A T-lymphoma transmembrane glycoprotein (gp180) is linked to the cytoskeletal protein, fodrin.
A major mouse T-lymphoma surface glycoprotein (gp180) has been identified by labeling cells with 125I and [3H]glucosamine. After ligand-induced receptor patching and/or capping, the amount of gp 180 in the membrane-associated cytoskeleton fraction increases in direct proportion to the percentage of patched/capped cells. There is a parallel increase in the amount of fodrin in the membrane-associated cytoskeleton fraction. Evidence is presented that gp180 is the same as or very similar to the T-lymphocyte-specific glycoprotein T-200. An immunobinding assay of Nonidet P-40-solubilized plasma membrane selectively co-isolates gp180 and fodrin. After induction of receptor rearrangement, double-label immunofluorescence reveals that fodrin accumulated directly beneath gp180 patches and caps. Membrane extraction with Triton X-114 followed by sucrose gradient centrifugation permits isolation of a gp180-fodrin complex with a 1:1 molar ratio and sedimentation coefficient(s) of approximately 20. This complex remains stable during isoelectric focusing and exhibits a pl in the range of 5.2-5.7. On the basis of our results we conclude that gp180, an integral membrane glycoprotein, and fodrin, a component of the membrane-associated cytoskeleton, are closely associated into a complex. Furthermore, we contend that, through fodrin's association with actin, this complex is of functional significance in ligand-induced patching and capping of gp180. We also propose that, through lateral interactions in the plane of the membrane, the gp180-fodrin complex might be responsible for linking other surface receptors to the intracellular microfilament network during lymphocyte patching and capping.


Effect of washing hands with soap on diarrhoea risk in the community: a systematic review.
We set out to determine the impact of washing hands with soap on the risk of diarrhoeal diseases in the community with a systematic review with random effects meta-analysis. Our data sources were studies linking handwashing with diarrhoeal diseases. Seven intervention studies, six case-control, two cross-sectional, and two cohort studies were located from electronic databases, hand searching, and the authors' collections. The pooled relative risk of diarrhoeal disease associated with not washing hands from the intervention trials was 1.88 (95% CI 1.31-2.68), implying that handwashing could reduce diarrhoea risk by 47%. When all studies, when only those of high quality, and when only those studies specifically mentioning soap were pooled, risk reduction ranged from 42-44%. The risks of severe intestinal infections and of shigellosis were associated with reductions of 48% and 59%, respectively. In the absence of adequate mortality studies, we extrapolate the potential number of diarrhoea deaths that could be averted by handwashing at about a million (1.1 million, lower estimate 0.5 million, upper estimate 1.4 million). Results may be affected by the poor quality of many of the studies and may be inflated by publication bias. On current evidence, washing hands with soap can reduce the risk of diarrhoeal diseases by 42-47% and interventions to promote handwashing might save a million lives. More and better-designed trials are needed to measure the impact of washing hands on diarrhoea and acute respiratory infections in developing countries.


Depression and risk of incident asthma in adults. The CARDIA study.
Asthma is associated with depression, but the temporality of the association has not been established. To examine the association between prevalent elevated depressive symptoms and incident asthma, and between prevalent asthma and incident elevated depressive symptoms in a cohort of young and middle-aged adults. We examined the longitudinal association between asthma and depressive symptoms bidirectionally in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. First, 3,614 participants, free of asthma, were classified by elevated depressive symptoms at the CARDIA Year-5 exam (n = 856 elevated vs. 2,758 not elevated; ages 23-35 yr) and followed for 20 years to incident asthma. Then, 3,016 participants, free of elevated depressive symptoms, were classified by self-reported current asthma status (n = 188 prevalent vs. 2,828 not prevalent) at the CARDIA Year-5 exam and followed for 20 years until onset of elevated depressive symptoms. The relative hazard of incident asthma among those with elevated depressive symptoms was 1.26 (95% confidence interval [CI] = 1.02-1.56) after adjustment for covariates. When depressive status was modeled as the total number of reports of elevated depressive symptoms before the onset of asthma, the adjusted hazard ratio was 1.15 (95% CI = 1.02-1.29). The hazard of incident elevated depressive symptoms for those with asthma was no different than the hazard in those without asthma (adjusted hazard ratio = 0.92; 95% CI = 0.70-1.20). This longitudinal observational study points to depression as a marker of risk for incident adult-onset asthma. On the other hand, prevalent asthma is not associated with incident adult-onset depression.


Association of low-activity ALDH2 and alcohol consumption with risk of esophageal cancer in Chinese adults: A population-based cohort study.
Existing evidence remains inconclusive as to how the association between inactive ALDH2 and esophageal cancer (EC) depends on alcohol consumption. The study is based on the China Kadoorie Biobank cohort, with 10 years follow-up of 0.5 million adults aged 30-79 years. ALDH2 activity was assessed by both self-reported flushing response and Glu504Lys (rs671 G > A) polymorphism. Among both male and female participants who consumed alcohol less than weekly (n = 69,519; 211 EC cases), low active or inactive ALDH2 was not associated with increased EC risk [HRs (95% CIs): GA vs. GG 0.75 (0.54, 1.04); AA vs. GG 1.01 (0.46, 2.20)]. Among male weekly alcohol consumers, both flushing response [n = 59,380; 501 EC cases; HRs (95% CIs): "soon after drinking" vs. "no" flushing response 1.45 (1.05, 2.01)] and rs671 [n = 10,692; 94 EC cases; GA vs. GG 3.31 (1.94, 5.67)] were associated with EC risk. The increased EC risk associated with "soon" response or rs671 GA was apparent in men consuming alcohol ≥30g/d. Among male daily consumers, the HRs (95% CIs) for EC associated with 15g/d of alcohol were 1.28 (1.15, 1.44) for "soon" response [vs. other responses: 1.12 (1.09, 1.15); pinteraction = 0.047; n = 36,401, 425 EC cases] and 1.41 (1.08, 1.82) for rs671 GA [vs. GG: 1.16 (1.06, 1.27); pinteraction = 0.493; n = 6,607, 80 EC cases]. Self-reported flushing response had low sensitivity (56.8%) and high specificity (88.4%) in identifying rs671 A allele among male weekly alcohol consumers. In conclusion, low-activity ALDH2 was associated with increased EC risk among male heavy alcohol consumers. More accurate measurement of alcohol-related EC risk allows better achievement of precision prevention.


The significance of pork as a source of dietary selenium - an evaluation of the situation in the Czech Republic.
The aim of this paper is to review current knowledge of the significance of pork as a source of Se for human consumption, and to evaluate the selenium content in pork produced in the Czech Republic. Selenium has an important role in human health. Pork could possibly be an important source of Se for the human diet. The Se content in meat can be increased by a higher dietary intake of selenium in animal feed. The magnitude of this increase is higher when organic Se from Se-enriched yeast is ingested. Selenium intoxication in pigs occurs only when very high Se concentrations are used in their diet (more than 5 mg/kg of Se). Organic Se sources produce fewer clinical signs of high toxicity than inorganic sodium selenite. Organic Se does not have a negative effect on meat quality. Altogether, 135 pork samples from 9 different herds in the Czech Republic were collected and analyzed for Se content. The average selenium content found in pork in our study was 87.10 microg/kg. Because the average annual consumption of pork in the Czech Republic is 42.0 kg per person, the annual selenium intake from pork represents 18.2% of the minimum yearly requirement for humans. The results of our study show that pork contributes significantly to the selenium intake of the human population in the Czech Republic.


Genetic variants in DNA repair pathway genes and risk of esophageal squamous cell carcinoma and gastric adenocarcinoma in a Chinese population.
The DNA repair pathways help to maintain genomic integrity and therefore genetic variation in the pathways could affect the propensity to develop cancer. Selected germline single nucleotide polymorphisms (SNPs) in the pathways have been associated with esophageal cancer and gastric cancer (GC) but few studies have comprehensively examined the pathway genes. We aimed to investigate associations between DNA repair pathway genes and risk of esophageal squamous cell carcinoma (ESCC) and GC, using data from a genome-wide association study in a Han Chinese population where ESCC and GC are the predominant cancers. In sum, 1942 ESCC cases, 1758 GC cases and 2111 controls from the Shanxi Upper Gastrointestinal Cancer Genetics Project (discovery set) and the Linxian Nutrition Intervention Trials (replication set) were genotyped for 1675 SNPs in 170 DNA repair-related genes. Logistic regression models were applied to evaluate SNP-level associations. Gene- and pathway-level associations were determined using the resampling-based adaptive rank-truncated product approach. The DNA repair pathways overall were significantly associated with risk of ESCC (P = 6.37 × 10(-4)), but not with GC (P = 0.20). The most significant gene in ESCC was CHEK2 (P = 2.00 × 10(-6)) and in GC was CLK2 (P = 3.02 × 10(-4)). We observed several other genes significantly associated with either ESCC (SMUG1, TDG, TP53, GTF2H3, FEN1, POLQ, HEL308, RAD54B, MPG, FANCE and BRCA1) or GC risk (MRE11A, RAD54L and POLE) (P < 0.05). We provide evidence for an association between specific genes in the DNA repair pathways and the risk of ESCC and GC. Further studies are warranted to validate these associations and to investigate underlying mechanisms.


