Molecular-Scale Characterization of Photoinduced Charge Separation in Mixed-Dimensional InSe-Organic van der Waals Heterostructures.
Layered indium selenide (InSe) is an emerging two-dimensional semiconductor that has shown significant promise for high-performance transistors and photodetectors. The range of optoelectronic applications for InSe can potentially be broadened by forming mixed-dimensional van der Waals heterostructures with zero-dimensional molecular systems that are widely employed in organic electronics and photovoltaics. Here, we report the spatially resolved investigation of photoinduced charge separation between InSe and two molecules (C70 and C8-BTBT) using scanning tunneling microscopy combined with laser illumination. We experimentally and computationally show that InSe forms type-II and type-I heterojunctions with C70 and C8-BTBT, respectively, due to an interplay of charge transfer and dielectric screening at the interface. Laser-excited scanning tunneling spectroscopy reveals a ∼0.25 eV decrease in the energy of the lowest unoccupied molecular orbital of C70 with optical illumination. Furthermore, photoluminescence spectroscopy and Kelvin probe force microscopy indicate that electron transfer from InSe to C70 in the type-II heterojunction induces a photovoltage that quantitatively matches the observed downshift in the tunneling spectra. In contrast, no significant changes are observed upon optical illumination in the type-I heterojunction formed between InSe and C8-BTBT. Density functional theory calculations further show that, despite the weak coupling between the molecular species and InSe, the band alignment of these mixed-dimensional heterostructures strongly differs from the one suggested by the ionization potential and electronic affinities of the isolated components. Self-energy-corrected density functional theory indicates that these effects are the result of the combination of charge redistribution at the interface and heterogeneous dielectric screening of the electron-electron interactions in the heterostructure. In addition to providing specific insight for mixed-dimensional InSe-organic van der Waals heterostructures, this work establishes a general experimental methodology for studying localized charge transfer at the molecular scale that is applicable to other photoactive nanoscale systems.


Upregulation of reduced folate carrier by vitamin D enhances brain folate uptake in mice lacking folate receptor alpha.
Folates are critical for central nervous system function. Folate transport is mediated by 3 major pathways, reduced folate carrier (RFC), proton-coupled folate transporter (PCFT), and folate receptor alpha (FRα/Folr1), known to be regulated by ligand-activated nuclear receptors. Cerebral folate delivery primarily occurs at the choroid plexus through FRα and PCFT; inactivation of these transport systems can result in very low folate levels in the cerebrospinal fluid causing childhood neurodegenerative disorders. These disorders have devastating effects in young children, and current therapeutic approaches are not sufficiently effective. Our group has previously reported in vitro that functional expression of RFC at the blood-brain barrier (BBB) and its upregulation by the vitamin D nuclear receptor (VDR) could provide an alternative route for brain folate uptake. In this study, we further demonstrated in vivo, using Folr1 knockout (KO) mice, that loss of FRα led to a substantial decrease of folate delivery to the brain and that pretreatment of Folr1 KO mice with the VDR activating ligand, calcitriol (1,25-dihydroxyvitamin D3), resulted in over a 6-fold increase in [13C5]-5-formyltetrahydrofolate ([13C5]-5-formylTHF) concentration in brain tissues, with levels comparable to wild-type animals. Brain-to-plasma concentration ratio of [13C5]-5-formylTHF was also significantly higher in calcitriol-treated Folr1 KO mice (15-fold), indicating a remarkable enhancement in brain folate delivery. These findings demonstrate that augmenting RFC functional expression at the BBB could effectively compensate for the loss of Folr1-mediated folate uptake at the choroid plexus, providing a therapeutic approach for neurometabolic disorders caused by defective brain folate transport.


Modification of calcium retention capacity of rat liver mitochondria by phosphate and tert-butyl hydroperoxide.
By determining the calcium retention capacity (CRC) of rat liver mitochondria, we confirmed and extended previous observations describing the activation of mitochondrial swelling by phosphate and tert-butyl hydroperoxide (t-BHP). Using CRC measurements, we showed that both phosphate and t-BHP decrease the extent of calcium accumulation required for the full mitochondrial permeability transition pore (MPTP) opening to 35 % of control values and to only 15 % when both phosphate and t-BHP are present in the medium. When changes in fluorescence were evaluated at higher resolution, we observed that in the presence of cyclosporine A fluorescence values return after each Ca(2+) addition to basal values obtained before the Ca(2+) addition. This indicates that the MPTP remains closed. However, in the absence of cyclosporine A, the basal fluorescence after each Ca(2+) addition continuously increased. This increase was potentiated both by phosphate and t-BHP until the moment when the concentration of intramitochondrial calcium required for the full opening of the MPTP was reached. We conclude that in the absence of cyclosporine A, the MPTP is slowly opened after each Ca(2+) addition and that this rate of opening can be modified by various factors such as the composition of the media and the experimental protocol used.


The Gut Microbiome and Its Potential Role in the Development and Function of Newborn Calf Gastrointestinal Tract.
A diverse microbial population colonizes the sterile mammalian gastrointestinal tract during and after the birth. There is increasing evidence that this complex microbiome plays a crucial role in the development of the mucosal immune system and influences newborn health. Microbial colonization is a complex process influenced by a two-way interaction between host and microbes and a variety of external factors, including maternal microbiota, birth process, diet, and antibiotics. Following this initial colonization, continuous exposure to host-specific microbes is not only essential for development and maturation of the mucosal immune system but also the nutrition and health of the animal. Thus, it is important to understand host-microbiome interactions within the context of individual animal species and specific management practices. Data is now being generated revealing significant associations between the early microbiome, development of the mucosal immune system, and the growth and health of newborn calves. The current review focuses on recent information and discusses the limitation of current data and the potential challenges to better characterizing key host-specific microbial interactions. We also discuss potential strategies that may be used to manipulate the early microbiome to improve production and health during the time when newborn calves are most susceptible to enteric disease.


Luciferase reporter mycobacteriophages for detection, identification, and antibiotic susceptibility testing of Mycobacterium tuberculosis in Mexico.
The utility of luciferase reporter mycobacteriophages (LRPs) for detection, identification, and antibiotic susceptibility testing of Mycobacterium tuberculosis was prospectively evaluated in a clinical microbiology laboratory in Mexico City, Mexico. Five hundred twenty-three consecutive sputum samples submitted to the laboratory during a 5-month period were included in this study. These specimens were cultivated in Middlebrook 7H9 (MADC), MGIT, and Löwenstein-Jensen (LJ) media. Of the 71 mycobacterial isolates recovered with any of the three media, 76% were detected with the LRPs, 97% were detected with the MGIT 960 method, and 90% were detected with LJ medium. When contaminated specimens were excluded from the analysis, the LRPs detected 92% (54 of 59) of the cultures. The median time to detection of bacteria was 7 days with both the LRPs and the MGIT 960 method. LRP detection of growth in the presence of p-nitro-alpha-acetylamino-beta-hydroxypropiophenone (NAP) was used for selective identification of M. tuberculosis complex (MTC) and compared to identification with BACTEC 460. Using the LRP NAP test, 47 (94%) out of 50 isolates were correctly identified as tuberculosis complex. The accuracy and speed of LRP antibiotic susceptibility testing with rifampin, streptomycin, isoniazid, and ethambutol were compared to those of the BACTEC 460 method, and discrepant results were checked by the conventional proportion method. In total, 50 MTC isolates were tested. The overall agreement between the LRP and BACTEC 460 results was 98.5%. The median LRP-based susceptibility turnaround time was 2 days (range, 2 to 4 days) compared to 10.5 days (range, 7 to 16 days) by the BACTEC 460 method. Phage resistance was not detected in any of the 243 MTC isolates tested. Mycobacteriophage-based approaches to tuberculosis diagnostics can be implemented in clinical laboratories with sensitivity, specificity, and rapidity that compare favorably with those of the MGIT 960 and BACTEC 460 methods. The phages currently provide the fastest phenotypic assay for susceptibility testing.


Arterial blood pressure responses to short-term exposure to low and high traffic-related air pollution with and without moderate physical activity.
Short-term exposure to traffic-related air pollution (TRAP) has been associated with adverse cardiovascular outcomes. Physical activity (PA) in polluted air may increase pollutant uptake and increase these effects. Crossover real-world exposure study in 28 healthy participants comparing systolic (SBP) and diastolic blood pressure (DBP) responses to four different exposure scenarios: 2 h exposure in high or low-TRAP environment, each at rest and combined with intermittent moderate PA consisting of 15 min intervals alternating rest and cycling on a stationary bicycle. Data was analyzed using mixed effect models for repeated measures. Exposure to high TRAP was associated with higher DBP (1.1 mm/Hg, p = 0.002) post-exposure, irrespective of exercise status. Ultrafine particles (UFP) increased DBP post-exposure (0.9 mm/Hg, p = 0.004). Interquartile increases in black carbon (BC), fine particulate matter (PM10 and PMcoarse), UFP, and nitric oxides (NOx) were associated with statistically significantly higher SBP post-exposure (1.2, 1.0, 1.1, and 1.1 mm/Hg, respectively). Intermittent PA compared with rest was associated with lower SBP post-exposure (-2.4 mm/Hg, p < 0.001). PA lowered SBP more after exposure to the low-TRAP site (-2.3 mm/Hg) compared with the high-TRAP site (-1.6 mm/Hg). We only found evidence of an interaction between PA and both PM10 and PMcoarse, increasing SBP. Both SBP and DBP increase after exposure to TRAP. Intermittent PA attenuates the TRAP-related increases in SBP, with the exception of PM10 and PMcoarse, which potentiate these increases. We showed that in low-TRAP environments intermittent PA has stronger beneficial effects on SBP than in high-TRAP environments.


A Simple Method for Automated Equilibration Detection in Molecular Simulations.
Molecular simulations intended to compute equilibrium properties are often initiated from configurations that are highly atypical of equilibrium samples, a practice which can generate a distinct initial transient in mechanical observables computed from the simulation trajectory. Traditional practice in simulation data analysis recommends this initial portion be discarded to equilibration, but no simple, general, and automated procedure for this process exists. Here, we suggest a conceptually simple automated procedure that does not make strict assumptions about the distribution of the observable of interest in which the equilibration time is chosen to maximize the number of effectively uncorrelated samples in the production timespan used to compute equilibrium averages. We present a simple Python reference implementation of this procedure and demonstrate its utility on typical molecular simulation data.


