 15, but prior to the conformational change of Bax at the mitochondria, cytochrome c (cyt c) release and apoptosis. Hence Noxa, Puma and Bim could potentially link p53 to Bax. We directly tested this hypothesis by the use of nullizygous mice. We show that Puma, but not Bim or Noxa, is a crucial mediator of DNA damage-induced neuronal apoptosis. Despite the powerful pro-apoptotic effects of overexpressed Puma in Bax-expressing neurons, Bax nullizygous neurons were resistant to Puma-induced death. Therefore, Puma provides the critical link between p53 and Bax, and is both necessary and sufficient to mediate DNA damage-induced apoptosis of sympathetic neurons.


The physiological equivalent temperature - a universal index for the biometeorological assessment of the thermal environment.
With considerably increased coverage of weather information in the news media in recent years in many countries, there is also more demand for data that are applicable and useful for everyday life. Both the perception of the thermal component of weather as well as the appropriate clothing for thermal comfort result from the integral effects of all meteorological parameters relevant for heat exchange between the body and its environment. Regulatory physiological processes can affect the relative importance of meteorological parameters, e.g. wind velocity becomes more important when the body is sweating. In order to take into account all these factors, it is necessary to use a heat-balance model of the human body. The physiological equivalent temperature (PET) is based on the Munich Energy-balance Model for Individuals (MEMI), which models the thermal conditions of the human body in a physiologically relevant way. PET is defined as the air temperature at which, in a typical indoor setting (without wind and solar radiation), the heat budget of the human body is balanced with the same core and skin temperature as under the complex outdoor conditions to be assessed. This way PET enables a layperson to compare the integral effects of complex thermal conditions outside with his or her own experience indoors. On hot summer days, for example, with direct solar irradiation the PET value may be more than 20 K higher than the air temperature, on a windy day in winter up to 15 K lower.


Spatial access disparities to primary health care in rural and remote Australia.
Poor spatial access to health care remains a key issue for rural populations worldwide. Whilst geographic information systems (GIS) have enabled the development of more sophisticated access measures, they are yet to be adopted into health policy and workforce planning. This paper provides and tests a new national-level approach to measuring primary health care (PHC) access for rural Australia, suitable for use in macro-level health policy. The new index was constructed using a modified two-step floating catchment area method framework and the smallest available geographic unit. Primary health care spatial access was operationalised using three broad components: availability of PHC (general practitioner) services; proximity of populations to PHC services; and PHC needs of the population. Data used in its measurement were specifically chosen for accuracy, reliability and ongoing availability for small areas. The resultant index reveals spatial disparities of access to PHC across rural Australia. While generally more remote areas experienced poorer access than more populated rural areas, there were numerous exceptions to this generalisation, with some rural areas close to metropolitan areas having very poor access and some increasingly remote areas having relatively good access. This new index provides a geographically-sensitive measure of access, which is readily updateable and enables a fine granulation of access disparities. Such an index can underpin national rural health programmes and policies designed to improve rural workforce recruitment and retention, and, importantly, health service planning and resource allocation decisions designed to improve equity of PHC access.


"Interactive surfaces" technology as a potential tool to stimulate physical activity in psychogeriatric nursing home residents.
The aims of this study were to determine whether and how psychogeriatric nursing home residents would respond to the interactive surfaces on the floor without receiving instructions and to determine how long residents would be physically active. The "interactive surfaces" technology includes different graphic shapes that are projected through a beamer on a floor. The surfaces are "activated" by a person's movements in the area of the projection field, which is detected by an infrared camera. Every day for 1 h during an 11-day period one of seven different projections was shown. Spontaneous observed physical responses were counted, clustered and visualized in a tree diagram. Duration of physically responses was measured per session and during the total observation period of 11 h. During 343 of 490 observations residents (n = 58) noticed the interactive surface and in 148 observations they engaged physically. In total, 4067 s (1 h, 7 min and 47 s) of physical activity were measured. Individual times that residents were active ranged from 3 to 415 s. Interactive surfaces technology may be a promising tool in psychogeriatric nursing home residents to stimulate physical activity. Further research is needed to assess its full potential. Implications for Rehabilitation Innovative technology used to adapt the environment might stimulate nursing home residents to become more physically active. The use of innovative technologies may increase physical activity without necessarily increasing the workload of care professionals.