Force Fields for Molecular Modeling of Sarin and its Simulants: DMMP and DIMP.
Even three decades after signing the Chemical Weapons Convention, organophosphorus chemical warfare agents (CWAs), such as sarin, remain a threat. The development of novel methods for the detection of CWAs, protection from CWAs, and CWA decontamination motivates research on their physicochemical properties. Due to the extreme toxicity of sarin, most of the experimental studies are carried out using less toxic simulant compounds. In addition to experimental studies of sarin simulants, both sarin and simulants can be studied using in silico experiments-molecular simulations. The results of classical molecular modeling of the compounds and their agreement with experimental data rely on the force field used to describe the system. In recent years, there have been several force fields proposed for sarin and its most common simulant dimethyl methylphosphonate (DMMP). However, other simulants frequently used in experiments received less attention from the molecular simulation perspective, for example, to date, there is no force field and no simulation data for diisopropyl methylphosphonate (DIMP). Here, we compare the literature force fields for sarin and DMMP, focusing specifically on the vapor-liquid equilibrium for the pure species. We carried out Monte Carlo and molecular dynamics simulations using the existing literature force fields from which we predicted the liquid densities and vapor pressures developing the entire binodal curves. We compared the predictions to the experimental data and showed that the TraPPE-UA force field outperformed the other force fields. Thus, we extended TraPPE-UA for DIMP, utilized this force field in molecular simulations, and predicted the liquid densities and vapor pressures for a range of temperatures (binodal curve), which agreed well with the published experimental data. From the binodal, we calculated the critical properties of DIMP and demonstrated that these parameters can be used in the Peng-Robinson equation of state for this compound.


School climate factors contributing to student and faculty perceptions of safety in select Arizona schools.
To ensure that schools are safe places where students can learn, researchers and educators must understand student and faculty safety concerns. This study examines student and teacher perceptions of school safety. Twenty-two focus groups with students and faculty were conducted in 11 secondary schools. Schools were selected from a stratified sample to vary in location, proximity to Indian reservations, size, and type. The data analysis was based on grounded theory. In 9 of 11 schools, neither faculty nor students voiced overwhelming concerns about safety. When asked what makes school safe, students tended to report physical security features. School climate and staff actions also increased feelings of safety. Faculty reported that relationships and climate are key factors in making schools safe. High student performance on standardized tests does not buffer students from unsafe behavior, nor does living in a dangerous neighborhood necessarily lead to more drug use or violence within school walls. School climate seemed to explain the difference between schools in which students and faculty reported higher versus lower levels of violence and alcohol and other drug use. The findings raise provocative questions about school safety and provide insight into elements that lead to perceptions of safety. Some schools have transcended issues of location and neighborhood to provide an environment perceived as safe. Further study of those schools could provide insights for policy makers, program planners, and educational leaders.


Exploring hydrophobic sites in proteins with xenon or krypton.
X-ray diffraction is used to study the binding of xenon and krypton to a variety of crystallised proteins: porcine pancreatic elastase; subtilisin Carlsberg from Bacillus licheniformis; cutinase from Fusarium solani; collagenase from Hypoderma lineatum; hen egg lysozyme, the lipoamide dehydrogenase domain from the outer membrane protein P64k from Neisseria meningitidis; urate-oxidase from Aspergillus flavus, mosquitocidal delta-endotoxin CytB from Bacillus thuringiensis and the ligand-binding domain of the human nuclear retinoid-X receptor RXR-alpha. Under gas pressures ranging from 8 to 20 bar, xenon is able to bind to discrete sites in hydrophobic cavities, ligand and substrate binding pockets, and into the pore of channel-like structures. These xenon complexes can be used to map hydrophobic sites in proteins, or as heavy-atom derivatives in the isomorphous replacement method of structure determination.


Scalable Parameter Estimation for Genome-Scale Biochemical Reaction Networks.
Mechanistic mathematical modeling of biochemical reaction networks using ordinary differential equation (ODE) models has improved our understanding of small- and medium-scale biological processes. While the same should in principle hold for large- and genome-scale processes, the computational methods for the analysis of ODE models which describe hundreds or thousands of biochemical species and reactions are missing so far. While individual simulations are feasible, the inference of the model parameters from experimental data is computationally too intensive. In this manuscript, we evaluate adjoint sensitivity analysis for parameter estimation in large scale biochemical reaction networks. We present the approach for time-discrete measurement and compare it to state-of-the-art methods used in systems and computational biology. Our comparison reveals a significantly improved computational efficiency and a superior scalability of adjoint sensitivity analysis. The computational complexity is effectively independent of the number of parameters, enabling the analysis of large- and genome-scale models. Our study of a comprehensive kinetic model of ErbB signaling shows that parameter estimation using adjoint sensitivity analysis requires a fraction of the computation time of established methods. The proposed method will facilitate mechanistic modeling of genome-scale cellular processes, as required in the age of omics.


Definition of Synchronous Oligometastatic Non-Small Cell Lung Cancer-A Consensus Report.
Improved outcome has been shown in patients with synchronous oligometastatic (sOM) NSCLC when treated with radical intent. As a uniform definition of sOM NSCLC is lacking, we developed a definition and diagnostic criteria by a consensus process. A pan-European multidisciplinary consensus group was established. Consensus questions were built on the basis of current controversies, and definitions were extracted from a survey, cases and a systematic review. This statement was formulated during a consensus meeting. It was determined that definition of sOM NSCLC is relevant when a radical treatment that may modify the disease course (leading to long-term disease control) is technically feasible for all tumor sites with acceptable toxicity. On the basis of the review, a maximum of five metastases and three organs was proposed. Mediastinal lymph node involvement was not counted as a metastatic site. Fludeoxyglucose F 18 positron emission tomography-computed tomography and brain imaging were considered mandatory. A dedicated liver magnetic resonance imaging scan was advised for a solitary liver metastasis, and thoracoscopy and biopsies of distant ipsilateral pleural sites were recommended for a solitary pleural metastasis. For mediastinal staging, fludeoxyglucose F 18 positron emission tomography-computed tomography was deemed the minimum requirement, with pathological confirmation recommended if this influences the treatment strategy. Biopsy of a solitary metastatic location was mandated unless the multidisciplinary team is of the opinion that the risks outweigh the benefits. A multidisciplinary consensus statement on the definition and staging of sOM NSCLC has been formulated. This statement will help to standardize inclusion criteria in future clinical trials.


Interventions for treating painful nipples among breastfeeding women.
Leading health authorities all recommend exclusive breastfeeding to six months' postpartum. While most women initiate breastfeeding, many discontinue due to difficulties encountered rather than maternal choice. One common breastfeeding difficulty is painful nipples. Research has identified poor infant positioning or latch as a common cause of painful nipples. While many different interventions designed to reduce nipple pain in breastfeeding women have been evaluated, it is unclear which intervention is the most effective treatment. An understanding of nipple pain and treatment options are needed to improve breastfeeding duration and exclusivity rates and to address systematically one of the most frequent difficulties encountered by breastfeeding women. To assess the effects of all interventions in the resolution or reduction of nipple pain and the impact of the interventions on other outcomes such as nipple trauma, nipple infections, breast mastitis, breastfeeding duration, breastfeeding exclusivity, and maternal satisfaction. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2014) and scanned secondary references. All randomised or quasi-randomised controlled trials designed to evaluate any intervention for treating nipple pain among breastfeeding women. Trials using a cluster-randomised design were eligible for inclusion. Cross-over trials were not eligible for inclusion. The following interventions were eligible for inclusion compared with each other or usual care (i.e. education only): pharmacological (e.g. antifungal creams); non-pharmacological topical treatments (e.g. lanolin); dressings (e.g. hydrogel dressings); nipple protection devices (e.g. breast shells), phototherapy, and expressed breast milk. Nipple pain in women who are feeding with expressed breast milk (i.e. women of infants in neonatal units) is associated with other methods of removing milk from the mother's breast such as manual expression and various types of breast pumps. Nipple pain and subsequent treatment is different in this unique maternal population and thus we excluded women solely feeding with expressed breast milk from this review. Two review authors independently assessed trials for inclusion, extracted data, evaluated methodological quality, and checked data for accuracy. We sought additional information from several trial researchers. We included four trials of good methodological quality involving 656 women in the review. The four included trials evaluated five different interventions including glycerine pads, lanolin with breast shells, lanolin alone, expressed breast milk, and an all-purpose nipple ointment. All studies included education to position the infant at the breast correctly as part of routine postpartum care to both treatment and control groups.Pooled data existed only for the comparison of lanolin versus usual care. We did not pool data for other outcomes due to either heterogeneity in outcome measures or differing interventions.There was no evidence that glycerine gel dressings or breast shells with lanolin significantly improved nipple pain. One trial found no clear differences in nipple pain (at one to three days, four to five days, or six to seven days' post-treatment) between women who applied lanolin or nothing to their nipples. In contrast, the same trial found that women who applied expressed breast milk had significantly lower perceptions of nipple pain following four to five days of treatment than women who applied lanolin. However, this beneficial effect was not maintained after six to seven days of treatment. There were no group differences in nipple pain perceptions at any assessment between women who applied expressed breast milk and women who applied nothing. Women who applied an "all-purpose nipple ointment", in comparison to women who applied lanolin, had no improvement in nipple pain after seven days of treatment. There was insufficient evidence that glycerine gel dressings, lanolin with breast shells, lanolin alone, expressed breast milk, or all-purpose nipple ointment improved maternal perceptions of nipple pain.Overall, there was insufficient evidence to recommend any intervention for the treatment of nipple pain. However, one important finding was that regardless of the treatment used, for most women nipple pain reduced to mild levels after approximately seven to 10 days' postpartum. The provision of anticipatory guidance regarding usual time to pain reduction may be a useful strategy in assisting women to continue to breastfeed and to do so exclusively. The overall quality of the evidence for the primary outcome of nipple pain as assessed using GRADE was of low quality, mainly because single studies with few participants contributed data for analysis. There was insufficient evidence that glycerine gel dressings, breast shells with lanolin, lanolin alone, or the all-purpose nipple ointment significantly improved maternal perceptions of nipple pain. The results from these four trials of good methodological quality suggested that applying nothing or just expressed breast milk may be equally or more beneficial in the short-term experience of nipple pain than the application of an ointment such as lanolin.The quality of the evidence for this review did not lead to robust conclusions regarding the objectives assessed. We included only four trials, incorporating 656 women, in the review and all four trials compared varying interventions, participants, study outcome measures, and standards of usual care. The methodological quality of the included studies was good but the overall quality of the evidence for the primary outcome of nipple pain was of low quality, mainly because single studies with few participants contributed data for analysis.