Host cell nucleolin is required to maintain the architecture of human cytomegalovirus replication compartments.
Drastic reorganization of the nucleus is a hallmark of herpesvirus replication. This reorganization includes the formation of viral replication compartments, the subnuclear structures in which the viral DNA genome is replicated. The architecture of replication compartments is poorly understood. However, recent work with human cytomegalovirus (HCMV) showed that the viral DNA polymerase subunit UL44 concentrates and viral DNA synthesis occurs at the periphery of these compartments. Any cellular factors involved in replication compartment architecture are largely unknown. Previously, we found that nucleolin, a major protein component of nucleoli, associates with HCMV UL44 in infected cells and is required for efficient viral DNA synthesis. Here, we show that nucleolin binds to purified UL44. Confocal immunofluorescence analysis demonstrated colocalization of nucleolin with UL44 at the periphery of replication compartments. Pharmacological inhibition of viral DNA synthesis prevented the formation of replication compartments but did not abrogate association of UL44 and nucleolin. Thus, association of UL44 and nucleolin is unlikely to be a nonspecific effect related to development of replication compartments. No detectable colocalization of 5-ethynyl-2'-deoxyuridine (EdU)-labeled viral DNA with nucleolin was observed, suggesting that nucleolin is not directly involved in viral DNA synthesis. Small interfering RNA (siRNA)-mediated knockdown of nucleolin caused improper localization of UL44 and a defect in EdU incorporation into viral DNA. We propose a model in which nucleolin anchors UL44 at the periphery of replication compartments to maintain their architecture and promote viral DNA synthesis. Human cytomegalovirus (HCMV) is an important human pathogen. HCMV infection causes considerable rearrangement of the structure of the nucleus, largely due to the formation of viral replication compartments within the nucleus. Within these compartments, the virus replicates its DNA genome. We previously demonstrated that nucleolin is required for efficient viral DNA synthesis and now find that the nucleolar protein nucleolin interacts with a subunit of the viral DNA polymerase, UL44, specifically at the periphery of replication compartments. Moreover, we find that nucleolin is required to properly localize UL44 at this region. Nucleolin is, therefore, involved in the organization of proteins within replication compartments. This, to our knowledge, is the first report identifying a cellular protein required for maintaining replication compartment architecture.


Metformin improves putative longevity effectors in peripheral mononuclear cells from subjects with prediabetes. A randomized controlled trial.
Prediabetes increases cardiovascular risk and is associated with excess mortality. In preclinical models, metformin has been shown to exert anti-ageing effects. In this study, we sought to assess whether metformin modulates putative effector longevity programs in prediabetic subjects. In a randomized, single-blind, placebo-controlled trial, 38 prediabetic subjects received metformin (1500 mg/day) or placebo for 2 months. At baseline and after treatment, we collected anthropometric and metabolic parameters. Gene and protein levels of SIRT1, mTOR, p53, p66Shc, SIRT1 activity, AMPK activation, telomere length, and SIRT1 promoter chromatin accessibility were determined in peripheral blood mononuclear cells (PBMCs). Plasma N-glycans, non-invasive surrogate markers of ageing, were also analysed. Compared to baseline, metformin significantly improved metabolic parameters and insulin sensitivity, increased SIRT1 gene/protein expression and SIRT1 promoter chromatin accessibility, elevated mTOR gene expression with concomitant reduction in p70S6K phosphorylation in subjects' PBMCs, and modified the plasma N-glycan profile. Compared to placebo, metformin increased SIRT1 protein expression and reduced p70S6K phosphorylation (a proxy of mTOR activity). Plasma N-glycans were also favourably modified by metformin compared to placebo. In individuals with prediabetes, metformin ameliorated effector pathways that have been shown to regulate longevity in animal models. ClinicalTrials. gov identifier: NCT01765946 - January 2013.


Health, lifestyle and employment beyond state-pension age.
The factors influencing one's choice to retire vary, with financial and health considerations being some of the main factors impacting or associated with people's timing of retirement. The aim of the study is to investigate the differences in current health and health-related behaviours, such as smoking, drinking and exercising, between people who kept on working beyond state-pension age and those who retired before or at state-pension age. Data from six waves (2003, 2008-2012) of the Scottish Health Survey (SHeS) are used. Descriptive analyses were used to characterise the population. Multivariate logistic regression was undertaken to analyse the relationship between retirement groups and gender, age, deprivation, marital status, housing tenure, general health, longstanding illness, cigarette smoking status, amount of exercise and mental health, using Stata. Reporting poor self-rated health or having a long-standing illness was associated with increased odds of retiring before state pension age (SPA) in groups with a medium deprivation profile in almost all the survey years. For the least deprived there was little evidence of an association between poor health and extended-working-life, while significant associations were observed for the most deprived. An increasing trend was observed for both genders in the number of people extending their working life. Similar associations between reporting poorer self-rated health and extended working lives were observed for men and women. Distinct gender differences were observed for the associations with reporting poor mental health and no exercise. In the adjusted models, both were significantly associated with retiring at or before SPA in almost every year for women, whereas no significant associations were observed (except in 1 year) for men. This study shows an increasing trend in the number of people extending their working lives and demonstrates significant associations between health and lifestyle behaviours and employment status past SPA. The results suggest that good health - both physically and mentally - along with either a need or a want to stay in employment could be important reasons for continuing to work beyond SPA.


Recapturing lost evanescent power by tuning end face total internal reflection capable tunneling modes at a roughened fiber end face.
We reveal that the overall evanescent wave (EW) power captured by an unclad multimode fiber employed in a sensing configuration is determined by the tunneling modes, not the guided modes. While enormous in strength, most of this power is inaccessible using traditional EW power enhancers. However, we found that by roughening the fiber end face, this supposedly lost power can be recaptured and thus can boost the detectable power level significantly. Intensive mode mixing events across various mode categories are proposed to interpret the observed phenomenon.


Synergistic combination of novel tubulin inhibitor ABI-274 and vemurafenib overcome vemurafenib acquired resistance in BRAFV600E melanoma.
Acquired clinical resistance to vemurafenib, a selective BRAF(V600E) inhibitor, arises frequently after short-term chemotherapy. Because inhibitions of targets in the RAF-MEK-ERK pathway result in G(0)-G(1) cell-cycle arrest, vemurafenib-resistant cancer cells are expected to escape this cell-cycle arrest and progress to the subsequent G(2)-M phase. We hypothesized that a combined therapy using vemurafenib with a G(2)-M phase blocking agent will trap resistant cells and overcome vemurafenib resistance. To test this hypothesis, we first determined the combination index (CI) values of our novel tubulin inhibitor ABI-274 and vemurafenib on parental human A375 and MDA-MB-435 melanoma cell lines to be 0.32 and 0.1, respectively, suggesting strong synergy for the combination. We then developed an A375RF21 subline with significant acquired resistance to vemurafenib and confirmed the strong synergistic effect. Next, we studied the potential mechanisms of overcoming vemurafenib resistance. Flow cytometry confirmed that the combination of ABI-274 and vemurafenib synergistically arrested cells in the G(1)-G(2)-M phase, and significantly increased apoptosis in both parental A375 and the vemurafenib-resistant A375RF21 cells. Western blot analysis revealed that the combination treatment effectively reduced the level of phosphorylated and total AKT, activated the apoptosis cascade, and increased cleaved caspase-3 and cleaved PARP, but had no significant influence on the level of extracellular signal-regulated kinase (ERK) phosphorylation. Finally, in vivo coadministration of vemurafenib with ABI-274 showed strong synergistic efficacy in the vemurafenib-resistant xenograft model in nude mice. Overall, these results offer a rational combination strategy to significantly enhance the therapeutic benefit in patients with melanoma who inevitably become resistant to current vemurafenib therapy.


Thirty-Day Hospital Revisit Rates and Factors Associated With Revisits in Patients Undergoing Septorhinoplasty.
Estimates of the 30-day hospital revisit rate following septorhinoplasty and the risk factors associated with revisits are unknown in the current literature. Surgical 30-day readmission rates are important to establish, as they are increasingly used as a quality care metric and can incur future financial penalties from third-party payers and government agencies. To determine the rate of 30-day hospital revisits following septorhinoplasty and the risk factors associated with revisits. A retrospective cohort analysis was conducted of 175 842 patients undergoing septorhinoplasty between January 1, 2005, and December 31, 2009, using data from the Healthcare Cost and Utilization Project state inpatient database, state ambulatory surgery database, and state emergency department database from California, Florida, and New York. Information on revisits for these patients was collected from the 3 databases between January 1, 2005, and December 31, 2012. Data analysis was conducted from September 1, 2014, to May 1, 2015. Hospital revisits within 30 days after an index septorhinoplasty and the primary diagnosis at the time of the revisit were the main outcome measures. The revisit rate was calculated within subgroups of patients based on different demographic and clinical characteristics. A multivariable model was then used to determine independent risk factors for the occurrence of a hospital revisit within 30 days of the septorhinoplasty procedure. In total, 11 456 of 175 842 patients (6.5%) who underwent septorhinoplasty procedures revisited the hospital within 30 days of the procedure. Most of these revisits (6353 [55.5%]) were to the emergency department. The most common primary diagnosis was bleeding or epistaxis, occurring in 2150 patients (1.2%). Multivariable logistic regression showed that patients aged 41 to 65 years (adjusted odds ratio [aOR], 1.09; 99% CI, 1.02-1.16) or older than 65 years (aOR, 1.23; 99% CI, 1.06-1.43) had an increased revisit rate, as did black patients (aOR, 1.39; 99% CI, 1.16-1.66); those with Medicare (aOR, 1.55; 99% CI, 1.32-1.81) and Medicaid (aOR, 1.63; 99% CI, 1.33-2.01); those with diagnoses of autoimmune disorders or immunodeficiency (aOR, 2.69; 99% CI, 1.20-6.03), coagulopathy (aOR, 2.06; 99% CI, 1.33-3.20), anxiety (aOR, 1.79; 99% CI, 1.55-2.07), and alcohol use (aOR, 1.70; 99% CI, 1.35-2.14); and those who had a conchal cartilage graft (aOR, 2.01; 99% CI, 1.29-3.14). The study results suggest that patients with more medical comorbidities and lower socioeconomic status most commonly returned to the emergency department for surgical complications, such as bleeding or epistaxis, in the 30-day period after the procedure. These data provide valuable preoperative counseling information for patients and physicians. In addition, this study provides data to third-party payers or government agencies in which postprocedure readmissions in the 30-day period are used as a quality care metric affecting reimbursements and financial penalties. 3.