A methodology for distinguishing divergent cell fates within a common progenitor population: adenoma- and neuroendocrine-like cells are confounders of rat ileal epithelial cell (IEC-18) culture.
IEC-18 cells are a non-transformed, immortal cell line derived from juvenile rat ileal crypt cells. They may have experimental advantages over tumor-derived gastrointestinal lineages, including preservation of phenotype, normal endocrine responses and retention of differentiation potential. However, their proclivity for spontaneous differentiation/transformation may be stereotypical and could represent a more profound experimental confounder than previously realized. We hypothesized that IEC-18 cells spontaneously diverge towards a uniform mixture of epigenetic fates, with corresponding phenotypes, rather than persist as a single progenitor lineage. IEC-18 cells were cultured for 72 hours in serum free media (SFM), with and without various insulin-like growth factor agonists to differentially boost the basal rate of proliferation. A strategy was employed to identify constitutive genes as markers of divergent fates through gene array analysis by cross-referencing fold-change trends for individual genes against crypt cell abundance in each treatment. We then confirmed the cell-specific phenotype by immunolocalization of proteins corresponding to those genes. The majority of IEC-18 cells in SFM alone had a loss in expression of the adenomatous polyposis coli (APC) gene at the mRNA and protein levels, consistent with adenoma-like transformation. In addition, a small subset of cells expressed the serotonin receptor 2A gene and had neuroendocrine-like morphology. IEC-18 cells commonly undergo a change in cell fate prior to reaching confluence. The most common fate switch that we were able to detect correlates with a down regulation of the APC gene and transformation into an adenoma-like phenotype.


Metal contaminant fluxes across the sediment water interface.
To date, most estimates of contaminant fluxes across the sediment/water interface in risk assessments have been done using diffusive flux models. However, the reliability of these is limited as the overall flux from the sediment may have contributions caused by advection and bioturbation. We found through a comparison of modelled fluxes versus measured fluxes, that the methods Benthic Flux Chamber and surface leaching tests in a risk assessment context showed similar magnitude while calculated fluxes deviated at least by a factor of 100 from measured fluxes. This may be explained by the flux contribution in connection with bioturbation. The chamber-measured fluxes of copper were low compared to those of zinc and cobalt, but this is consistent with leaching tests that indicated copper to be more strongly bound. Risk assessments based on total concentrations may be misleading.


Alpha-decay--induced fracturing in zircon: the transition from the crystalline to the metamict state.
A natural single crystal of zircon, ZrSiO(4,) from Sri Lanka exhibited zonation due to alpha-decay damage. The zones vary in thickness on a scale from one to hundreds of micrometers. The uranium and thorium concentrations vary from zone to zone such that the alpha-decay dose is between 0.2 x 10(16) and 0.8 x 10(16) alpha-events per milligram (0.15 to 0.60 displacement per atom). The transition from the crystalline to the aperiodic metamict state occurs over this dose range. Differential expansion of individual layers due to variations in their alpha-decay dose caused a systematic pattern of fractures that do not propagate across aperiodic layers. High-resolution transmission electron microscopy revealed a systematic change in the microstructure from a periodic atomic array to an aperiodic array with increasing alpha-decay dose. At doses greater than 0.8 x 10(16) alpha-events per milligram there is no evidence for long-range order. This type of damage will accumulate in actinide-bearing, ceramic nuclear waste forms. The systematic pattern of fractures would occur in crystalline phases that are zoned with respect to actinide radionuclides.