Dietary fibre in under- and overnutrition in childhood.
Children in developing countries pass stools that are very different from those passed by children in Europe. These stools reflect a diet of unrefined carbohydrate with low-energy density, and which due to the large volume results in an energy deficit in the child. This energy deficit is now considered to be the major cause of the almost universal undernutrition. Much of the improved health in European children during the last century has probably arisen through better nutrition due to more-refined carbohydrates and to more fat in the diet. Over the same period as children have become healthier, diseases of civilisation have appeared. One factor in such diseases is clearly that of diet, and these diseases may partly be caused by the high-energy density and the low-dietary fibre content. Changes in diet offer the greatest hope for a rapid improvement in health. In the developing world we need to find a means for making foods with a high-energy density more easily available to overcome the undernutrition in childhood. In industrialised countries older children need to become accustomed to a diet of lower-energy than at present, containing more unrefined carbohydrate and less fat.


Chemically modulating the photophysics of the GFP chromophore.
There is growing interest in engineering the properties of fluorescent proteins through modifications to the chromophore structure utilizing mutagenesis with either natural or unnatural amino acids. This entails an understanding of the photophysical and photochemical properties of the modified chromophore. In this work, a range of GFP chromophores with different alkyl substituents are synthesized and their electronic spectra, pH dependence, and ultrafast fluorescence decay kinetics are investigated. The weakly electron donating character of the alkyl substituents leads to dramatic red shifts in the electronic spectra of the anions, which are accompanied by increased fluorescence decay times. This high sensitivity of electronic structure to substitution is also characteristic of some fluorescent proteins. The solvent viscosity dependence of the decay kinetics are investigated, and found to be consistent with a bimodal radiationless relaxation coordinate. Some substituents are shown to distort the planar structure of the chromophore, which results in a blue shift in the electronic spectra and a strong enhancement of the radiationless decay. The significance of these data for the rational design of novel fluorescent proteins is discussed.


Helicobacter pylori in First Nations and recent immigrant populations in Canada.
The diminishing prevalence of Helicobacter pylori infection among most segments of the Canadian population has led to changes in the etiologies and patterns of associated upper gastrointestinal diseases, including fewer peptic ulcers and their complications. Canadian Aboriginals and recent immigrants are among populations in which the prevalence of H pylori infection remains high and, therefore, the health risks imposed by H pylori remain a significant concern. Population-based strategies for H pylori eradication in groups with a low prevalence of infection are unlikely to be cost effective, but such measures are attractive in groups in which the prevalence rates of infection remain substantial. In addition to a lower prevalence of peptic ulcers and dyspepsia, the public health value of eradication may be particularly important if this leads to a reduction in the prevalence of gastric cancer in high prevalence groups. Therefore The Canadian Helicobacter Study Group held a conference that brought together experts in the field to address these issues, the results of which are reviewed in the present article. Canadians with the highest prevalence of H pylori infection are an appropriate focus for considering the health advantages of eradicating persistent infection. In Canadian communities with a high prevalence of both H pylori and gastric cancer, there remains an opportunity to test the hypothesis that H pylori infection is a treatable risk factor for malignancy.


Efficacy and safety of percutaneous nephrolithotomy (PCNL): a prospective and randomized study comparing regional epidural anesthesia with general anesthesia.
To compare the efficacy and safety of regional epidural anesthesia and general anesthesia in patients who underwent PCNL. Fifty patients submitted to percutaneous nephrolithotomy (PCNL) were randomized into two groups: Group I (N = 26) received general anesthesia and Group II (N = 24) received regional epidural anesthesia. Demographic and operative data including age, BMI, stone position, stone size, postoperative pain, amount of postoperative analgesic usage, length of hospital stay, patient satisfaction, preoperative and postoperative hemoglobin and hematocrit, adverse effects and surgical complications were compared between both groups. Average pain score at 1 hour. was 6.88 in group I and 3.12 in group II (p < 0.001), at 4 hours. 5.07 in group I and 3.42 in group II (p = 0.025). Less morphine was required in the regional epidural anesthesia group compared to the general anesthesia group. Higher satisfaction was found in the regional epidural group. 6 (23.07 %) patients in Group I and 1 patient (4.19 %) in Group II had postoperative nausea and vomiting, respectively (p = 0.05). Pain score at 12 hours, 24 hours, 48 hours, 72 hours, preoperative and postoperative hemoglobin and hematocrit, length of hospital stay, and adverse effects were no different between the two groups. Regional epidural anesthesia is an alternative technique for PCNL which achieves more patient satisfaction, less early postoperative pain and less adverse effects from medication with the same efficacy and safety compared to general anesthesia.


Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation.
Cardiac macrophages are crucial for tissue repair after cardiac injury but are not well characterized. Here we identify four populations of cardiac macrophages. At steady state, resident macrophages were primarily maintained through local proliferation. However, after macrophage depletion or during cardiac inflammation, Ly6c(hi) monocytes contributed to all four macrophage populations, whereas resident macrophages also expanded numerically through proliferation. Genetic fate mapping revealed that yolk-sac and fetal monocyte progenitors gave rise to the majority of cardiac macrophages, and the heart was among a minority of organs in which substantial numbers of yolk-sac macrophages persisted in adulthood. CCR2 expression and dependence distinguished cardiac macrophages of adult monocyte versus embryonic origin. Transcriptional and functional data revealed that monocyte-derived macrophages coordinate cardiac inflammation, while playing redundant but lesser roles in antigen sampling and efferocytosis. These data highlight the presence of multiple cardiac macrophage subsets, with different functions, origins, and strategies to regulate compartment size.


Antibiotic resistance-the need for global solutions.
The causes of antibiotic resistance are complex and include human behaviour at many levels of society; the consequences affect everybody in the world. Similarities with climate change are evident. Many efforts have been made to describe the many different facets of antibiotic resistance and the interventions needed to meet the challenge. However, coordinated action is largely absent, especially at the political level, both nationally and internationally. Antibiotics paved the way for unprecedented medical and societal developments, and are today indispensible in all health systems. Achievements in modern medicine, such as major surgery, organ transplantation, treatment of preterm babies, and cancer chemotherapy, which we today take for granted, would not be possible without access to effective treatment for bacterial infections. Within just a few years, we might be faced with dire setbacks, medically, socially, and economically, unless real and unprecedented global coordinated actions are immediately taken. Here, we describe the global situation of antibiotic resistance, its major causes and consequences, and identify key areas in which action is urgently needed.