Light turning mirrors for hybrid integration of SiON-based optical waveguides and photo-detectors.
For hybrid integration of an optical chip with an electronic chip containing photo-diodes and processing electronics, light must be coupled from the optical to the electronic chip. This paper presents a method to fabricate quasi-total-internal-reflecting mirrors on an optical chip, placed at an angle of 45° with the chip surface, that enable 90° out-of-plane light coupling between flip-chip bonded chips. The fabrication method utilizes a metal-free, parallel process and is fully compatible with conventional fabrication of optical chips. The mirrors are created using anisotropic etching of 45° facets in a Si substrate, followed by fabrication of the optical structures. After removal of the mirror-defining Si structures by isotropic etching, the obtained interfaces between optical structure and air direct the output from optical waveguides to out-of-plane photo-detectors on the electronic chip, which is aimed to be flip-chip mounted on the optical chip. For transverse-electric (transverse-magnetic) polarization simulations predict a functional loss of 7% (15%), while 7% (18%) is measured.


A systematic review of the validity and reliability of apathy scales in neurodegenerative conditions.
There are several scales used to detect apathy in disease populations. Since apathy is a prevalent symptom in many neurodegenerative diseases, this is an especially important context in which to identify and compare scales. To provide an overview of apathy scales validated in generic and specific neurodegenerative disease populations, compare validation studies' methodological quality and the psychometric properties of the validated apathy scales. A systematic review of literature was conducted of articles published between 1980 and 2013. The final articles selected for review were rated on methodological quality and the psychometric properties of the scales used were interpreted. Sixteen articles validating apathy scales were included in the review, five in a generic neurodegenerative sample and eleven in specific neurodegenerative samples. The methodological quality of specific studies varied from poor to excellent. The highest quality, which had psychometrically favorable scales, were the dementia apathy interview and rating (DAIR) and the apathy evaluation scale-clinical version (AES-C) in Alzheimer's disease and the Lille apathy rating scale (LARS) in Parkinson's disease. Generic neurodegenerative disease validation studies were of average methodological quality and yielded inconsistent psychometric properties. Several instruments can be recommended for use in some specific neurodegenerative diseases. Other instruments should either be validated or developed to assess apathy in more generic populations.


Systematic Review of N-of-1 Studies in Rare Genetic Neurodevelopmental Disorders: The Power of 1.
To improve the use of N-of-1 studies in rare genetic neurodevelopmental disorders, we systematically reviewed the literature and formulated recommendations for future studies. The systematic review protocol was registered in the PROSPERO International Prospective Register of Systematic Reviews (CRD42020154720). EMBASE and MEDLINE were searched for relevant studies. Information was recorded on types of interventions, outcome measures, validity, strengths, and limitations using standard reporting guidelines and critical appraisal tools. Qualitative and descriptive analyses were performed. Twelve studies met the N-of-1 inclusion criteria, including both single trials and series. Interventions were mainly directed to neuropsychiatric manifestations. Main strengths were the use of personalized and clinically relevant outcomes in most studies. Generalizability was compromised due to limited use of validated and generalizable outcome measures. N-of-1 studies are sporadically reported in rare genetic neurodevelopmental disorders. Properly executed N-of-1 studies may provide a powerful alternative to larger randomized controlled trials in rare disorders and a much needed bridge between practice and science. We provide recommendations for future N-of-1 studies in rare genetic neurodevelopmental disorders, ultimately optimizing evidence-based and personalized care.


Atlas-based improved prediction of magnetic field inhomogeneity for distortion correction of EPI data.
We describe a method for atlas-based segmentation of structural MRI for calculation of magnetic fieldmaps. CT data sets are used to construct a probabilistic atlas of the head and corresponding MR is used to train a classifier that segments soft tissue, air, and bone. Subject-specific fieldmaps are computed from the segmentations using a perturbation field model. Previous work has shown that distortion in echo-planar images can be corrected using predicted fieldmaps. We obtain results that agree well with acquired fieldmaps: 90% of voxel shifts from predicted fieldmaps show subvoxel disagreement with those computed from acquired fieldmaps. In addition, our fieldmap predictions show statistically significant improvement following inclusion of the atlas.


Small-world network models of intercellular coupling predict enhanced synchronization in the suprachiasmatic nucleus.
The suprachiasmatic nucleus (SCN) of the hypothalamus is a multioscillator system that drives daily rhythms in mammalian behavior and physiology. Based on recent data implicating vasoactive intestinal polypeptide (VIP) as the key intercellular synchronizing agent, we developed a multicellular SCN model to investigate the effects of cellular heterogeneity and intercellular connectivity on circadian behavior. A 2-dimensional grid was populated with 400 model cells that were heterogeneous with respect to their uncoupled rhythmic behavior (intrinsic and damped pacemakers with a range of oscillation periods) and VIP release characteristics (VIP producers and nonproducers). We constructed small-world network architectures in which local connections between VIP producing cells and their 4 nearest neighbors were augmented with random connections, resulting in long-range coupling across the grid. With only 10% of the total possible connections, the small-world network model was able to produce similar phase synchronization indices as a mean-field model with VIP producing cells connected to all other cells. Partial removal of random connections decreased the synchrony among neurons, the amplitude of VIP and cAMP response element binding protein oscillations, the mean period of intrinsic periods across the population, and the percentage of oscillating cells. These results indicate that small-world connectivity provides the optimal compromise between the number of connections and control of circadian amplitude and synchrony. This model predicts that small decreases in long-range VIP connections in the SCN could have dramatic effects on period and amplitude of daily rhythms, features commonly described with aging.


Preparation of polylactide-co-glycolide nanoparticles incorporating celecoxib and their antitumor activity against brain tumor cells.
Celecoxib, a cyclo-oxygenase (COX)-2 inhibitor, has been reported to mediate growth inhibitory effects and to induce apoptosis in various cancer cell lines. In this study, we examined the potential effects of celecoxib on glioma cell proliferation, migration, and inhibition of COX-2 expression in vitro. Celecoxib was incorporated into poly DL-lactide-co-glycolide (PLGA) nanoparticles for antitumor drug delivery. PLGA nanoparticles incorporating celecoxib had spherical shapes and their particle sizes were in the range of 50-200 nm. Drug-loading efficiency was not significantly changed according to the solvent used, except for acetone. Celecoxib was released from the PLGA nanoparticles for more than 2 days, and the higher the drug content, the longer the duration of drug release. PLGA nanoparticles incorporating celecoxib showed cytotoxicity against U87MG tumor cells similar to that of celecoxib administered alone. Furthermore, celecoxib did not affect the degree of migration of U87MG cells. PLGA nanoparticles incorporating celecoxib showed dose-dependent cytotoxicity similar to that of celecoxib alone in C6 rat glioma cells. Western blot assay of the C6 cells showed that neither celecoxib alone nor PLGA nanoparticles incorporating celecoxib affected COX-2 expression. PLGA nanoparticles incorporating celecoxib had antitumor activity similar to that of celecoxib alone, even though these particles did not affect the degree of migration or COX-2 expression in the tumor cells.


Microbial degradation of methyl tert-butyl ether and tert-butyl alcohol in the subsurface.
The fate of fuel oxygenates such as methyl tert-butyl ether (MTBE) in the subsurface is governed by their degradability under various redox conditions. The key intermediate in degradation of MTBE and ethyl tert-butyl ether (ETBE) is tert-butyl alcohol (TBA) which was often found as accumulating intermediate or dead-end product in lab studies using microcosms or isolated cell suspensions. This review discusses in detail the thermodynamics of the degradation processes utilizing various terminal electron acceptors, and the aerobic degradation pathways of MTBE and TBA. It summarizes the present knowledge on MTBE and TBA degradation gained from either microcosm or pure culture studies and emphasizes the potential of compound-specific isotope analysis (CSIA) for identification and quantification of degradation processes of slowly biodegradable pollutants such as MTBE and TBA. Microcosm studies demonstrated that MTBE and TBA may be biodegradable under oxic and nearly all anoxic conditions, although results of various studies are often contradictory, which suggests that site-specific conditions are important parameters. So far, TBA degradation has not been shown under methanogenic conditions and it is currently widely accepted that TBA is a recalcitrant dead-end product of MTBE under these conditions. Reliable in situ degradation rates for MTBE and TBA under various geochemical conditions are not yet available. Furthermore, degradation pathways under anoxic conditions have not yet been elucidated. All pure cultures capable of MTBE or TBA degradation isolated so far use oxygen as terminal electron acceptor. In general, compared with hydrocarbons present in gasoline, fuel oxygenates biodegrade much slower, if at all. The presence of MTBE and related compounds in groundwater therefore frequently limits the use of in situ biodegradation as remediation option at gasoline-contaminated sites. Though degradation of MTBE and TBA in field studies has been reported under oxic conditions, there is hardly any evidence of substantial degradation in the absence of oxygen. The increasing availability of field data from CSIA will foster our understanding and may even allow the quantification of degradation of these recalcitrant compounds. Such information will help to elucidate the crucial factors of site-specific biogeochemical conditions that govern the capability of intrinsic oxygenate degradation.