An Audit of Neural Tube Defects in the Republic Of Ireland for 2012-2015.
Neural tube defects (NTD) are potentially preventable in two-thirds of cases by periconceptional maternal Folic Acid (FA) supplementation. A national audit for the years 2009-11 showed no decline in NTD rates over twenty years. The aim of this national audit was to determine trends/rates and inform revision of national FA supplementation and food fortification strategies. Of 274,732 live and stillbirths there were 121(42.0%) cases of anencephaly, 136(47.2%) cases of spina bifida and 31(10.8%) cases of encephalocoele giving a total of 288 and overall rate of 1.05/1000 compared with 1.04/1000 in 2009-11(NS). In the 184 women where the information was available, only 29.9%(n=55) reported starting FA before pregnancy. The number of cases diagnosed antenatally was 91%(n=262) and 53%(n=154) were live-born. This audit confirms that over a generation, healthcare interventions have not succeeded in decreasing the number of pregnancies in Ireland complicated by NTD, and that revised strategies need to be developed and implemented.


C2 photosynthesis: a promising route towards crop improvement?
C2 photosynthesis is a carbon concentrating mechanism that can increase net CO2 assimilation by capturing, concentrating and re-assimilating CO2 released by photorespiration. Empirical and modelling studies indicate that C2 plants assimilate more carbon than C3 plants under high temperature, bright light, and low CO2 conditions. I argue that engineering C2 photosynthesis into C3 crops is a promising approach to improve photosynthetic performance under these - and temporally heterogeneous - environments, and review the modifications that may re-create a C2 phenotype in C3 plants. Although a C2 engineering program would encounter many of the same challenges faced by C4 engineering programmes, the simpler leaf anatomical requirements make C2 engineering a feasible approach to improve crops in the medium term.


"People power" or "pester power"? YouTube as a forum for the generation of evidence and patient advocacy.
Venoplasty has been proposed, alongside the theory of chronic cerebrospinal venous insufficiency (CCSVI), as a treatment for multiple sclerosis (MS). Despite concerns about its efficacy and safety, thousands of patients have undergone the procedure. This paper analyses YouTube videos where patients have shared their treatment experiences. Content analysis on the 100 most viewed videos from over 4000 identified in a search for 'CCSVI', and qualitative thematic analysis on popular 'channels' demonstrating patients' experiences. Videos adopt an overwhelmingly positive stance towards CCSVI; many were uploaded by patients and present pre- and/or post-treatment experiences. Patients demonstrate rather than merely describe their symptoms, performing tests on themselves before and after treatment to quantify improvement. Videos combine medical terminology and tests with personal experiences of living with MS. Social media technologies provide patients with novel opportunities for advocating for particular treatments; generating alternative forms of 'evidence' built on a hybrid of personal experience and medical knowledge. Healthcare practitioners need to engage with new digital forms of content, including online social media. Instead of disregarding sources not considered 'evidence-based', practitioners should enhance their understanding of what 'experiential-evidence' is deemed significant to patients, particularly in contested areas of healthcare.


Sonic hedgehog regulates its own receptor on postcrossing commissural axons in a glypican1-dependent manner.
Upon reaching their intermediate target, the floorplate, commissural axons acquire responsiveness to repulsive guidance cues, allowing the axons to exit the midline and adopt a contralateral, longitudinal trajectory. The molecular mechanisms that regulate this switch from attraction to repulsion remain poorly defined. Here, we show that the heparan sulfate proteoglycan Glypican1 (GPC1) is required as a coreceptor for the Shh-dependent induction of Hedgehog-interacting protein (Hhip) in commissural neurons. In turn, Hhip is required for postcrossing axons to respond to a repulsive anteroposterior Shh gradient. Thus, Shh is a cue with dual function. In precrossing axons it acts as an attractive guidance molecule in a transcription-independent manner. At the same time, Shh binds to GPC1 to induce the expression of its own receptor, Hhip, which mediates the repulsive response of postcrossing axons to Shh. Our study characterizes a molecular mechanism by which navigating axons switch their responsiveness at intermediate targets.


Markov-chain Monte Carlo approach to the design of multilayer thin-film optical coatings.
We reconsider the problem of locating the globally optimal solution of a multilayer-optical-coating design problem, within some predetermined space of parameters, with the aim of obtaining a robust technique that requires a minimum of user intervention. The approach we adopt centers on exploring the space of the parameters of interest by using a Markov-chain Monte Carlo sampling algorithm. This technique enables one to locate the global optimum automatically with high confidence and without the need for a good starting design. It also allows the trivial inclusion of prior constraints on the variables and provides a natural means for investigating the robustness of the optimal solution.