Verifiable metamodels for nitrate losses to drains and groundwater in the Corn Belt, USA.
Nitrate leaching in the unsaturated zone poses a risk to groundwater, whereas nitrate in tile drainage is conveyed directly to streams. We developed metamodels (MMs) consisting of artificial neural networks to simplify and upscale mechanistic fate and transport models for prediction of nitrate losses by drains and leaching in the Corn Belt, USA. The two final MMs predicted nitrate concentration and flux, respectively, in the shallow subsurface. Because each MM considered both tile drainage and leaching, they represent an integrated approach to vulnerability assessment. The MMs used readily available data comprising farm fertilizer nitrogen (N), weather data, and soil properties as inputs; therefore, they were well suited for regional extrapolation. The MMs effectively related the outputs of the underlying mechanistic model (Root Zone Water Quality Model) to the inputs (R(2) = 0.986 for the nitrate concentration MM). Predicted nitrate concentration was compared with measured nitrate in 38 samples of recently recharged groundwater, yielding a Pearson's r of 0.466 (p = 0.003). Predicted nitrate generally was higher than that measured in groundwater, possibly as a result of the time-lag for modern recharge to reach well screens, denitrification in groundwater, or interception of recharge by tile drains. In a qualitative comparison, predicted nitrate concentration also compared favorably with results from a previous regression model that predicted total N in streams.


Immunization by a bacterial aerosol.
By manufacturing a single-particle system in two particulate forms (i.e., micrometer size and nanometer size), we have designed a bacterial vaccine form that exhibits improved efficacy of immunization. Microstructural properties are adapted to alter dispersive and aerosol properties independently. Dried "nanomicroparticle" vaccines possess two axes of nanoscale dimensions and a third axis of micrometer dimension; the last one permits effective micrometer-like physical dispersion, and the former provides alignment of the principal nanodimension particle axes with the direction of airflow. Particles formed with this combination of nano- and micrometer-scale dimensions possess a greater ability to aerosolize than particles of standard spherical isotropic shape and of similar geometric diameter. Here, we demonstrate effective application of this biomaterial by using the live attenuated tuberculosis vaccine bacille Calmette-Guérin (BCG). Prepared as a spray-dried nanomicroparticle aerosol, BCG vaccine exhibited high-efficiency delivery and peripheral lung targeting capacity from a low-cost and technically simple delivery system. Aerosol delivery of the BCG nanomicroparticle to normal guinea pigs subsequently challenged with virulent Mycobacterium tuberculosis significantly reduced bacterial burden and lung pathology both relative to untreated animals and to control animals immunized with the standard parenteral BCG.


12(R)-Hydroxy-5(Z),8(Z),10(E),14(Z)-eicosatetraenoic acid [12(R)-HETE], an arachidonic acid derivative, is an activator of the aryl hydrocarbon receptor.
The aryl hydrocarbon receptor (AHR) is a ligand-regulated transcription factor that can be activated by structurally diverse chemicals, ranging from environmental carcinogens to dietary metabolites. Evidence supporting a necessary role for the AHR in normal biology has been established; however, identification of key endogenous ligand/activator remains to be established. Here, we report the ability of 12(R)-hydroxy-5(Z),8(Z),10(E), 14(Z)-eicosatetraenoic acid [12(R)-HETE], an arachidonic acid metabolite produced by either a lipoxygenase or cytochrome P-450 pathway, to act as a potent indirect modulator of the AHR pathway. In contrast, structurally similar HETE isomers failed to demonstrate significant activation of the AHR. Electrophoretic mobility shift assays, together with ligand competition binding experiments, have demonstrated the inability of 12(R)-HETE to directly bind or directly activate the AHR to a DNA binding species in vitro. However, cell-based xenobiotic-responsive element-driven luciferase reporter assays indicate the ability of 12(R)-HETE to modulate AHR activity, and quantitation of induction of an AHR target gene confirmed 12(R)-HETE's ability to activate AHR-mediated transcription, even at high nanomolar concentrations in human hepatoma (HepG2)- and keratinocyte (HaCaT)-derived cell lines. One explanation for these results is that a metabolite of 12(R)-HETE is acting as a direct ligand for the AHR. However, several known metabolites failed to exhibit AHR activity. The ability of 12(R)-HETE to activate AHR target genes required receptor expression. These results indicate that 12(R)-HETE can serve as a potent activator of AHR activity and suggest that in normal and inflammatory disease conditions in skin, 12(R)-HETE is produced, perhaps leading to AHR activation.


Could spirituality and religion promote stress resilience in survivors of childhood trauma?
Trauma is a precursor to many mental health conditions that greatly impact victims, their loved ones, and society. Studies indicate that neurobiological associations with adverse childhood experiences are mediated by interpersonal relationships and play a role in adult behavior, often leading to cycles of intergenerational trauma. There is a critical need to identify cost effective community resources that optimize stress resilience. Faith-based communities may promote forgiveness rather than retaliation, opportunities for cathartic emotional release, and social support, all of which have been related to neurobiology, behavior, and health outcomes. While spirituality and religion can be related to guilt, neurotic, and psychotic disorders, they also can be powerful sources of hope, meaning, peace, comfort, and forgiveness for the self and others. This article provides an overview of religion and spirituality as they relate to the neurobiology of resilience in victims of childhood trauma.


Manganese-Enhanced Magnetic Resonance Imaging in Takotsubo Syndrome.
Takotsubo syndrome is an acute cardiac emergency characterized by transient left ventricular systolic dysfunction typically following a stressful event. Despite its rapidly rising incidence, its pathophysiology remains poorly understood. Takotsubo syndrome may pass unrecognized, especially if timely diagnostic imaging is not performed. Defective myocardial calcium homeostasis is a central cause of contractile dysfunction and has not been explored in takotsubo syndrome. We aimed to investigate myocardial calcium handling using manganese-enhanced magnetic resonance imaging during the acute and recovery phases of takotsubo syndrome. Twenty patients with takotsubo syndrome (63±12 years of age; 90% female) and 20 volunteers matched on age, sex, and cardiovascular risk factors (59±11 years of age; 70% female) were recruited from the Edinburgh Heart Centre between March 2020 and October 2021. Patients underwent gadolinium and manganese-enhanced magnetic resonance imaging during index hospitalization with repeat manganese-enhanced magnetic resonance imaging performed after at least 3 months. Compared with matched control volunteers, patients had a reduced left ventricular ejection fraction (51±11 versus 67±8%; P<0.001), increased left ventricular mass (86±11 versus 57±14 g/m2; P<0.001), and, in affected myocardial segments, elevated native T1 (1358±49 versus 1211±28 ms; P<0.001) and T2 (60±7 versus 38±3 ms; P<0.0001) values at their index presentation. During manganese-enhanced imaging, kinetic modeling demonstrated a substantial reduction in myocardial manganese uptake (5.1±0.5 versus 8.2±1.1 mL/[100 g of tissue ·min], respectively; P<0.0001), consistent with markedly abnormal myocardial calcium handling. After recovery, left ejection fraction, left ventricular mass, and T2 values were comparable with those of matched control volunteers. Despite this, native and postmanganese T1 and myocardial manganese uptake remained abnormal compared with matched control volunteers (6.6±0.5 versus 8.2±1.1 mL/[100 g of tissue ·min]; P<0.0001). In patients with takotsubo syndrome, there is a profound perturbation of myocardial manganese uptake, which is most marked in the acute phase but persists for at least 3 months despite apparent restoration of normal left ventricular ejection fraction and resolution of myocardial edema, suggesting abnormal myocardial calcium handling may be implicated in the pathophysiology of takotsubo syndrome. Manganese-enhanced magnetic resonance imaging has major potential to assist in the diagnosis, characterization, and risk stratification of patients with takotsubo syndrome. URL: https://www. gov; Unique identifier: NCT04623788.


Remarkable tumor lysis in a hepatocellular carcinoma patient immediately following glypican-3-derived peptide vaccination: an autopsy case.
We recently reported the safety, immunological and clinical responses to a GPC3-derived peptide vaccine in a phase I clinical trial of patients with advanced hepatocellular carcinoma (HCC). We conducted a subsequent trial in advanced HCC to assess the histopathological findings before and after vaccination with the GPC3 peptide. Here, we present the clinical course and the pathological study including the autopsy of a patient with advanced HCC in the ongoing clinical trial. A 62-year old patient suffering from HCC refractory to sorafenib therapy received the GPC3 peptide vaccine. The patient had fever and remarkably impaired liver function twice after vaccination. Contrast-enhanced CT after the second vaccination showed multiple low-density areas in the liver tumor, indicating tumor necrosis. In contrast, the tumor thrombus in the right atrium increased. The patient discontinued protocol treatment due to disease progression and died 30 days after the second vaccination. An autopsy was performed to determine the main cause of death and to evaluate the antitumor effect of the vaccination. A histological examination showed central necrosis in most of the intrahepatic tumor. The main cause of death was circulatory failure due to tumor thrombus, which occupied most of the right atrium. An immunohistochemical analysis revealed infiltration of CD8-positive T cells in the residual carcinoma, but not within the cirrhotic area. Ex vivo IFN-γ enzyme-linked immunospot analysis revealed vaccine-induced immune-reactivity against the GPC3 peptide. A histopathological examination at the estimated time of a strong immunological response demonstrated a GPC3 peptide vaccination-induced cytotoxic T-lymphocyte response with an anti-tumor effect.