Pharmacology and clinical efficacy of desloratadine as an anti-allergic and anti-inflammatory drug.
Desloratadine is a biologically active metabolite of the second-generation antihistamine loratadine. Desloratadine is a highly selective peripheral H1 receptor antagonist that is significantly more potent than loratadine. Results of in vitro and in vivo studies have suggested that desloratadine has anti-allergic effects that are unrelated to its ability to antagonise the effects of histamine. Desloratadine inhibits the expression of cell adhesion molecules, inhibits the generation and release of inflammatory mediators and cytokines, attenuates eosinophil chemotaxis, adhesion and superoxide generation. Studies in animals indicate that desloratadine does not cross the blood-brain barrier and therefore does not cause sedation and does not impair cognition or psychomotor performance. Desloratadine has an excellent overall safety profile. It has no effect on QRS and QTc intervals and does not cause arrhythmias. Desloratadine is not associated with any significant changes in gastrointestinal function. In clinical studies, oral desloratadine is rapidly absorbed and bioavailability is not affected by ingestion with food or grapefruit juice. The half-life of desloratadine in humans is 27 h; the linear kinetic profile is unaltered by race or gender. Desloratadine is not a substrate for P-glycoprotein or organic anion transport polypeptide and the drug does not appear to be metabolised to a significant extent by the cytochrome P450 CYP3A4 pathway. It therefore may be safely administered with ketoconazole, erythromycin, fluoxetine, or azithromycin. Clinically, desloratadine effectively controls both nasal and non-nasal symptoms of seasonal allergic rhinitis (SAR), including nasal congestion. Desloratadine also provides significant relief of SAR symptoms in patients with co-existing asthma and is effective in the treatment of chronic idiopathic urticaria. Desloratadine improves quality of life and is well-tolerated.


Increased cardiac sympathetic nerve activity in heart failure is not due to desensitization of the arterial baroreflex.
Increased sympathetic drive to the heart worsens prognosis in heart failure, but the level of cardiac sympathetic nerve activity (CSNA) has been assessed only by indirect methods, which do not permit testing of whether its control by arterial baroreceptors is defective. To do this, CSNA was measured directly in 16 female sheep, 8 of which had been ventricularly paced at 200-220 beats/min for 4-6 wk, until their ejection fraction fell to between 35 and 40%. Recording electrodes were surgically implanted in the cardiac sympathetic nerves, and after 3 days' recovery the responses to intravenous phenylephrine and nitroprusside infusions were measured in conscious sheep. Electrophysiological recordings showed that resting CSNA (bursts/100 heartbeats) was significantly elevated in heart-failure sheep (89 +/- 3) compared with normal animals (46 +/- 6; P < 0.001). This increased CSNA was not accompanied by any increase in the low-frequency power of heart-rate variability. The baroreceptor-heart rate reflex was significantly depressed in heart failure (maximum gain -3.29 +/- 0.56 vs. -5.34 +/- 0.66 beats.min(-1).mmHg(-1) in normal animals), confirming published findings. In contrast, the baroreflex control of CSNA was undiminished (maximum gain in heart failure -6.33 +/- 1.06 vs. -6.03 +/- 0.95%max/mmHg in normal sheep). Direct recordings in a sheep model of heart failure thus show that resting CSNA is strikingly increased, but this is not due to defective control by arterial baroreceptors.


Systematic review of cost-effectiveness analyses of treatments for psoriasis.
Psoriasis is a chronic inflammatory disease of the skin that has a major effect on an individual's physical and mental function. The disease is associated with increased healthcare resource use and costs, therefore cost-effectiveness analysis (CEA) can be used to assist decision makers with determining which treatments are optimal within a constrained healthcare system budget. Our aim was to systematically review the current literature on the CEA of existing treatment options for psoriasis, assess the quality of these studies, and summarize the evidence on the drivers of cost effectiveness. A literature search using Medical Subject Headings and keywords was performed in the MEDLINE, EMBASE and Health Technology Assessment databases, as well as the National Health Service Economic Evaluation Database; the CEA Registry was searched using keywords only. All references within the relevant review articles were examined manually. Two researchers independently determined the final articles and a third researcher resolved any discrepancies. We evaluated study quality in terms of the study perspective, effectiveness measures, cost measures, economic model, and time horizon. Any sensitivity analyses conducted in the studies were examined to identify the drivers of cost effectiveness, which included any variables leading to changes in the study conclusions. Fifty-three articles were included in our final review: 70% did not explicitly include costs related to adverse events; approximately one-quarter used quality-adjusted life-years; and 34% applied a time horizon under 1 year. In 18 of the 38 studies that conducted a sensitivity analysis, the cost-effectiveness results were impacted by uncertainty. The main key drivers of cost effectiveness were the costs related to the treatment, values and choice of efficacy, utility values, hospitalization for non-responders, time horizon, model structure, and utility mapping method. High-quality cost-effectiveness studies are required to facilitate resource allocation decision making. To improve study quality, future research should provide evidence on the long-term experience with psoriasis treatments, and resolve the uncertainty associated with key drivers of cost effectiveness.


Association between parenteral fluids and symptoms in hospital end-of-life care: an observational study of 280 patients.
To investigate whether dying patients receiving parenteral fluids (PF) suffer from more or less symptoms than patients who do not receive PF. Today's evidence on how PF affects palliative patients' symptoms is very scarce. Nevertheless, 40% of the patients who die expectedly in Swedish hospitals receive PF during their last 24 h of life. A historical cohort study of medical records was performed. Of the 530 patients who were reported to have died expectedly at hospital in Västerbotten county (Sweden) between 1 January 2011 and 30 June 2012, 140 cases who had received PF and 140 controls who had not received PF were identified by stratified randomisation and matched by age, sex and main disease. The groups were compared regarding documented presence of dyspnoea, respiratory secretions, anxiety, nausea and confusion during the last 24 h and the last week of life. The prevalence of documented dyspnoea in the PF groups was higher than in the non-PF groups (51% vs 22% last 24 h, p<0.0001; 70% vs 45% last 7 days, p<0.001). The proportions of patients suffering from dyspnoea increased with larger administered volume. Although our main hypothesis--that the prevalence of respiratory secretions would be higher in the PF group--was not confirmed, we found a tendency in that direction (63% vs 50% last week, p=0.072). No clinically significant differences in anxiety, nausea or confusion were found. There is an association between PF administration and increased frequency of documented dyspnoea for terminally ill patients in their last week of life.


Endocrine disruptor, dioxin (TCDD)-induced mitochondrial dysfunction and apoptosis in human trophoblast-like JAR cells.
The endocrine disruptor 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been demonstrated to disrupt hormone signalling, reduce fertility, interfere with embryo development and cause spontaneous miscarriage in humans. The precise mechanisms of its effects on early implantation in humans are still unclear. In this study, we examined the relationship between mitochondrial function and dioxin-induced toxicity in JAR cells, a human trophoblast-like cell line. Several experiments were performed to address the effects of TCDD on cell viability, reactive oxygen species (ROS) generation, oxidative damage (indicated by the presence of lipoperoxides and oxidized DNA bases), mitochondrial DNA (mtDNA) copy number, ATP content, mtDNA mutations and the protein levels of p53, Bax, Bcl2, cytochrome c and caspase 3. Increased oxidative damage and mitochondrial dysfunction in TCDD-treated trophoblast-like cells was demonstrated. A 2.58-fold increase in lipid peroxides was detected in cells treated with 2 nM TCDD for 4 h. The oxidative DNA damage marker 8-hydroxy-2'-deoxyguanosine was significantly increased by TCDD treatment in a time-dependent manner. Meanwhile, reductions in mtDNA copy number and ATP content and an increase in mtDNA deletions were found. Furthermore, we observed increased apoptosis, p53 accumulation, Bax overexpression, cytochrome c release and sequential caspase 3 activation after TCDD exposure. These results indicate that oxidative damage and mitochondrial dysfunction may be responsible for the apoptotic effects of TCDD.


Trapped pulse generation by femtosecond soliton pulse in birefringent optical fibers.
A novel phenomenon of trapped pulse generation by orthogonally polarized femtosecond soliton pulse is discovered in low birefringent optical fiber. As pulse propagation, wavelengths of soliton pulse and trapped pulse are shifted toward longer wavelength side due to effects of soliton selffrequency shift and pulse trapping. The energy of trapped pulse is increased exponentially through Raman gain of soliton pulse and orthogonally polarized and temporally overlapped two colored femtosecond twin pulses are generated. The spectrogram of output pulses is observed using crosscorrelation frequency resolved optical gating technique. The characteristics of this phenomenon are also analyzed numerically and numerical results are almost in agreement with experimental ones.


Development and Evaluation of Reference Standards for Image-based Telemedicine Diagnosis and Clinical Research Studies in Ophthalmology.
Information systems managing image-based data for telemedicine or clinical research applications require a reference standard representing the correct diagnosis. Accurate reference standards are difficult to establish because of imperfect agreement among physicians, and discrepancies between clinical vs. image-based diagnosis. This study is designed to describe the development and evaluation of reference standards for image-based diagnosis, which combine diagnostic impressions of multiple image readers with the actual clinical diagnoses. We show that agreement between image reading and clinical examinations was imperfect (689 [32%] discrepancies in 2148 image readings), as was inter-reader agreement (kappa 0.490-0.652). This was improved by establishing an image-based reference standard defined as the majority diagnosis given by three readers (13% discrepancies with image readers). It was further improved by establishing an overall reference standard that incorporated the clinical diagnosis (10% discrepancies with image readers). These principles of establishing reference standards may be applied to improve robustness of real-world systems supporting image-based diagnosis.


Mortality and morbidity remain high despite captopril and/or Valsartan therapy in elderly patients with left ventricular systolic dysfunction, heart failure, or both after acute myocardial infarction: results from the Valsartan in Acute Myocardial Infarction Trial (VALIANT).
The elderly constitute an increasing proportion of acute myocardial infarction patients and have disproportionately high mortality and morbidity. Those with heart failure or impaired left ventricular left ventricular function after acute myocardial infarction have high complication and mortality rates. Little is known about outcomes with contemporary therapies in these patients. The Valsartan in Acute Myocardial Infarction Trial (VALIANT) randomized 14,703 patients with heart failure and/or left ventricular ejection fraction <40% to receive captopril, valsartan, or both. Mortality and a composite end point, including cardiovascular mortality, readmission for heart failure, reinfarction, stroke, and resuscitated cardiac arrest, were compared for the age groups of <65 (n=6988), 65 to 74 (n=4555), 75 to 84 (n=2777), and > or =85 (n=383) years. With increasing age, 3-year mortality almost quadrupled (13.4%, 26.3%, 36.0%, and 52.1%, respectively), composite end-point events more than doubled (25.2%, 41.0%, 52.3%, and 66.8%), and hospital admissions for heart failure almost tripled (12.0%, 23.1%, 31.3%, and 35.4%). Outcomes did not differ between the 3 study treatments in any age group. Adverse events associated with captopril and valsartan were more common in the elderly and in patients receiving combination therapy. With increasing age, use of aspirin, beta-blockers, and statins declined, and use of digoxin, calcium-channel blockers, and non-potassium-sparing diuretics increased. On 3-year multivariable analysis, each 10-year age increase was associated with a hazard ratio of 1.49 (95% CI, 1.426 to 1.557; P<0.0001) for mortality and an odds ratio of 1.38 (95% CI, 1.31 to 1.46; P<0.0001) for readmission with heart failure. Outcomes remained poor in elderly patients with heart failure and/or impaired left ventricular systolic function after acute myocardial infarction, although most received beta-blockers and all received an ACE inhibitor and/or an angiotensin receptor blocker. Better therapies and increased use of aspirin, beta-blockers, and statins are needed in this important and increasing patient group.