Female gender and Helicobacter pylori infection, the most important predisposition factors in a cohort of gastric cancer: A longitudinal study.
Gastric cancer (GC) is one of the most common Cancers in the world and Helicobacter pylori (HP) infection is considered a causative factor. The aim of this study was to determine the characteristics and the associated factors of (GC) in a small cohort. Overall, 54 patients with diagnosed gastric cancer were followed-up at the Department of Gastroenterology & Hepatology at Baqiyatallah University of Medical Sciences. 37 (68.5%) of them were positive for H pylori infection in histopathological evaluations. Univariate and multivariate regression analyses were used to determine the associations of demographic features and HP infection status with GC characteristics and prognosis. Univariate analysis showed female gender (odds ratio (OR): 6.53; 95% confidence interval (95%CI): 1.59-26.8; P=0.008), and illiteracy (compared to intermediate education; OR: 5.9, 95%CI: 1.37-25.43; p=0.05) were associated significantly with higher rate of HP infection. After a mean±SD follow-up duration of 254±329 months, only female gender was significantly associated with HP infection in GC (OR:4.56; 95% CI: 1.0-21.76; P=0.05). H pylori positive patients had significantly higher grade of GC (OR: 3.97; 95% CI: 1.0-16.16; P=0.05), and a trend toward greater GC stage (OR: 4.46, 95% CI: 9.39-21.23; p=0.06). There was no association between survival rate and H pylori infection. In the current study, we found a significant association of female gender with GN and an association of higher grade of GC with female gender. These findings may indicate a sex disparity in susceptibility to HP infection regarding GC future studies of larger populations are recommended.


Cytapheresis in inflammatory bowel diseases: current evidence and perspectives.
Ulcerative colitis and Crohn's disease are inflammatory bowel diseases with a chronic relapsing course. Management of both conditions is far from being fully satisfactory. For this reason in the last decade a large number of biological therapies, targeting cytokines involved in intestinal inflammation, has been developed with various results in terms of efficacy, safety and costs. Activated granulocytes and monocytes represent the major sources of pro-inflammatory cytokines in the intestinal mucosa, playing a pivotal role in inducing and maintaining intestinal inflammation. Leukocytapheresis using an adsorptive carrier-based system (Adacolumn) or a removal filter column (Cellsorba) has been proposed as a feasible, safe and effective therapy for ulcerative colitis and Crohn's disease. The objective of this paper is to provide an overview on the current knowledge about mechanisms of action, available clinical data and the possible future perspectives for the use of Adacolumn and Cellsorba in the management of inflammatory bowel diseases.


Prevalence of suicide ideation and suicide attempts in nine countries.
There are few cross-national comparisons of the rates of suicide ideation and attempts across diverse countries. Nine independently conducted epidemiological surveys using similar diagnostic assessment and criteria provided an opportunity to obtain that data. Suicide ideation and attempts were assessed on the Diagnostic Interview Schedule in over 40000 subjects drawn from the United States, Canada, Puerto Rico, France, West Germany, Lebanon, Taiwan, Korea and New Zealand. The lifetime prevalence rates/100 for suicide ideation ranged from 2.09 (Beirut) to 18.51 (Christchurch, New Zealand). Lifetime prevalence rates/100 for suicide attempts ranged from 0.72 (Beirut) to 5.93 (Puerto Rico). Females as compared to males had only marginally higher rates of suicidal ideation in most countries, reaching a two-fold increase in Taiwan. Females as compared to males had more consistently higher rates for suicide attempts, reaching a two- to three-fold increase in most countries. Suicide ideation and attempts in most countries were associated with being currently divorced/separated as compared to currently married. While the rates of suicide ideation varied widely by country, the rates of suicide attempts were more consistent across most countries. The variations were only partly explained by variation in rates of psychiatric disorders, divorce or separation among countries and are probably due to cultural features that we do not, as yet, understand.