Revisiting the Value of Drains After Low Anterior Resection for Rectal Cancer: a Multi-institutional Analysis of 996 Patients.
Intraoperative pelvic drains are often placed during low anterior resection (LAR) to evacuate postoperative fluid collections and identify/control potential anastomotic leaks. Our aim was to assess the validity of this practice. Patients from the US Rectal Cancer Consortium (2007-2017) who underwent curative-intent LAR for a primary rectal cancer were included. Patients were categorized as receiving a closed suction drain intraoperatively or not. Primary outcomes were superficial surgical site infection (SSI), deep SSI, intraabdominal abscess, anastomotic leak, and need for secondary drain placement. Three subgroup analyses were conducted in patients who received neoadjuvant chemoradiation, had a diverting loop ileostomy (DLI), and had low anastomoses < 6 cm from the anal verge. Of 996 patients 67% (n = 551) received a drain. Drain patients were more likely to be male (64 vs 54%), have a smoking history (25 vs 19%), have received neoadjuvant chemoradiation (73 vs 61%), have low tumors (56 vs 36%), and have received a DLI (80 vs 71%) (all p < 0.05). Drains were associated with an increased anastomotic leak rate (14 vs 8%, p = 0.041), although there was no difference in the need for a secondary drainage procedure to control the leak (82 vs 88%, p = 0.924). These findings persisted in all subset analyses. Drains were not associated with increased superficial SSI, deep SSI, or intraabdominal abscess in the entire cohort or each subset analysis. Reoperation (12 vs 10%, p = 0.478) and readmission rates (28 vs 31%, p = 0.511) were similar. Although not associated with increased infectious complications, intraoperatively placed pelvic drains after low anterior resection for rectal cancer are associated with an increase in anastomotic leak rate and no reduction in the need for secondary drain placement or reoperation. Routine drainage appears to be unnecessary.


Component separation improves outcomes in VRAM flap donor sites with excessive fascial tension.
The vertical rectus abdominis musculocutaneous (VRAM) flap has numerous uses in pelvic reconstruction; however, flap harvest can result in abdominal wall morbidity. The authors hypothesized that combining component separation with fascial advancement closure would result in acceptable surgical donor-site outcomes. Patients were evaluated who underwent VRAM flap reconstruction for contaminated pelvic defects and component separation with fascial advancement closure or tension-bearing primary fascial closure for VRAM flap donor-site defects between 2006 and 2009. The indication for component separation was the inability to approximate fascial edges (1) at all or (2) without excessive fascial tension, creating a high risk of postoperative failure. Primary outcome indicators included wound complications, myofascial laxity, and incisional hernia. Seventy-four patients were included in the study: 15 who underwent component separation and 59 who underwent primary fascial closure. The mean follow-up was 16 months (range, 6 to 39 months). The incidences of seroma, infection, and skin and fascial dehiscence were higher in the primary fascial closure group (39 percent) than in the component separation group (13 percent) (p<0.053). There was a fourfold greater incidence of incisional hernia in the primary fascial closure group (24 percent) than in the component separation group (6 percent). There was also a trend toward a higher incidence of myofascial laxity in the primary fascial closure group (14 percent) than in the component separation group (6 percent). Component separation was effective in allowing closure of VRAM donor sites that were otherwise impossible to reapproximate without excessive fascial tension. Component separation closures resulted in fewer postoperative wound complications, hernias, and bulges, despite a more difficult closure, and should be considered when fascial closure tension would be excessive.


The LRS and SIN domains: two structurally equivalent but functionally distinct nucleosomal surfaces required for transcriptional silencing.
Genetic experiments have identified two structurally similar nucleosomal domains, SIN and LRS, required for transcriptional repression at genes regulated by the SWI/SNF chromatin remodeling complex or for heterochromatic gene silencing, respectively. Each of these domains consists of histone H3 and H4 L1 and L2 loops that form a DNA-binding surface at either superhelical location (SHL) +/-2.5 (LRS) or SHL +/-0.5 (SIN). Here we show that alterations in the LRS domain do not result in Sin(-) phenotypes, nor does disruption of the SIN domain lead to loss of ribosomal DNA heterochromatic gene silencing (Lrs(-) phenotype). Furthermore, whereas disruption of the SIN domain eliminates intramolecular folding of nucleosomal arrays in vitro, alterations in the LRS domain have no effect on chromatin folding in vitro. In contrast to these dissimilarities, we find that the SIN and LRS domains are both required for recruitment of Sir2p and Sir4p to telomeric and silent mating type loci, suggesting that both surfaces can contribute to heterochromatin formation. Our study shows that structurally similar nucleosomal surfaces provide distinct functionalities in vivo and in vitro.


The clinical course of postinfectious irritable bowel syndrome: a five-year follow-up study.
Irritable bowel syndrome (IBS) is a common disorder seen in general practice. Bacterial gastroenteritis has been known to be a risk factor for IBS. We investigated the clinical course, risk factors, and prognosis of postinfectious IBS (PI-IBS) 5 years after Shigella infection. We recruited 153 individuals and used a questionnaire to investigate their current bowel habits. We also looked for the presence of other functional bowel disorders (FBDs). The Shigella-exposed group consisted of hospital employees and medical students who experienced abdominal pain, diarrhea, or fever during the shigellosis outbreak and whose stool culture revealed Shigella sonnei. The control group consisted of age-matched and sex-matched subjects who corresponded fairly well with patients, considering that they were enrolled from the same hospital and were not infected. Complete data were obtained from 119 individuals who were divided into the Shigella-exposed group (59) and the control group (60). In the Shigella-exposed group, 3 patients had IBS before infection (previous IBS) and 6 out of 13 cases of PI-IBS after 3 years showed persistent IBS after 5 years. Five out of 11 PI-IBS patients (45.5%, 2 excluded), 3 out of 6 previous IBS patients (50%) in the Shigella-exposed group, and 7 out of 11 previous IBS patients (63.6%) in the control group recovered after 5 years (P>0.05). Five cases in the Shigella-exposed group and 3 in the control group developed new cases of IBS after 5 years. The prevalence of PI-IBS after 5 years in the previous FBD groups was 63.6%, whereas the prevalence of PI-IBS without a history of FBDs was 36.4% (P<0.05). There were no significant differences among the other risk factors in each group. About half of PI-IBS and previous IBS patients with or without infection recover over 5 years. Previous IBS and FBDs are risk factors of PI-IBS after 5 years. We suggest that our results support the understanding of the clinical course and prognosis of PI-IBS.


Familial aggregation of MATRICS Consensus Cognitive Battery scores in a large sample of outpatients with schizophrenia and their unaffected relatives.
The increased use of the MATRICS Consensus Cognitive Battery (MCCB) to investigate cognitive dysfunctions in schizophrenia fostered interest in its sensitivity in the context of family studies. As various measures of the same cognitive domains may have different power to distinguish between unaffected relatives of patients and controls, the relative sensitivity of MCCB tests for relative-control differences has to be established. We compared MCCB scores of 852 outpatients with schizophrenia (SCZ) with those of 342 unaffected relatives (REL) and a normative Italian sample of 774 healthy subjects (HCS). We examined familial aggregation of cognitive impairment by investigating within-family prediction of MCCB scores based on probands' scores. Multivariate analysis of variance was used to analyze group differences in adjusted MCCB scores. Weighted least-squares analysis was used to investigate whether probands' MCCB scores predicted REL neurocognitive performance. SCZ were significantly impaired on all MCCB domains. REL had intermediate scores between SCZ and HCS, showing a similar pattern of impairment, except for social cognition. Proband's scores significantly predicted REL MCCB scores on all domains except for visual learning. In a large sample of stable patients with schizophrenia, living in the community, and in their unaffected relatives, MCCB demonstrated sensitivity to cognitive deficits in both groups. Our findings of significant within-family prediction of MCCB scores might reflect disease-related genetic or environmental factors.


Human-animal bonds between zoo professionals and the animals in their care.
Some human-animal relationships can be so positive that they confer emotional well-being to both partners and can thus be viewed as bonds. In this study, 130 delegates at zoo research and training events completed questionnaires in which they were asked about their professional work in the zoo and whether they believed they had established bonds with any animals. They were also asked to indicate agreement or disagreement with several statements about human-animal bonds. Results showed that many zoo professionals consider that they have established bonds with some of their animals; 103 respondents believed that they had a bond with at least one animal, and 78 of these identified that the bond was with a zoo animal. The most frequent bonds reported were with primates (n = 24) and carnivores (n = 28). Perceived benefits of these bonds to the respondents included both operational (animal easier to handle, easier to administer treatments to) and affective (sense of well-being, enjoyment at being with the animal). Identifying benefits to the animals was more difficult. Most respondents identified similar benefits for their animals as for themselves, i.e. operational (animal responded more calmly, appeared less stressed) and affective (animal appeared to enjoy contact with respondent, seemed more content). This suggests that bonding between zoo professionals and their animals could have profound consequences for the management and welfare of the animals, not to mention the job satisfaction of the people involved.