Maternal use of mild analgesics during pregnancy associated with reduced anogenital distance in sons: a cohort study of 1027 mother-child pairs.
Is maternal use of mild analgesics in pregnancy associated with anogenital distance (AGD)-the distance from the anus to the genitals-in the offspring? Maternal use of mild analgesics [especially simultaneous use of paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs)] during pregnancy was associated with a shorter AGD in boys whereas no effect was found in girls. Mild analgesics including paracetamol (acetaminophen) and NSAIDs (e.g. ibuprofen and acetyl salicylic acid) have endocrine disrupting properties and in utero exposure reduces AGD in male rats. In humans, maternal exposure has been associated with cryptorchidism and hypospadias in male offspring but no studies have examined AGD. A prospective birth cohort study. Between 2010 and 2012, 2500 pregnant women were recruited from the Odense Child Cohort. Children were examined 3 months after the expected date of birth. Pregnant women were asked about use of medication including mild analgesics (paracetamol and NSAID) during pregnancy at recruitment (gestational age (GA) week 10-27) and at GA week 28. AGD and penile width were measured 3 months after expected date of birth by trained personnel. A total of 1027 women answered both questionnaires and their children were examined. Associations between prenatal exposure to mild analgesics and AGD and penile width were estimated using multivariable linear regression adjusting for age and weight-for-age SD score. A total of 40% of the women reported use of paracetamol and/or NSAIDs (4.4%) during the first 28 weeks of pregnancy. Exposure to analgesics during pregnancy was associated with a reduced AGD in boys, although statistically significant only for NSAIDs. The association was significant among 20 boys exposed to both paracetamol and NSAIDs (AGD -4.1 mm; CI 95%: -6.4; -1.7). Maternal intake of analgesics did not show any clear association with AGD in female offspring. No effect on penile width was found. Only 27 boys and 18 girls were exposed to NSAIDs and most of them were also exposed to paracetamol. This makes it impossible to distinguish between exposures to NSAIDs alone and a potential mixture effect. Moreover, use of mild analgesics was self-reported up to 2 months after intake, which could have caused misclassification of exposure but is probably not associated with AGD as this was unknown to the women at time of reply to the questionnaire thereby underestimating the association. Confounding by indication may also explain our findings, as the condition for which the analgesic was taken may be associated with a reduction in AGD, rather than the use of the analgesic medication. This is the first study to report such an association in humans and further studies are needed to confirm our findings. A negative association was observed between exposure to analgesics during pregnancy and AGD in boys, suggesting disruption of androgen action. The health implications of a shorter AGD are still uncertain, but in cross-sectional studies among adult men a shorter AGD is associated with poorer semen quality and lower testosterone. As 41% of the women used these painkillers the finding are of public health importance and pregnant women should be advised about the potentially harmful effects of painkiller use. The study was funded by the Danish Environmental Protection Agency by way of the Center on Endocrine Disruptors Danish Center for Hormone Disrupting Chemicals, the Danish Foundation for Scientific Innovation and Technology (09-067180), the Danish Research Council (4004-00352B_FSS), Novo Nordic Foundation (NNF15OC0017734), Ronald McDonald Children Foundation, K.A. Rohde's and wife's Foundation, Odense University Hospital and Region of Southern Denmark, Municipality of Odense, the Danish Council for Strategic Research, Program Commission on Health, Food and Welfare (2101-08-0058), Odense University Hospital Research Foundation and Odense Patient data Exploratory Network (OPEN). The authors declare they have no competing interests. Not applicable.


Sexual Dimorphism and Retinal Mosaic Diversification following the Evolution of a Violet Receptor in Butterflies.
Numerous animal lineages have expanded and diversified the opsin-based photoreceptors in their eyes underlying color vision behavior. However, the selective pressures giving rise to new photoreceptors and their spectral tuning remain mostly obscure. Previously, we identified a violet receptor (UV2) that is the result of a UV opsin gene duplication specific to Heliconius butterflies. At the same time the violet receptor evolved, Heliconius evolved UV-yellow coloration on their wings, due to the pigment 3-hydroxykynurenine (3-OHK) and the nanostructure architecture of the scale cells. In order to better understand the selective pressures giving rise to the violet receptor, we characterized opsin expression patterns using immunostaining (14 species) and RNA-Seq (18 species), and reconstructed evolutionary histories of visual traits in five major lineages within Heliconius and one species from the genus Eueides. Opsin expression patterns are hyperdiverse within Heliconius. We identified six unique retinal mosaics and three distinct forms of sexual dimorphism based on ommatidial types within the genus Heliconius. Additionally, phylogenetic analysis revealed independent losses of opsin expression, pseudogenization events, and relaxation of selection on UVRh2 in one lineage. Despite this diversity, the newly evolved violet receptor is retained across most species and sexes surveyed. Discriminability modeling of behaviorally preferred 3-OHK yellow wing coloration suggests that the violet receptor may facilitate Heliconius color vision in the context of conspecific recognition. Our observations give insights into the selective pressures underlying the origins of new visual receptors.


IL-17 receptor adaptor protein Act1/CIKS plays an evolutionarily conserved role in antiviral signaling.
Double-stranded RNA-induced antiviral gene expression in mammalian cells requires activation of IFN regulatory factor 3 (IRF3). In this study, we show that the IL-17R adaptor protein Act1/CIKS is involved in this process. Small interfering RNA-mediated knockdown of Act1 in primary human skin fibroblasts specifically attenuates expression of IFN-β and IFN-stimulated antiviral genes induced by a synthetic viral mimic, polyinosinic-polycytidylic acid. Ectopic expression of Act1 potentiates the IRF3-driven expression of a synthetic reporter construct as well as the induction of antiviral genes. We demonstrate that this effect is dependent on the ability of Act1 to functionally and physically interact with IκB kinase ε (IKKε), a known IRF3 kinase, and IRF3: 1) Act1 binds IKKε and IRF3; 2) Act1-induced IRF3 activation can be blocked specifically by coexpression of a catalytically inactive mutant of IKKε; and 3) mutants of IRF3, either lacking the C terminus or mutated at the key phosphorylation sites, important for its activation by IKKε, do not support Act1-dependent IRF3 activation. We also show that a zebrafish Act1 protein is able to trigger antiviral gene expression in human cells, which suggests an evolutionarily conserved function of vertebrate Act1 in the host defense against viruses. On the whole, our study demonstrates that Act1 is a component of antiviral signaling.


DNA methylation changes elicited by social stimuli in the brains of worker honey bees.
Social environments are notoriously multifactorial, yet studies in rodents have suggested that single variables such as maternal care can in fact be disentangled and correlated with specific DNA methylation changes. This study assesses whether non-detrimental social environmental variation in a highly plastic social insect is correlated with epigenomic modifications at the DNA methylation level. Honey bee workers perform tasks such as nursing and foraging in response to the social environment in the hive, in an age-linked but not age-dependent manner. In this study, the methylation levels of 83 cytosine-phosphate-guanosine dinucleotides over eight genomic regions were compared between the brains of age-matched bees performing nursing or foraging tasks. The results reveal more changes correlated with task than with chronological age, and also hive-associated methylation at some sites. One methylation site from a gene encoding Protein Kinase C binding protein 1 was consistently more methylated in foragers than nurses, which is suggested to lead to production of task-specific protein isoforms via alternative splicing. This study illustrates the ability of the neural epigenome to dynamically respond to complex social stimuli.


Carcinogenesis in MYH-associated polyposis follows a distinct genetic pathway.
Colorectal carcinomas develop according to particular genetic pathways, including the chromosomal instability (CIN+), microsatellite instability (MSI+) and MSI- CIN- routes. We have determined the genetic pathway in patients with MYH-associated polyposis (MAP), a syndrome of colorectal adenomas and cancer that results from defective base excision repair (BER). As in previous studies, MAP tumors showed a high frequency of G>T mutations in APC, in accordance with defective BER. We found that K-ras mutations were common in MAP tumors, all of the changes comprising conversion of the first guanine residue of codon 12 to thymidine (G12C, GGT>TGT). We found no BRAF mutations at the codon 599 hotspot or elsewhere in exon 14. Almost all of the MAP cancers were near-diploid (CIN-), and none was MSI+. A few p53 mutations were found, but these were not predominantly G>T changes. p53 overexpression was, however, frequent. No SMAD4 or TGFBIIR mutations were found. MAP tumors appear to follow a distinct genetic pathway, with some features of both the CIN and MSI pathways. BER deficiency is rarely accompanied by CIN or MSI. The spectrum of somatic mutations in MAP tumors reflects both selection and hypermutation to which certain guanine residues are particularly prone.


School and neighborhood characteristics associated with school rates of alcohol, cigarette, and marijuana use.
Previous research has noted that schools vary in substance use prevalence rates, but explanations for school differences have received little empirical attention. We assess variability across elementary schools (N = 36) in rates of early adolescent alcohol, cigarette, and marijuana use. Characteristics of neighborhoods and schools potentially related to school prevalence rates are examined, as well as whether these characteristics have independent effects or whether neighborhood characteristics are mediated by school characteristics. Neighborhood and school characteristics were measured using student, parent, and archival data. The findings show substantial variation across schools in substance use. Attributes of neighborhoods and schools are statistically significantly related to school rates of lifetime alcohol use, lifetime cigarette use, and current cigarette use. Contrary to expectations, lifetime alcohol and cigarette use rates are higher in schools located in neighborhoods having greater social advantages as indicated by the perceptions of residents and archival data. Neighborhood effects are expressed both directly and indirectly through school characteristics. The findings are discussed in light of contagion and social disorganization theories.