Restricted movements and mangrove dependency of the nervous shark Carcharhinus cautus in nearshore coastal waters.
This study used a network of acoustic receivers deployed around a no-take zone in Mangrove Bay, within the Ningaloo Reef Marine Park in Western Australia, to study residency and habitat preference of a small coastal shark, the nervous shark Carcharhinus cautus. Twelve C. cautus were tagged with acoustic tags and monitored for up to 579 days. Based on individuals detected within the receiver array for at least 2 months, C. cautus had small core (50% kernel utilization distribution, KUD) and home ranges (95% KUD) of 0.66 and 3.64 km2, respectively, and showed a strong habitat preference for mangroves, which are only found in the no-take zone. This resulted in C. cautus spending most of their detected time within the no-take zone boundaries (mean = 81.5%), showing that such a protected area could be beneficial to protect this species from extensive fishing pressure and local depletion, where required. Not all C. cautus remained within the acoustic array, however, suggesting that individual variations occur and that not all individuals would benefit from such protection. This study provides important information about the habitat, residency and movements of C. cautus that can be used for management and conservation. The strong affinity and residency of C. cautus within a mangrove-fringing coastline, emphasizes the importance of mangrove habitat to the species and suggests that such preferences can be used to design appropriate no-take zones for this species or others with similar habitat preferences.


Efficiency enhancement in a backside illuminated 1.12 μm pixel CMOS image sensor via parabolic color filters.
The shrinkage of pixel size down to sub-2 μm in high-resolution CMOS image sensors (CISs) results in degraded efficiency and increased crosstalk. The backside illumination technology can increase the efficiency, but the crosstalk still remains an critical issue to improve the image quality of the CIS devices. In this paper, by adopting a parabolic color filter (P-CF), we demonstrate efficiency enhancement without any noticeable change in optical crosstalk of a backside illuminated 1.12 μm pixel CIS with deep-trench-isolation structure. To identify the observed results, we have investigated the effect of radius of curvature (r) of the P-CF on the efficiency and optical crosstalk of the CIS by performing an electromagnetic analysis. As the r of P-CF becomes equal to (or half) that of the microlens, the efficiencies of the B-, G-, and R-pixels increase by a factor of 14.1% (20.3%), 9.8% (15.3%), and 15.0% (15.7%) with respect to the flat CF cases without any noticeable crosstalk change. Also, as the incident angle increases up to 30°, the angular dependence of the efficiency and crosstalk significantly decreases by utilizing the P-CF in the CIS. Meanwhile, further reduction of r severely increases the optical crosstalk due to the increased diffraction effect, which has been confirmed with the simulated electric-field intensity distribution inside the devices.


The barrier height, unimolecular rate constant, and lifetime for the dissociation of HN(2).
Although never spectroscopically identified in the laboratory, hydrogenated nitrogen (HN(2)) is thought to be an important species in combustion chemistry. The classical barrier height (10.6+/-0.2 kcal mol(-1)) and exothermicity (3.6+/-0.2 kcal mol(-1)) for the HN(2)-->N(2)+H reaction are predicted by high level ab initio quantum mechanical methods [up to CCSDT(Q)]. Total energies are extrapolated to the complete basis set limit applying the focal point analysis. Zero-point vibrational energies are computed using fundamental (anharmonic) frequencies obtained from a quartic force field. Relativistic and diagonal Born-Oppenheimer corrections are also taken into account. The quantum mechanical barrier with these corrections is predicted to be 6.4+/-0.2 kcal mol(-1) and the reaction exothermicity to be 8.8+/-0.2 kcal mol(-1). The importance of these parameters for the thermal NO(x) decomposition (De-NO(x)) process is discussed. The unimolecular rate constant for dissociation of the HN(2) molecule and its lifetime are estimated by canonical transition-state theory and Rice-Ramsperger-Kassel-Marcus theory. The lifetime of the HN(2) molecule is here estimated to be 2.8x10(-10) s at room temperature. Our result is in marginal agreement with the latest experimental kinetic modeling studies (tau=1.5x10(-8) s), albeit consistent with the very rough experimental upper limit (tau<0.5 mus). For the dissociation reaction, kinetic isotope effects are investigated. Our analysis demonstrates that the DN(2) molecule has a longer lifetime than the HN(2) molecule. Thus, DN(2) might be more readily identified experimentally. The ionization potential of the HN(2) molecule is determined by analogous high level ab initio methods and focal point analysis. The adiabatic IP of HN(2) is predicted to be 8.19+/-0.05 eV, in only fair agreement with the experimental upper limit of 7.92 eV deduced from sychrothon-radiation-based photoionization mass spectrometry.