PlnTFDB: an integrative plant transcription factor database.
Transcription factors (TFs) are key regulatory proteins that enhance or repress the transcriptional rate of their target genes by binding to specific promoter regions (i.e. cis-acting elements) upon activation or de-activation of upstream signaling cascades. TFs thus constitute master control elements of dynamic transcriptional networks. TFs have fundamental roles in almost all biological processes (development, growth and response to environmental factors) and it is assumed that they play immensely important functions in the evolution of species. In plants, TFs have been employed to manipulate various types of metabolic, developmental and stress response pathways. Cross-species comparison and identification of regulatory modules and hence TFs is thought to become increasingly important for the rational design of new plant biomass. Up to now, however, no computational repository is available that provides access to the largely complete sets of transcription factors of sequenced plant genomes. PlnTFDB is an integrative plant transcription factor database that provides a web interface to access large (close to complete) sets of transcription factors of several plant species, currently encompassing Arabidopsis thaliana (thale cress), Populus trichocarpa (poplar), Oryza sativa (rice), Chlamydomonas reinhardtii and Ostreococcus tauri. It also provides an access point to its daughter databases of a species-centered representation of transcription factors (OstreoTFDB, ChlamyTFDB, ArabTFDB, PoplarTFDB and RiceTFDB). Information including protein sequences, coding regions, genomic sequences, expressed sequence tags (ESTs), domain architecture and scientific literature is provided for each family. We have created lists of putatively complete sets of transcription factors and other transcriptional regulators for five plant genomes. They are publicly available through http://plntfdb.bio.uni-potsdam.de. Further data will be included in the future when the sequences of other plant genomes become available.


Uranyl acetate-induced sensorimotor deficit and increased nitric oxide generation in the central nervous system in rats.
We investigated the effects of uranyl acetate on sensorimotor behavior, generation of nitric oxide and the central cholinergic system of rats. Male Sprague-Dawley rats were treated with intramuscular injection of 0.1 and 1 mg/kg uranyl acetate in water, daily for 7 days. Control animals received equivalent amount of water. The treatment was stopped after the seventh injection because the animals in the 1-mg/kg group appeared lethargic. The animals were maintained for an additional observation period of 30 days. The study was initiated as a dose-finding study that covered doses of 10 and 100 mg/kg, as well. However, all the animals in the 100-mg/kg treatment group died after the third and fourth injections, and all animals given 10 mg/kg died after the fifth and sixth injections. On Day 30 following the cessation of treatment, the sensorimotor functions of the animals in the 0.1- and 1-mg/kg treatment groups were evaluated using a battery of tests that included measurements of postural reflexes, limb placing, orientation to vibrissae touch, grip time, beam walking and inclined plane performance. The animals were sacrificed the same day and the cerebral cortex, brainstem, cerebellum and midbrain were dissected. The levels of nitric oxide as marker for increased oxidative stress, and the integrity of the cholinergic system as reflected in acetylcholinesterase (AChE) activity and m2 muscarinic acetylcholine receptors ligand binding, were determined. The data from behavioral observations show that there was a dose-related deficit at the 0.1- and 1-mg/kg treatment groups for inclined plane performance. Both doses reduced grip time, but there was no significant difference between the two doses. Similarly, both beam-walk score and beam-walk time were impaired at both doses as compared with the controls. A significant increase in nitric oxide was seen at 0.1 mg/kg dose in cortex and midbrain, whereas brainstem and cerebellum showed an insignificant decrease at both the doses. Similarly, there was no significant change in nitric oxide levels in kidneys and liver of the treated animals as compared with the controls. There was a significant increase in AChE activity in the cortex of the animals treated with 1 mg/kg uranyl acetate, but not in other brain regions. Ligand binding densities for the m2 muscarinic receptor did not show any change. These results show that low-dose, multiple exposure to uranyl acetate caused prolonged neurobehavioral deficits after the initial exposure has ceased.


Uncoupling of cardiac cells by fatty acids: structure-activity relationships.
The permeability and conductance of gap junctions between pairs of neonatal rat heart cells were rapidly and reversibly decreased by oleic acid in a dose- and time-dependent manner. Other unsaturated fatty acids (C-18: cis 6, 9, or 11, and C-18, 16, and 14, cis 9), saturated fatty acids (C-10, 12, and 14), and saturated fatty alcohols (C-8, 10, and 12) also caused uncoupling. The most effective compounds of the unsaturated and saturated fatty acid and saturated fatty alcohol series caused essentially complete uncoupling at comparable aqueous concentrations. However, oleic acid uncoupled cells at membrane concentrations as low as 1 mol%, whereas decanoic acid required upwards of 35 mol%. The channels that support the action potential remained functional at these same membrane concentrations. The data are discussed in terms of the possible mechanism by which these compounds cause uncoupling and the possible role of uncoupling by nonesterified free fatty acids in the initiation of arrhythmias during and after ischemic insults.


Using the Aesop's fable paradigm to investigate causal understanding of water displacement by New Caledonian crows.
Understanding causal regularities in the world is a key feature of human cognition. However, the extent to which non-human animals are capable of causal understanding is not well understood. Here, we used the Aesop's fable paradigm--in which subjects drop stones into water to raise the water level and obtain an out of reach reward--to assess New Caledonian crows' causal understanding of water displacement. We found that crows preferentially dropped stones into a water-filled tube instead of a sand-filled tube; they dropped sinking objects rather than floating objects; solid objects rather than hollow objects, and they dropped objects into a tube with a high water level rather than a low one. However, they failed two more challenging tasks which required them to attend to the width of the tube, and to counter-intuitive causal cues in a U-shaped apparatus. Our results indicate that New Caledonian crows possess a sophisticated, but incomplete, understanding of the causal properties of displacement, rivalling that of 5-7 year old children.


MIP-1δ activates NFATc1 and enhances osteoclastogenesis: involvement of both PLCγ2 and NFκB signaling.
Pathological bone resorption is a source of significant morbidity in diseases affecting the skeleton such as rheumatoid arthritis, periodontitis, and cancer metastasis to bone. Evidence indicates that elevated levels of inflammatory mediators such as IL-1, IL-6, and TNF-α play a role in this process by promoting the formation of bone-resorbing osteoclasts. Additionally, current studies have identified inflammatory chemokines of the macrophage inflammatory protein (MIP) family as potential mediators of pathological bone resorption, where both MIP-1α and -3α have been shown to enhance osteoclast (OCL) development. In this study we provide evidence that MIP-1δ, whose expression is associated with renal cell carcinoma bone metastasis and rheumatoid arthritis, enhances OCL formation in vitro via a direct effect on OCL precursors. Consistent with this ability, exposure of OCL precursors to MIP-1δ resulted in the activation of PLCγ2 and NF-κB, two signaling pathways known to regulate OCL differentiation. Moreover, MIP-1δ induced expression and nuclear translocation of NFATc1, a master regulator of osteoclastogenesis, which was dependent on activation of both the PLCγ2 and NFκB signaling pathways. Lastly, consistent with in vitro studies, in vivo administration of MIP-1δ significantly increased OCL number and resorption area as determined using a murine calvarial bone resorption model. Taken together, these data highlight the potential of MIP-1δ as a mediator of pathological bone resorption and provide insight into the molecular mechanism through which MIP-1δ enhances osteoclastogenesis.


Current and Military-Specific Gender Minority Stress Factors and Their Relationship with Suicide Ideation in Transgender Veterans.
Research suggests the prevalence of suicide ideation and suicide attempts in the transgender veteran community may be upwards of 20 times higher than nontransgender veterans, who are known to be at increased risk than the general US population. This study aimed to understand the potential influence of external and internal minority stress experienced during and after military service on past-year and recent suicide ideation in a sample of 201 transgender veterans. Nonparametric bootstrapping analyses indicated past-year transgender-specific discrimination and rejection (external minority stress) indirectly predicted frequency of both past-year and past 2-week suicide ideation through past-year shame related to gender identity (internal minority stress). This result was significant when controlling for symptoms of depression and demographics. Similar patterns emerged when examining relationships among military external and internal minority stress on suicide outcomes. These results suggest that attempts to reduce both the experience and impact of minority stressors related to gender identity during and after military service may be an important avenue for suicide prevention.


Sequential visibility-graph motifs.
Visibility algorithms transform time series into graphs and encode dynamical information in their topology, paving the way for graph-theoretical time series analysis as well as building a bridge between nonlinear dynamics and network science. In this work we introduce and study the concept of sequential visibility-graph motifs, smaller substructures of n consecutive nodes that appear with characteristic frequencies. We develop a theory to compute in an exact way the motif profiles associated with general classes of deterministic and stochastic dynamics. We find that this simple property is indeed a highly informative and computationally efficient feature capable of distinguishing among different dynamics and robust against noise contamination. We finally confirm that it can be used in practice to perform unsupervised learning, by extracting motif profiles from experimental heart-rate series and being able, accordingly, to disentangle meditative from other relaxation states. Applications of this general theory include the automatic classification and description of physical, biological, and financial time series.