Characterization of neural activity recorded from the descending tracts of the rat spinal cord.
A multi-electrode array (MEA) was implanted in the dorsolateral funiculus of the cervical spinal cord to record descending information during behavior in freely moving rats. Neural signals were characterized in terms of frequency and information content. Frequency analysis revealed components both at the range of local field potentials and multi-unit activity. Coherence between channels decreased steadily with inter-contact distance and frequency suggesting greater spatial selectivity for multi-unit activity compared to local field potentials. Principal component analysis (PCA) extracted multiple channels of neural activity with patterns that correlated to the behavior, indicating multiple dimensionality of the signals. Two different behaviors involving the forelimbs, face cleaning and food reaching, generated neural signals through distinctly different combination of neural channels, which suggested that these two behaviors could readily be differentiated from recordings. This preliminary data demonstrated that descending spinal cord signals recorded with MEAs can be used to extract multiple channels of command control information and potentially be utilized as a means of communication in high level spinal cord injury subjects.


Clinicoetiological Pattern and Outcome of Neonates Requiring Mechanical Ventilation: Study in a Tertiary Care Centre.
The clinical and etiological pattern of ventilated newborns, their outcome in relation to morbidity and mortality was studied with 50 ventilated newborns, including outborns. M:f ratio was 2.1:1. The most common gestational age 28-36 weeks (60%) and mostly were appropriate for gestational age (66%). Survival rate 40% (20/50) being directly proportional to the gestational age and intrauterine growth pattern (P < 0.01). Babies by LSCS Lower Segment Cessarian Section survived more than born by normal vaginal delivery (46.7% vs. 37.1%). More outborn survival could be related to their advanced gestational age on presentation. The initial assessment of APGAR score of >7 had a better outcome (56.3%; P < 0.03). The most common indication of ventilation was hyaline membrane disease (19/50) but the survival rate best in babies with meconium aspiration syndrome (54.5%). The most prevalent complication was sepsis (survival rate 60%) while conditions such as shock, intraventricular hemorrhage, disseminated intravascular coagulation, air leak syndrome, and pulmonary hemorrhage had 100% mortality. Thus, the outcome as survival is constrained by many factors; newborn's profile, conditions at birth, and postnatal resuscitation.


Domain Movements upon Activation of Phenylalanine Hydroxylase Characterized by Crystallography and Chromatography-Coupled Small-Angle X-ray Scattering.
Mammalian phenylalanine hydroxylase (PheH) is an allosteric enzyme that catalyzes the first step in the catabolism of the amino acid phenylalanine. Following allosteric activation by high phenylalanine levels, the enzyme catalyzes the pterin-dependent conversion of phenylalanine to tyrosine. Inability to control elevated phenylalanine levels in the blood leads to increased risk of mental disabilities commonly associated with the inherited metabolic disorder, phenylketonuria. Although extensively studied, structural changes associated with allosteric activation in mammalian PheH have been elusive. Here, we examine the complex allosteric mechanisms of rat PheH using X-ray crystallography, isothermal titration calorimetry (ITC), and small-angle X-ray scattering (SAXS). We describe crystal structures of the preactivated state of the PheH tetramer depicting the regulatory domains docked against the catalytic domains and preventing substrate binding. Using SAXS, we further describe the domain movements involved in allosteric activation of PheH in solution and present the first demonstration of chromatography-coupled SAXS with Evolving Factor Analysis (EFA), a powerful method for separating scattering components in a model-independent way. Together, these results support a model for allostery in PheH in which phenylalanine stabilizes the dimerization of the regulatory domains and exposes the active site for substrate binding and other structural changes needed for activity.


Management of alcoholic hepatitis: Current concepts.
Alcoholic hepatitis is a devastating form of acute liver injury seen in chronic alcohol abusers with significant morbidity and mortality. It is a multisystem disease that is precipitated by ingesting large quantities of alcohol with genetic and environmental factors playing a role. Prognostic criteria have been developed to predict disease severity and these criteria can serve as indicators to initiate medical therapy. Primary therapy remains abstinence and supportive care, as continued alcohol abuse is the most important risk factor for disease progression. The cornerstone of supportive care remains aggressive nutritional support, and although acute alcoholic hepatitis has been extensively studied, few specific medical therapies have been successful. Corticosteroids remain the most effective medical therapy available in improving short term survival in a select group of patients with alcoholic hepatitis; however, the long-term outcome of drug therapies is still not entirely clear and further clinical investigation is necessary. While liver transplantation for acute alcoholic hepatitis have demonstrated promising results, this practice remains controversial and has not been advocated universally, with most transplant centers requiring a prolonged period of abstinence before considering transplantation. Extracorporeal liver support devices, although still experimental, have been developed as a form of liver support to give additional time for liver regeneration. These have the potential for a significant therapeutic option in the future for this unfortunately dreadful disease.


Few-Wall Carbon Nanotube Coils.
While various electronic components based on carbon nanotubes (CNTs) have already been demonstrated, the realization of miniature electromagnetic coils based on CNTs remains a challenge. Coils made of single-wall CNTs with accessible ends for contacting have been recently demonstrated but were found unsuitable to act as electromagnetic coils because of electrical shorting between their turns. Coils made of a few-wall CNT could in principle allow an insulated flow of current and thus be potential candidates for realizing CNT-based electromagnetic coils. However, no such CNT structure has been produced so far. Here, we demonstrate the formation of few-wall CNT coils and characterize their structural, optical, vibrational, and electrical properties using experimental and computational tools. The coils are made of CNTs with 2, 3, or 4 walls. They have accessible ends for electrical contacts and low defect densities. The coil diameters are on the order of one micron, like those of single-wall CNT coils, despite the higher rigidity of few-wall CNTs. Coils with as many as 163 turns were found, with their turns organized in a rippled raft configuration. These coils are promising candidates for a variety of miniature devices based on electromagnetic coils, such as electromagnets, inductors, transformers, and motors. Being chirally and enantiomerically pure few-wall CNT bundles, they are also ideal for fundamental studies of interwall coupling and superconductivity in CNTs.


Computed tomography-guided percutaneous needle biopsy of indeterminate pulmonary pathology: efficacy of obtaining a diagnostic sample in immunocompetent and immunocompromised patients.
We aimed to evaluate the efficacy of computed tomography (CT)-guided percutaneous lung biopsy of pulmonary nodules with indeterminate radiologic characteristics in patients at risk for malignant and nonmalignant processes such as infection or inflammation. From January 2003 to September 2008, 262 patients (mean age, 59 years; range, 18-92 years) with pulmonary nodules or a mass of uncertain etiology and with indeterminate radiologic characteristics underwent CT-guided percutaneous lung biopsy. Patients with discordant clinical history and imaging findings or immunocompromised patients at risk for both etiologies were included. Specimens were submitted for both cytology and microbiology. Of the entire cohort, 166 patients (63.4%) had a nonmalignant process, and 96 patients (36.6%) had a malignancy. CT-guided percutaneous lung biopsy established a diagnosis in 166 patients (63.4%). Of the 166 patients with a nonmalignant etiology and 96 patients with malignancy, it provided a definitive diagnosis in 91 patients (54.8%) and 75 patients (78.1%), respectively, a difference that was statistically significant (P = .0001). Overall diagnostic efficacy between immunocompetent and immunocompromised patients was comparable (P = .2); however, detection of infection or inflammation in individual groups was lower compared with detection of malignancy (P = .002 and P = .06, respectively). CT-guided percutaneous lung biopsy in patients who are clinically at risk for both nonmalignant and malignant processes continues to be a challenge. Although CT-guided percutaneous biopsy can establish an accurate diagnosis in a large majority of patients with malignancy, it is significantly less sensitive for infectious or inflammatory processes.


[Decline and social inequalities of infant mortality caused by diarrhea].
This ecological study describes the temporal trend from 1977 to 1998, and spatial patterns of infant mortality from diarrhea in the city of Salvador, Bahia State, Brazil. The annual proportional of infant mortality and specific-cause mortality rate were estimated. Spatial units of geographical zones within the city's urban area were utilized for administrative purposes, which were aggregated according to quartile of living conditions indicators. Over the study period, the diarrhea-induced infant mortality rate decreased 91.9%. The mortality risk from diarrhea in the lowest living condition strata was 90% greater than in the highest conditions. Also, infant mortality due to diarrhea increases proportionally as living conditions worsen, which necessitates a review of the control policies concerning this important public health problem. Although the infant mortality rate declined during the study period, social inequalities related to infant mortality due to diarrhea persist, reflecting a continuing poor social development.


A functional lesion in developmental dyslexia: left angular gyral blood flow predicts severity.
Functional imaging studies have shown reduced regional cerebral blood flow (rCBF) in temporal and inferior parietal regions in dyslexia. To relate such abnormalities to the severity of dyslexia, correlations between reading skill and rCBF during a series of reading tasks and visual fixation were mapped for 17 right-handed dyslexic men, ages 18-40, and 14 matched controls. These correlations uniquely identified the left angular gyrus as the most probable site of a functional lesion in dyslexia: Here, higher rCBF was associated with better reading skill in controls (p <.01), but with worse reading skill in dyslexia (p <.01). This suggests that greater reliance on this region normally facilitates reading, but impairs reading in dyslexia. Thus, developmental dyslexia may share a common localization with alexia.