The role of visual feedback of hand position in the control of manual prehension.
Although it is obvious that vision plays a primary role in reaching and grasping objects, the sources of the visual information used in programming and controlling various aspects of these movements is still being investigated. One source of visual information is feedback relating to the characteristics of the reach itself for example, the speed and trajectory of the moving limb and the change in the posture of the hand and fingers. The present study selectively eliminated this source of visual information by blocking the subject's view of the reaching limb with an opaque barrier while still enabling subjects to view the goal object. Thus, a direct comparison was made between standard (closed-loop) and object-only (open-loop) visual-feedback conditions in a situation in which the light levels and contrast between an object and its surroundings were equivalent in both viewing conditions. Reach duration was longer with proportionate increases in both the acceleration and deceleration phases when visual feedback of the reaching limb was prevented. Maximum grip aperture and the proportion of movement time at which it occurred were the same in both conditions. Thus, in contrast to previous studies that did not employ constant light levels across closed- and open-loop reaching conditions, a dissociation was found between the spatial and temporal dimensions of grip formation. It appears that the posture of the hand can be programmed without visual feedback of the hand--presumably via a combination of visual information about the goal object and proprioceptive feedback (and/or efference copy). Nevertheless, maximum grip aperture (like the kinematic markers examined in the transport component) was also delayed when visual feedback of the reaching limb was selectively prevented. In other words, the relative timing of kinematic events was essentially unchanged, reflecting perhaps a tight coupling between the transport and grip components.


Long-term liver-related morbidity and mortality related to chronic hepatitis C virus infection in Swedish patients with inherited bleeding disorders.
Hepatitis C virus (HCV) infection is common in patients with inherited bleeding disorders treated with clotting factor concentrates prior to the introduction of viral inactivation of these products. The long-term consequences of hepatitis C infection in Swedish patients are not fully understood. To examine the impact of HCV infection on liver-related morbidity and mortality in Swedish patients with inherited bleeding disorders. We retrospectively collected data on 183 patients with inherited bleeding disorders infected with HCV who attended the Coagulation Unit at Karolinska University Hospital, Sweden. Data regarding end-stage liver disease (ESLD), defined as presence of ascites, encephalopathy, variceal bleeding, hepatocellular carcinoma or liver-related death, were collected from the patient records and the national registers. The median follow-up time was 35.9 years (IQR 29.0-41.2). A total of 41% had achieved sustained virological response (SVR) after treatment. In total, 14.2% developed ESLD at the median age of 52.6 years (IQR 46.5-64.7). Nineteen (35.8%) of all deaths were due to liver-related causes. Co-infection with human immunodeficiency virus (HIV), older age at time of infection and severe form of bleeding disorder was associated with higher risk of developing ESLD, while SVR was a strong protective factor. This study demonstrated that liver-related morbidity and mortality was significant in patients with bleeding disorders and HCV infection in Sweden. Patients with HCV-infection should be candidates for treatment with the new highly effective antiviral drugs, since SVR proved to be a strong protective factor.


How can emergency physicians protect their work in the era of pseudo publishing?
Recently scientists have been targets of pseudo journals (fake, hijacked or predatory journals). These journals provide a low barrier to publication and quick publication times compared to high quality journals and exploit the pay-to-publish system in order to charge publication fees but they provide no formal peer-review. We aim to increase awareness among emergency physicians about pseudo journals. Trying to list all of fake, hijacked or predatory journals is not the solution because new journals are launched almost everyday and the fast proliferation of journals makes it difficult to identify and list all of them. Only an understanding of the practices and markers of legitimate and predatory publishers will allow the researcher to keep pace with danger because fraud is an ever-changing field. In this review we offer basic information (our top list of strategies and potential red flags) to recognize these journals to avoid submission and suggest some solutions if a paper has already been submitted or published in these journals.