Nine-month follow-up of the insulin receptor signalling cascade in the brain of streptozotocin rat model of sporadic Alzheimer's disease.
Sporadic Alzheimer disease (sAD) is associated with impairment of insulin receptor (IR) signalling in the brain. Rats used to model sAD develop insulin-resistant brain state following intracerebroventricular treatment with a betacytotoxic drug streptozotocin (STZ-icv). Brain IR signalling has been explored usually at only one time point in periods ≤3 months after the STZ-icv administration. We have investigated insulin signalling in the rat hippocampus at five time points in periods ≤9 months after STZ-icv treatment. Male Wistar rats were given vehicle (control)- or STZ (3 mg/kg)-icv injection and killed 0.5, 1, 3, 6 and 9 months afterwards. Insulin-1 (Ins-1), IR, phospho- and total (p/t)-glycogen synthase kinase 3-β (GSK-3β), p/t-tau and insulin degrading enzyme (IDE) mRNA and/or protein were measured. Acute upregulation of tau and IR mRNA (p < 0.05) was followed by a pronounced downregulation of Ins-1, IR and IDE mRNA (p < 0.05) in the course of time. Acute decrement in p/t-tau and p/t-GSK-3β ratios (p < 0.05) was followed by increment in both ratios (3-6 months, p < 0.05) after which p/t-tau ratio demonstrated a steep rise and p/t-GSK-3β ratio a steep fall up to 9 months (p < 0.05). Acute decline in IDE and IR expression (p < 0.05) was followed by a slow progression of the former and a slow recovery of the latter in 3-9 months. Results indicate a biphasic pattern in time dependency of onset and progression of changes in brain insulin signalling of STZ-icv model (partly reversible acute toxicity and chronic AD-like changes) which should be considered when using this model as a tool in translational sAD research.


Alzheimer's disease susceptibility variants in the MS4A6A gene are associated with altered levels of MS4A6A expression in blood.
An increased risk of developing Alzheimer's disease (AD) has previously been found to be associated with variants at the MS4A6A locus. We sought to identify which genes and transcripts in this region have altered expression in AD and mild cognitive impairment (MCI) and are influenced by the AD risk variant(s), as a first step to understanding the molecular basis of AD susceptibility at this locus. Common variants located within highly expressed MS4A6A transcripts were significantly associated with AD and MS4A6A expression levels in blood from MCI and AD subjects (p < 0.05, rs610932, rs7232, rs583791). More copies of the protective (minor) allele were associated with lower MS4A6A expression of each transcript (e.g., p = 0.019; rs610932-total MS4A6A). Furthermore, in heterozygous AD subjects, relative expression of the protective allele of V4-MS4A6A transcripts was lower (p < 0.008). Irrespective of genotype, MS4A6A transcripts were increased in blood from people with AD (p < 0.003), whereas lower expression of full length V1-MS4A6A (p = 0.002) and higher expression of V4-MS4A6A (p = 1.8 × 10(-4)) were observed in MCI, relative to elderly controls. The association between genotype and expression was less consistent in brain, although BA9 did have a similar genotype association with V4-MS4A6A transcripts as in blood. MS4A6A transcripts were widely expressed in tissues and cells, with the exception of V4-MS4A6A, which was not expressed in neuronal cells. Together these results suggest that high levels of MS4A6A in emerging AD pathology are detrimental. Persons with MCI may lower MS4A6A expression to minimize detrimental disease associated MS4A6A activity. However, those with the susceptibility allele appear unable to decrease expression sufficiently, which may explain their increased risk for developing AD. Inhibiting MS4A6A may therefore promote a more neuroprotective phenotype, although further work is needed to establish whether this is the case.


Pressure tuning of light-induced superconductivity in K3C60.
Optical excitation at terahertz frequencies has emerged as an effective means to dynamically manipulate complex materials. In the molecular solid K3C60, short mid-infrared pulses transform the high-temperature metal into a non-equilibrium state with the optical properties of a superconductor. Here we tune this effect with hydrostatic pressure and find that the superconducting-like features gradually disappear at around 0.3 GPa. Reduction with pressure underscores the similarity with the equilibrium superconducting phase of K3C60, in which a larger electronic bandwidth induced by pressure is also detrimental for pairing. Crucially, our observation excludes alternative interpretations based on a high-mobility metallic phase. The pressure dependence also suggests that transient, incipient superconductivity occurs far above the 150 K hypothesised previously, and rather extends all the way to room temperature.


Thymic stromal-derived lymphopoietin distinguishes fetal from adult B cell development.
Deletions of interleukin 7 (IL-7) or its receptor components permit fetal but not adult B cell development in mice. Mice deficient in IL-7 receptor alpha (IL-7R alpha) had 1% the number of B cells of controls and 10% that of mice deficient in the common gamma chain. As IL-7R alpha is also a receptor for thymic stromal-derived lymphopoietin (TSLP), we assayed the ability of TSLP to support proliferation of fetal or adult precursor B cells. Only fetal-derived pro-B cells were able to respond to TSLP, although pre-B cells from both origins were TSLP-responsive. Fetal but not adult precursors generated a measurable B cell compartment in the absence of IL-7. The residual B cells found in IL-7R alpha-deficient mice required fetal liver kinase 2 (Flk-2) for their development. Thus, IL-7R alpha- and Flk-2-mediated signals account for the generation of almost all mouse B lymphocytes.


TSH ratio as a novel diagnostic method for Cushing's syndrome.
Circadian variations impact thyrotropin (TSH) secretion; in Cushing's syndrome (CS) patients, the nocturnal serum TSH surge is abolished. The aim of this prospective study is to examine whether serum TSH surge may be a useful diagnostic method for CS. This prospective study recruited 136 inpatients for differential diagnosis of CS or subclinical CS (SCS), and 21 inpatients with depression at Osaka University Hospital. Serum TSH surge was assessed by the midnight-to-morning serum TSH ratio (2300-2400 h to 0800-0900 h). The diagnostic accuracy (sensitivity and specificity) between TSH ratio and ordinary screening tests [low-dose dexamethasone suppression test (LDDST), late-night serum cortisol and urine free cortisol (UFC)] were compared. Twenty-two patients were diagnosed as CS (12 overt CS and 10 SCS) and the remaining 120 patients were excluded for CS. The diagnostic accuracy of TSH ratio (cutoff value 1.0) yielded sensitivity 90.9% [95% confidence interval (CI) 70.8-98.9], specificity 95.0% (95% CI 89.4-98.1), and a high positive and low negative likelihood ratio [18.2 (95% CI 8.2-40.1) and 0.096 (95% CI 0.026-0.359), respectively]. The specificity of TSH ratio was significantly higher than LDDST and midnight serum cortisol test. The sensitivity of TSH ratio was significantly higher than UFC. TSH ratio showed more than 1.0 in all patients with depression and CYP3A4 inducer users. TSH ratio is a novel supportive diagnostic method with higher specificity than the current diagnostic methods for CS.


What lies downstream: Cellular oxygen delivery during hemodialysis.
Hemodialysis has been linked to structural and functional damage to vital organs such as the brain and heart, possibly via repetitive intradialytic organ ischemia. There is increasing recognition that tissue ischemia can occur without changes in standard hemodynamic parameters such as blood pressure, leading to interest in more direct assessment of the adequacy of oxygen delivery to tissues. In this article, we discuss our current understanding of what happens to cellular oxygen delivery during hemodialysis: we review the underlying physiology, potential measurement techniques, and the clinical literature to date.


Conformational mAb as a tool for integrin ligand discovery.
alpha(4)beta(1)-Integrin (very late antigen-4 (VLA-4)) mediates cell adhesion to cell surface ligands (VCAM-1). Binding of VLA-4 to VCAM-1 initiates rolling and firm adhesion of leukocytes to vascular endothelium followed by the extravasation into the tissue. VLA-4-dependent adhesion plays a key role in controlling leukocyte adhesive events. Small molecules that bind to the integrin ligand-binding site and block its interaction with natural ligands represent promising candidates for treatment of several diseases. Following a flow cytometric screen for small molecule discovery, we took advantage of a conformationally sensitive anti-beta(1)-integrin antibody (HUTS-21) and a small LDV-containing ligand (LDV-FITC) with known affinity to study binding affinities of several known and recently discovered integrin ligands. We found that binding of the LDV-containing small molecule induced exposure of HUTS-21 epitope and that the EC(50) for antibody binding was equal to previously reported K(d) for fluorescent LDV (LDV-FITC). Thus, binding of HUTS-21 can be used to report ligand-binding site occupancy. We studied binding of two known integrin ligands (YLDV and TR14035), as well as of two novel compounds. EC(50) values for HUTS-21 binding showed good correlation with K(i)s determined in the competition assay with LDV-FITC for all ligands. A docking model suggests a common mode of binding for the small molecule VLA-4 ligands. This novel approach described here can be used to determine ligand-binding affinities for unlabeled integrin ligands, and can be adapted to a high-throughput screening format for identification of unknown integrin ligands.