GATA6 activates Wnt signaling in pancreatic cancer by negatively regulating the Wnt antagonist Dickkopf-1.
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease characterized by late diagnosis and treatment resistance. Recurrent genetic alterations in defined genes in association with perturbations of developmental cell signaling pathways have been associated with PDAC development and progression. Here, we show that GATA6 contributes to pancreatic carcinogenesis during the temporal progression of pancreatic intraepithelial neoplasia by virtue of Wnt pathway activation. GATA6 is recurrently amplified by both quantitative-PCR and fluorescent in-situ hybridization in human pancreatic intraepithelial neoplasia and in PDAC tissues, and GATA6 copy number is significantly correlated with overall patient survival. Forced overexpression of GATA6 in cancer cell lines enhanced cell proliferation and colony formation in soft agar in vitro and growth in vivo, as well as increased Wnt signaling. By contrast siRNA mediated knockdown of GATA6 led to corresponding decreases in these same parameters. The effects of GATA6 were found to be due to its ability to bind DNA, as forced overexpression of a DNA-binding mutant of GATA6 had no effects on cell growth in vitro or in vivo, nor did they affect Wnt signaling levels in these same cells. A microarray analysis revealed the Wnt antagonist Dickopf-1 (DKK1) as a dysregulated gene in association with GATA6 knockdown, and direct binding of GATA6 to the DKK1 promoter was confirmed by chromatin immunoprecipitation and electrophoretic mobility shift assays. Transient transfection of GATA6, but not mutant GATA6, into cancer cell lines led to decreased DKK1 mRNA expression and secretion of DKK1 protein into culture media. Forced overexpression of DKK1 antagonized the effects of GATA6 on Wnt signaling in pancreatic cancer cells. These findings illustrate that one mechanism by which GATA6 promotes pancreatic carcinogenesis is by virtue of its activation of canonical Wnt signaling via regulation of DKK1.


Gas chromatography on self-assembled, single-walled carbon nanotubes.
High-performance stationary phases, which provide high resolutions and are stable at high temperatures, are of significant importance in gas chromatographic analysis. Carbon nanotubes are nanosized carbon-based sorbents that have a high surface area and a large aspect ratio and are known to be stable at high temperatures. It is, therefore, conceivable that gas chromatography can benefit from their unique properties. This paper reports gas chromatography separations in an open tubular format on self-assembled, single-walled carbon nanotubes (SWNTs) inside silica-lined steel capillary tubing. A SWNT film with an average thickness of 300 nm was self-assembled by a unique, single-step, catalytic chemical vapor deposition (CVD) process consisting of dissolved cobalt and molybdenum salts in ethanol. A variety of organic compounds with varying polarity were separated at high resolution, and the column efficiency demonstrated approximately 1000 theoretical plates/m. Comparison of capacity factors' and isosteric heats of adsorption with a packed column containing a commercial sorbent (Carbopack C) showed comparable results. This demonstrated high capacity and strong sorbate-sorbent interactions on the SWNT phase. Evaluation of the McReynolds constants suggested that the SWNT was a nonpolar phase.


The fully-active and structurally-stable form of the mitochondrial ATP synthase of Polytomella sp. is dimeric.
Mitochondrial F(1)F(O)-ATP synthase of chlorophycean algae is a stable dimeric complex of 1,600 kDa. It lacks the classic subunits that constitute the peripheral stator-stalk and the orthodox polypeptides involved in the dimerization of the complex. Instead, it contains nine polypeptides of unknown evolutionary origin named ASA1 to ASA9. The isolated enzyme exhibited a very low ATPase activity (0.03 Units/mg), that increased upon heat treatment, due to the release of the F(1) sector. Oligomycin was found to stabilize the dimeric structure of the enzyme, providing partial resistance to heat dissociation. Incubation in the presence of low concentrations of several non-ionic detergents increased the oligomycin-sensitive ATPase activity up to 7.0-9.0 Units/mg. Incubation with 3% (w/v) taurodeoxycholate monomerized the enzyme. The monomeric form of the enzyme exhibited diminished activity in the presence of detergents and diminished oligomycin sensitivity. Cross-linking experiments carried out with the dimeric and monomeric forms of the ATP synthase suggested the participation of the ASA6 subunit in the dimerization of the enzyme. The dimeric enzyme was more resistant to heat treatment, high hydrostatic pressures, and protease digestion than the monomeric enzyme, which was readily disrupted by these treatments. We conclude that the fully-active algal mitochondrial ATP synthase is a stable catalytically active dimer; the monomeric form is less active and less stable. Monomer-monomer interactions could be mediated by the membrane-bound subunits ASA6 and ASA9, and may be further stabilized by other polypeptides such as ASA1 and ASA5.


On the activation mechanism of store-operated calcium channels.
The development of the patch clamp technique has revolutionised our understanding of the life sciences. One area in which it has made an enormous contribution is cellular signalling. In many cell types, calcium influx across the plasma membrane is essential for the regulation of a wide range of critical physiological responses including secretion, gene transcription and cell growth. For many years the calcium influx pathways in non-excitable cells remained unknown, despite their importance in physiological and pathophysiological states. Very careful and insightful work by James Putney led to the formulation of the capacitative calcium entry (store-operated calcium influx) model, in which the process of emptying intracellular calcium stores resulted in the activation of calcium entry channels. Unequivocal evidence for this revolutionary model was provided by patch clamp studies carried out by Markus Hoth and Reinhold Penner, who demonstrated that store depletion activated a novel class of calcium channel called the CRAC channel. This review provides a historical perspective on the development of store-operated calcium influx and how patch clamping resolved a long-standing controversy in cell physiology. The review also discusses current ideas relating to how store emptying opens channels in the plasma membrane.


The first GCC Marine Biotechnology Symposium: Emerging Opportunities and Future Perspectives.
With its diverse, living marine resources and rapidly growing educational and research infrastructure, the Sultanate of Oman is well-positioned to take advantage of the commercial opportunities presented by marine biotechnology. In recognition of potential development, an international symposium, Marine Biotechnology-Emerging Opportunities and Future Perspectives, was held in Muscat, November 12-13, 2013. Three keynote addresses were given, 23 oral presentations made, and a poster exhibition held. The final session reviewed national and regional issues, and the delegates agreed informally on a number of future actions. The potential for future development of marine biotechnology was recognized by all delegates, and following the symposium, they were surveyed for their views on how best to sustain and develop new activities. One hundred percent of respondents found the meeting useful and would support future symposia in the region. Fifty-one percent of Omani respondents recognized major organizational challenges and obstacles to the development of marine biotechnology compared with 23 % of overseas respondents. The need for greater collaboration between research institutions within the GCC region was recognized by 98 % of all respondents. The presentations and survey outcomes are reviewed in this paper.


Fetching felines: a survey of cat owners on the diversity of cat (Felis catus) fetching behaviour.
Domesticated animals are famous for the ease with which they can accommodate to diverse human environments and roles, but less well-studied is the ease with which domestic animals can manipulate their human caregivers to their own ends. For example, domestic animals may start and end their play behaviour with humans at times of their choice. Here we present the results of a survey of 924 cat owners who report fetching behaviour in 1154 cats. The overwhelming majority (94.4%) of these owners report that fetching emerged in the absence of explicit training. Fetching was primarily first noticed when the cats were less than one year old (n = 701) or 1-7 years old (n = 415). Cats initiated and terminated fetching bouts more often than did their owners. Thus, cats who fetch demonstrate independent and co-ordinated agency in the onset and maintenance of fetching behaviour with their human partners. Additional findings highlight the diversity of objects fetched and the diversity in household demographics. Our thematic analysis reveals owners' perspectives on (a) the process of a fetching session, (b) the initial acquisition of fetching, and (c) the circumstantial factors that influence fetching patterns. In summary, cats who fetch largely determine when they engage in fetching sessions and actively influence the play behaviour of their owners.


Plasma proteome profiles associated with inflammation, angiogenesis, and cancer.
Tumor development is accompanied by a complex host systemic response, which includes inflammatory and angiogenic reactions. Both tumor-derived and systemic response proteins are detected in plasma from cancer patients. However, given their non-specific nature, systemic response proteins can confound the detection or diagnosis of neoplasia. Here, we have applied an in-depth quantitative proteomic approach to analyze plasma protein changes in mouse models of subacute irritant-driven inflammation, autoreactive inflammation, and matrix associated angiogenesis and compared results to previously described findings from mouse models of polyoma middle T-driven breast cancer and Pdx1-Cre Kras(G12D) Ink4a/Arf (lox/lox)-induced pancreatic cancer. Among the confounding models, approximately 1/3 of all quantified plasma proteins exhibited a significant change in abundance compared to control mice. Of the proteins that changed in abundance, the majority were unique to each model. Altered proteins included those involved in acute phase response, inflammation, extracellular matrix remodeling, angiogenesis, and TGFβ signaling. Comparison of changes in plasma proteins between the confounder models and the two cancer models revealed proteins that were restricted to the cancer-bearing mice, reflecting the known biology of these tumors. This approach provides a basis for distinguishing between protein changes in plasma that are cancer-related and those that are part of a non-specific host response.


Multidrug Resistance Acinetobacter Bacteremia Secondary to Ventilator-Associated Pneumonia: Risk Factors and Outcome.
Acinetobacter baumannii is a multidrug resistant (MDR), gram-negative bacterium commonly implicated in ventilator-associated pneumonia (VAP) in critically ill patients. Patients in the intensive care unit (ICU) with VAP often subsequently develop A baumannii bacteremia, which may significantly worsen outcomes. In this study, we retrospectively reviewed the clinical and laboratory records of 129 ICU patients spanning 6 years with MDR A baumannii VAP; 46 (35%) of these patients had concomitant MDR A baumannii bacteremia. The ICU mortality rate was higher in patients with VAP having A baumannii bacteremia compared to nonbacteremic patients (32.4% vs 9.6% respectively, P < .005). Age >65 years, an Acute Physiology and Chronic Health Evaluation II (APACHE-II) score higher than 20, a Sequential Organ Failure Assessment (SOFA) score higher than 7 on the day of bacteremia, and the presence of comorbid disease (chronic obstructive pulmonary disease [COPD] and chronic renal failure) were found to be independent risk factors for in-hospital mortality in this population. Multidrug resistant A baumannii was not an independent risk factor for mortality. Although the presence of comorbid diseases (COPD and chronic renal failure) and severity of disease (APACHE > 20 and SOFA >7) were found to be independent risk factors for ICU mortality, MDR A baumannii bacteremia was not an independent risk factor for mortality in our critically ill population.