Discovery of a novel pharmacological and structural class of gamma secretase modulators derived from the extract of Actaea racemosa.
A screen of a library of synthetic drugs and natural product extracts identified a botanical extract that modulates the processing of amyloid precursor protein (APP) in cultured cells to produce a lowered ratio of amyloid-beta peptide (1-42) (Aβ42) relative to Aβ40. This profile is of interest as a potential treatment for Alzheimer's disease. The extract, from the black cohosh plant (Actaea racemosa), was subjected to bioassay guided fractionation to isolate active components. Using a combination of normal-phase and reverse-phase chromatography, a novel triterpene monoglycoside, 1, was isolated. This compound was found to have an IC(50) of 100 nM for selectively reducing the production of amyloidogenic Aβ42 while having a much smaller effect on the production of Aβ40 (IC(50) 6.3 μM) in cultured cells overexpressing APP. Using IP-MS methods, this compound was found to modulate the pool of total Aβ produced by reducing the proportion of Aβ42 while increasing the relative amounts of shorter and less amyloidogenic Aβ37 and Aβ39. Concentrations of 1 sufficient to lower levels of Aβ42 substantially (up to 10 μM) did not significantly affect the processing of Notch or other aspects of APP processing. When 1 (10 μg) was administered to CD-1 normal mice intracerebroventricularly, the level of Aβ42 in brain was reduced. Assays for off-target pharmacology and the absence of overt signs of toxicity in mice dosed with compound 1 suggest a comparatively selective pharmacology for this triterpenoid. Compound 1 represents a new lead for the development of potential treatments for Alzheimer's disease via modulation of gamma-secretase.


Multilevel Maxwell-Bloch simulations in inhomogeneously broadened media.
A compact numerical method for simulating ultrafast pulse interaction with inhomogeneously broadened multi-level media is reported. We use a low-dispersion pseudospectral scheme with fourth order time stepping for Maxwell's equations, and a weakly coupled operator splitting method for the Bloch equations where inhomogeneous broadening and relaxations are also taken into account. The underlying physics is briefly discussed with emphasis on the formalism used.


Spino-pelvic alignment influences disc hydration properties after AIS surgery: a prospective MRI-based study.
To analyze the disc hydration and volumetric changes of the intervertebral disc after scoliosis surgery depending on the sagittal spino-pelvic organization. We conducted a prospective MRI study in 45 patients with surgically treated adolescent idiopathic scoliosis (AIS) with a minimum 2-year follow-up. Fusion ended at L1 (n = 13), L2 (n = 14), L3 (n = 11) or L4 (n = 7). Total disc (Vd) and nucleus volumes (Vn) were extrapolated from 3D reconstruction using a custom-made image processing software (Biomechlab, Toulouse, France). Nucleus and external disc contours were semi-automatically detected on turbo spin echo T2-weighted sequence joined 3-mm sagittal cuts. Disc hydration was extrapolated from the nucleus-disc volume ratio (Vn/Vd). Radiographic sagittal parameters were measured pre- and post-operatively on full spine standing views (pelvic incidence, sacral slope, L1S1 lumbar lordosis). Lumbo-pelvic congruity was calculated by the ratio LL/SS according to Stagnara. Mean PI of the cohort was 55° (34°-85°). After surgical correction, lumbar lordosis was slightly increased by 3° (p = 0.02) decreasing lumbo-pelvic congruity from 1.37 to 1.27 (p < 0.01). When pelvic incidence was less than 55° (mean PI 46°), nucleus volumes have increased on average by 30 % compared to the preoperative status in the unfused lumbar discs, while the total disc volumes has remained stable. Five-year follow-up (n = 13) confirmed the constant improvement of the disc hydration ratio. When PI was high (mean PI 64°), volumetric changes were very mild and significant changes in nucleus volumes and disc hydration ratio concerned only the intermediate lumbar levels (L2L3, L3L4 and L4L5). This prospective MRI study showed a significant and sustainable improvement in T2 hypersignal of the disc, indirectly indicating improvement of disc hydration content after AIS surgery. Analysis of disc volumetric changes according to the pelvic incidence suggests that these changes are under the influence of the sagittal spino-pelvic alignment. PI seems to play a key role in the homeostasis of the discs under fusion and should be taken into account for preoperative planning. The restoration of the lumbo-pelvic congruence may help to limit early degenerative changes in the free-motion segment discs after AIS surgery. Hydration content was less sensitive to surgery when PI was high, suggesting higher shear stress in the lower discs. Longer follow-up is required to confirm this hypothesis.


Toll-like receptor 2 (TLR2) and TLR9 signaling results in HIV-long terminal repeat trans-activation and HIV replication in HIV-1 transgenic mouse spleen cells: implications of simultaneous activation of TLRs on HIV replication.
Opportunistic infections are common in HIV-infected patients; they activate HIV replication and contribute to disease progression. In the present study we examined the role of Toll-like receptor 2 (TLR2) and TLR9 in HIV-long terminal repeat (HIV-LTR) trans-activation and assessed whether TLR4 synergized with TLR2 or TLR9 to induce HIV replication. Soluble Mycobacterium tuberculosis factor (STF) and phenol-soluble modulin from Staphylococcus epidermidis induced HIV-LTR trans-activation in human microvessel endothelial cells cotransfected with TLR2 cDNA. Stimulation of ex vivo spleen cells from HIV-1 transgenic mice with TLR4, TLR2, and TLR9 ligands (LPS, STF, and CpG DNA, respectively) induced p24 Ag production in a dose-dependent manner. Costimulation of HIV-1 transgenic mice spleen cells with LPS and STF or CpG DNA induced TNF-alpha and IFN-gamma production in a synergistic manner and p24 production in an additive fashion. In the THP-1 human monocytic cell line stably expressing the HIV-LTR-luciferase construct, LPS and STF also induced HIV-LTR trans-activation in an additive manner. This is the first time that TLR2 and TLR9 and costimulation of TLRs have been shown to induce HIV replication. Together these results underscore the importance of TLRs in bacterial Ag- and CpG DNA-induced HIV-LTR trans-activation and HIV replication. These observations may be important in understanding the role of the innate immune system and the molecular mechanisms involved in the increased HIV replication and HIV disease progression associated with multiple opportunistic infections.


The impact of miRNA-based molecular diagnostics and treatment of NRF2-stabilized tumors.
NF-E2-related factor 2 (NRF2) is a master transcriptional regulator that integrates cellular stress responses and is negatively regulated by Kelch-like ECH-associated protein 1 (KEAP1) at the posttranslational level. In human cancers, aberrantly stabilized NRF2, either by mutation of NRF2 or KEAP1, plays a vital role in chemoresistance and tumor cell growth through the transcriptional activation of target genes, suggesting that targeted inhibition of NRF2 is a potential therapy for NRF2-stabilized tumors. MicroRNAs (miRNA) are endogenous small noncoding RNAs that can negatively regulate gene expression by interfering with the translation or stability of target transcripts. Moreover, tumor-suppressor miRNAs have been suggested to be useful for cancer treatment. Here, a reporter-coupled miRNA library screen identified four miRNAs (miR-507, -634, -450a, and -129-5p) that negatively regulate the NRF2-mediated oncogenic pathway by directly targeting NRF2. Importantly, downregulation of these miRNAs, in addition to the somatic mutation of NRF2 or KEAP1, is associated with stabilized NRF2 and poor prognosis in esophageal squamous cell carcinoma (ESCC). Furthermore, administration of a miR-507 alone or in combination with cisplatin inhibited tumor growth in vivo. Thus, these findings reveal that miRNA-based therapy is effective against NRF2-stabilized ESCC tumors. This study determines the potential of miRNA-based molecular diagnostics and therapeutics in NRF2-stablized tumors.