Expression and activation of mitogen-activated protein kinases in the optic nerve head in a rat model of ocular hypertension.
Glaucoma is a leading cause of irreversible blindness manifesting as an age-related, progressive optic neuropathy with associated retinal ganglion cell (RGC) loss. Mitogen-activated protein kinases (MAPKs: p42/44 MAPK, SAPK/JNK, p38 MAPK) are activated in various retinal disease models and likely contribute to the mechanisms of RGC death. Although MAPKs play roles in the development of retinal pathology, their action in the optic nerve head (ONH), where the initial insult to RGC axons likely resides in glaucoma, remains unexplored. An experimental paradigm representing glaucoma was established by induction of chronic ocular hypertension (OHT) via laser-induced coagulation of the trabecular meshwork in Sprague-Dawley rats. MAPKs were subsequently investigated over the following days for expression and activity alterations, using RT-PCR, immunohistochemistry and Western immunoblot. p42/44 MAPK expression was unaltered after intraocular pressure (IOP) elevation, but there was a significant activation of this enzyme in ONH astrocytes after 6-24 h. Activated SAPK/JNK isoforms were present throughout healthy RGC axons but after IOP elevation or optic nerve crush, they both accumulated at the ONH, likely due to RGC axon transport disruption, and were subject to additional activation. p38 MAPK was expressed by a population of microglia which were significantly more populous following IOP elevation. However it was only significantly activated in microglia after 3 days, and then only in the ONH and optic nerve; in the retina it was solely activated in RGC perikarya. In conclusion, each of the MAPKs showed a specific spatio-temporal expression and activation pattern in the retina, ONH and optic nerve as a result of IOP elevation. These findings likely reflect the roles of the individual enzymes, and the cells in which they reside, in the developing pathology following IOP elevation. These data have implications for understanding the mechanisms of ocular pathology in diseases such as glaucoma.


ABCB5 maintains melanoma-initiating cells through a proinflammatory cytokine signaling circuit.
The drug efflux transporter ABCB5 identifies cancer stem-like cells (CSC) in diverse human malignancies, where its expression is associated with clinical disease progression and tumor recurrence. ABCB5 confers therapeutic resistance, but other functions in tumorigenesis independent of drug efflux have not been described that might help explain why it is so broadly overexpressed in human cancer. Here we show that in melanoma-initiating cells, ABCB5 controls IL1β secretion, which serves to maintain slow cycling, chemoresistant cells through an IL1β/IL8/CXCR1 cytokine signaling circuit. This CSC maintenance circuit involved reciprocal paracrine interactions with ABCB5-negative cancer cell populations. ABCB5 blockade induced cellular differentiation, reversed resistance to multiple chemotherapeutic agents, and impaired tumor growth in vivo. Together, our results defined a novel function for ABCB5 in CSC maintenance and tumor growth.


Association between multiple sclerosis and epilepsy: large population-based record-linkage studies.
Multiple sclerosis (MS) and epilepsy are both fairly common and it follows that they may sometimes occur together in the same people by chance. We sought to determine whether hospitalisation for MS and hospitalisation for epilepsy occur together more often than expected by chance alone. We analysed two datasets of linked statistical hospital admission records covering the Oxford Record Linkage Study area (ORLS, 1963-1998) and all England (1999-2011). In each, we calculated the rate of occurrence of hospital admission for epilepsy in people after admission for MS, compared with equivalent rates in a control cohort, and expressed the results as a relative risk (RR). The RR for hospital admission for epilepsy following an admission for MS was significantly high at 4.1 (95% confidence interval 3.1-5.3) in the ORLS and 3.3 (95% CI 3.1-3.4) in the all-England cohort. The RR for a first recorded admission for epilepsy 10 years and more after first recorded admission for MS was 4.7 (2.8-7.3) in ORLS and 3.9 (3.1-4.9) in the national cohort. The RR for the converse-MS following hospitalisation for epilepsy-was 2.5 (95% CI 1.7-3.5) in the ORLS and 1.9 (95% CI 1.8-2.1) in the English dataset. MS and epilepsy occur together more commonly than by chance. One possible explanation is that an MS lesion acts as a focus of an epileptic seizure; but other possibilities are discussed. Clinicians should be aware of the risk of epilepsy in people with MS. The findings may also suggest clues for researchers in developing hypotheses about underlying mechanisms for the two conditions.


Daily intake of antioxidants in relation to survival among adult patients diagnosed with malignant glioma.
Malignant glioma is a rare cancer with poor survival. The influence of diet and antioxidant intake on glioma survival is not well understood. The current study examines the association between antioxidant intake and survival after glioma diagnosis. Adult patients diagnosed with malignant glioma during 1991-1994 and 1997-2001 were enrolled in a population-based study. Diagnosis was confirmed by review of pathology specimens. A modified food-frequency questionnaire interview was completed by each glioma patient or a designated proxy. Intake of each food item was converted to grams consumed/day. From this nutrient database, 16 antioxidants, calcium, a total antioxidant index and 3 macronutrients were available for survival analysis. Cox regression estimated mortality hazard ratios associated with each nutrient and the antioxidant index adjusting for potential confounders. Nutrient values were categorized into tertiles. Models were stratified by histology (Grades II, III, and IV) and conducted for all (including proxy) subjects and for a subset of self-reported subjects. Geometric mean values for 11 fat-soluble and 6 water-soluble individual antioxidants, antioxidant index and 3 macronutrients were virtually the same when comparing all cases (n=748) to self-reported cases only (n=450). For patients diagnosed with Grade II and Grade III histology, moderate (915.8-2118.3 mcg) intake of fat-soluble lycopene was associated with poorer survival when compared to low intake (0.0-914.8 mcg), for self-reported cases only. High intake of vitamin E and moderate/high intake of secoisolariciresinol among Grade III patients indicated greater survival for all cases. In Grade IV patients, moderate/high intake of cryptoxanthin and high intake of secoisolariciresinol were associated with poorer survival among all cases. Among Grade II patients, moderate intake of water-soluble folate was associated with greater survival for all cases; high intake of vitamin C and genistein and the highest level of the antioxidant index were associated with poorer survival for all cases. The associations observed in our study suggest that the influence of some antioxidants on survival following a diagnosis of malignant glioma are inconsistent and vary by histology group. Further research in a large sample of glioma patients is needed to confirm/refute our results.


MAFA missense mutation causes familial insulinomatosis and diabetes mellitus.
The β-cell-enriched MAFA transcription factor plays a central role in regulating glucose-stimulated insulin secretion while also demonstrating oncogenic transformation potential in vitro. No disease-causing MAFA variants have been previously described. We investigated a large pedigree with autosomal dominant inheritance of diabetes mellitus or insulinomatosis, an adult-onset condition of recurrent hyperinsulinemic hypoglycemia caused by multiple insulin-secreting neuroendocrine tumors of the pancreas. Using exome sequencing, we identified a missense MAFA mutation (p.Ser64Phe, c.191C>T) segregating with both phenotypes of insulinomatosis and diabetes. This mutation was also found in a second unrelated family with the same clinical phenotype, while no germline or somatic MAFA mutations were identified in nine patients with sporadic insulinomatosis. In the two families, insulinomatosis presented more frequently in females (eight females/two males) and diabetes more often in males (12 males/four females). Four patients from the index family, including two homozygotes, had a history of congenital cataract and/or glaucoma. The p.Ser64Phe mutation was found to impair phosphorylation within the transactivation domain of MAFA and profoundly increased MAFA protein stability under both high and low glucose concentrations in β-cell lines. In addition, the transactivation potential of p.Ser64Phe MAFA in β-cell lines was enhanced compared with wild-type MAFA. In summary, the p.Ser64Phe missense MAFA mutation leads to familial insulinomatosis or diabetes by impacting MAFA protein stability and transactivation ability. The human phenotypes associated with the p.Ser64Phe MAFA missense mutation reflect both the oncogenic capacity of MAFA and its key role in islet β-cell activity.


Targeted linkage map densification to improve cell wall related QTL detection and interpretation in maize.
Several QTLs for cell wall degradability and lignin content were previously detected in the F288 × F271 maize RIL progeny, including a set of major QTLs located in bin 6.06. Unexpectedly, allelic sequencing of genes located around the bin 6.06 QTL positions revealed a monomorphous region, suggesting that these QTLs were likely "ghost" QTLs. Refining the positions of all QTLs detected in this population was thus considered, based on a linkage map densification in most important QTL regions, and in several large still unmarked regions. Re-analysis of data with an improved genetic map (173 markers instead of 108) showed that ghost QTLs located in bin 6.06 were then fractionated over two QTL positions located upstream and downstream of the monomorphic region. The area located upstream of bin 6.06 position carried the major QTLs, which explained from 37 to 59 % of the phenotypic variation for per se values and extended on only 6 cM, corresponding to a physical distance of 2.2 Mbp. Among the 92 genes present in the corresponding area of the B73 maize reference genome, nine could putatively be considered as involved in the formation of the secondary cell wall [bHLH, FKBP, laccase, fasciclin, zinc finger C2H2-type and C3HC4-type (two genes), NF-YB, and WRKY]. In addition, based on the currently improved genetic map, eight QTLs were detected in bin 4.09, while only one QTL was highlighted in the initial investigation. Moreover, significant epistatic interaction effects were shown for all traits between these QTLs located in bin 4.09 and the major QTLs located in bin 6.05. Three genes related to secondary cell wall assembly (ZmMYB42, COV1-like, PAL-like) underlay QTL support intervals in this newly identified bin 4.09 region. The current investigations, even if they were based only on one RIL progeny, illustrated the interest of a targeted marker mapping on a genetic map to improve QTL position.


Heart Failure Association, Heart Failure Society of America, and Japanese Heart Failure Society Position Statement on Endomyocardial Biopsy.
Endomyocardial biopsy (EMB) is an invasive procedure, globally most often used for the monitoring of heart transplant rejection. In addition, EMB can have an important complementary role to the clinical assessment in establishing the diagnosis of diverse cardiac disorders, including myocarditis, cardiomyopathies, drug-related cardiotoxicity, amyloidosis, other infiltrative and storage disorders, and cardiac tumors. Improvements in EMB equipment and the development of new techniques for the analysis of EMB samples has significantly improved the diagnostic precision of EMB. The present document is the result of the Trilateral Cooperation Project between the Heart Failure Association of the European Society of Cardiology, Heart Failure Society of America, and the Japanese Heart Failure Society. It represents an expert consensus aiming to provide a comprehensive, up-to-date perspective on EMB, with a focus on the following main issues: (1) an overview of the practical approach to EMB, (2) an update on indications for EMB, (3) a revised plan for heart transplant rejection surveillance, (4) the impact of multimodality imaging on EMB, and (5) the current clinical practice in the worldwide use of EMB.