SEVENS: a database for comprehensive GPCR genes obtained from genomes: -Update to 68 eukaryotes.
We report the development of the SEVENS database, which contains information on G-protein coupled receptor (GPCR) genes that are identified with high confidence levels (A, B, C, and D) from various eukaryotic genomes, by using a pipeline comprising bioinformatics softwares, including a gene finder, a sequence alignment tool, a motif and domain assignment tool, and a transmembrane helix predictor. SEVENS compiles detailed information on GPCR genes, such as chromosomal mapping position, phylogenetic tree, sequence similarity to known genes, and protein function described by motif/domain and transmembrane helices. They are presented in a user-friendly interface. Because of the comprehensive gene findings from genomes, SEVENS contains a larger data set than that of previous databases and enables the performance of a genome-scale overview of all the GPCR genes. We surveyed the complete genomes of 68 eukaryotes, and found that there were between 6 and 3,470 GPCR genes for each genome (Level A data). Within these genes, the number of receptors for various molecules, including biological amines, peptides, and lipids, were conserved in mammals, birds, and fishes, whereas the numbers of odorant receptors and pheromone receptors were highly diverse in mammals. SEVENS is freely available at http://sevens.cbrc.jp or http://sevens.chem.aoyama.ac.jp.


Walnut ingestion in adults at risk for diabetes: effects on body composition, diet quality, and cardiac risk measures.
Despite their energy density, walnuts can be included in the diet without adverse effects on weight or body composition. The effect of habitual walnut intake on total calorie intake is not well studied. Effects on overall diet quality have not been reported. Randomized, controlled, modified Latin square parallel design study with 2 treatment arms. The 112 participants were randomly assigned to a diet with or without dietary counseling to adjust calorie intake. Within each treatment arm, participants were further randomized to 1 of the 2 possible sequence permutations to receive a walnut-included diet with 56 g (providing 366 kcal) of walnuts per day and a walnut-excluded diet. Participants were assessed for diet quality, body composition, and cardiac risk measures. When compared with a walnut-excluded diet, a walnut-included diet for 6 months, with or without dietary counseling to adjust caloric intake, significantly improved diet quality as measured by the Healthy Eating Index 2010 (9.14±17.71 vs 0.40±15.13; p=0.02 and 7.02±15.89 vs -5.92±21.84; p=0.001, respectively). Endothelial function, total and low-density lipoprotein (LDL) cholesterol improved significantly from baseline in the walnut-included diet. Body mass index, percent body fat, visceral fat, fasting glucose, glycated hemoglobin, and blood pressure did not change significantly. The inclusion of walnuts in an ad libitum diet for 6 months, with or without dietary counseling to adjust calorie intake, significantly improved diet quality, endothelial function, total and LDL cholesterol, but had no effects on anthropometric measures, blood glucose level, and blood pressure. NCT02330848.


The neuroinflammatory response in plaques and amyloid angiopathy in Alzheimer's disease: therapeutic implications.
The amyloid plaques in Alzheimer's disease (AD) brains are co-localised with a broad variety of inflammation-related proteins (complement proteins, acute-phase proteins, pro-inflammatory cytokines) and clusters of activated microglia. The present data suggest that the Abeta depositions in the neuroparenchyma are closely associated with a locally-induced, non-immune-mediated chronic inflammatory response. Clinicopathological and neuroradiological data show that activation of microglia are a relatively early pathogenic event that precedes the process of severe neuropil destruction in patients. Recent gene findings (cDNA microarray) confirm the immunohistochemical findings of an early involvement of inflammatory and regenerative pathways in AD pathogenesis. Abeta deposition, inflammation and regenerative mechanisms are also early pathogenic events in transgenic mice models harbouring the pathological AD mutations, while "later" neurodegenerative characteristics are not seen in these models. Next to the plaques, Abeta amyloid deposition is frequently found in the walls of cerebral vessels (cerebral amyloid angiopathy). Most common is the type of amyloid deposition in the walls of meningeal and medium-sized cortical arteries, and more rarely, microcapillary amyloid angiopathy (dyshoric angiopathy). Immunohistochemical studies show that in AD patients, the majority of the amyloid deposits in the walls of the larger vessels is not associated with a chronic inflammatory response in contrast to micro-capillary amyloid angiopathy. In this contribution, we will give an overview of the similarities and differences between the involvement of inflammatory mechanisms in vascular and plaque amyloid in AD and transgenic models. The implications of the reviewed studies for an inflammation-based therapeutical approach in AD will be discussed.


Integrating molecular probes and molecular dynamics to reveal binding modes of GLUT5 activatory and inhibitory ligands.
Fructose transporter GLUT5 is characterized by unusual substrate specificity and is linked to a variety of metabolic disorders. A series of high-affinity GLUT5-specific sugar-based probes - ManCous - have been very recently described and efficiently used as reporters of GLUT5 activity in cells. Here we present several 1 microsecond molecular dynamics (MD) simulations of GLUT5 and its complexes with fructose and two different ManCou probes, in a solvated cell membrane environment. These simulations show key molecular interactions within GLUT5 that promote the passage of the substrate through vs. blockage of the transport mechanism. Identification of these specific interactions and their long-range effects on GLUT5 structure and dynamics provides an essential basis for the future development of GLUT5-specific inhibitors.


Safety and efficacy of a feed additive consisting of a dried extract from the roots of Arctium lappa L. (A. lappa dry extract) for use in cats and dogs (C.I.A.M.).
Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of a dried extract prepared from the roots of Arctium lappa L. (A. lappa dry extract) when used as a sensory additive (flavouring compound) in feed for cats and dogs. A. lappa dry extract is specified to contain at least 2% inulin. Since uncertainty remains concerning the nature of up to 77% of the additive, the FEEDAP Panel was unable to conclude on the safety of the extract at the proposed use levels of up to 40 mg/kg complete feed for cats and dogs. In the absence of data, no conclusions can be drawn on the safety for the user. In the absence of convincing evidence that the extract acts as a flavour in animal feed or has an effect on palatability, the FEEDAP Panel was unable to conclude on the efficacy of the additive.


Assessing four-dimensional radiotherapy planning and respiratory motion-induced dose difference based on biologically effective uniform dose.
Four-dimensional (4D) radiotherapy is considered as a feasible and ideal solution to accommodate intra-fractional respiratory motion during conformal radiation therapy. With explicit inclusion of the temporal changes in anatomy during the imaging, planning, and delivery of radiotherapy, 4D treatment planning in principle provides better dose conformity. However, the clinical benefits of developing 4D treatment plans in terms of tumor control rate and normal tissue complication probability as compared to other treatment plans based on CT images of a fixed respiratory phase remains mostly unproven. The aim of our study is to comprehensively evaluate 4D treatment planning for nine lung tumor cases with both physical and biological measures using biologically effective uniform dose (D =) together with complication-free tumor control probability, P+. Based on the examined lung cancer patients and PTV margin applied, we found similar but not identical curves of DVH, and slightly different mean doses in tumor (up to 1.5%) and normal tissue in all cases when comparing 4D, P0%, and P50% plans. When it comes to biological evaluations, we did not observe definitively PTV size dependence in P+ among these nine lung cancer patients with various sizes of PTV. Moreover, it is not necessary that 4D plans would have better target coverage or higher P+ as compared to a fixed phase IMRT plan. However, on the contrary to significant deviations in P+ (up to 14.7%) observed if delivering the IMRT plan made at end-inhalation incorrectly at end-exhalation phase, we estimated the overall P+, PB, and PI for 4D composite plans that have accounted for intra-fractional respiratory motion.


Plasma noradrenaline concentration and blood pressure in essential hypertension, phaeochromocytoma and depression.
1. Mean plasma noradrenaline concentration was elevated in forty-four patients with established essential hypertension. Eighteen of the hypertensive patients had resting plasma noradrenaline concentrations in the normal range. 2. Patients with endogenous depression had higher mean plasma noradrenaline concentrations but significantly lower blood pressure than patients with essential hypertension. 3. Patients with phaeochromocytoma had plasma noradrenaline concentrations twenty-eight times greater than those found in essential hypertension, but blood pressures were less than 20% higher. 4. It is concluded that excess of sympathetic drive only partly explains the level of the blood pressure in essential hypertension.


Female genital mutilation: what every paediatrician should know.
Female genital mutilation (FGM) is almost always performed on children and consequently paediatricians should have a central role in the detection and prevention of FGM. FGM has no health benefits and can cause lifelong damage to physical and psychological health. Extensive migration of FGM practising communities means that FGM is now a global problem. Paediatricians worldwide need to be familiar with the identification and classification of FGM and its impact upon health as well as current trends in practice. However information about FGM is hampered by the secrecy surrounding the procedure and a lack of rigorous evidence based research. This review summarises what is currently known about the health aspects of FGM and how paediatricians should manage children with FGM in their clinical practice.


Effectiveness of pulse oximetry screening for congenital heart disease in asymptomatic newborns.
To determine the sensitivity, specificity, predictive value, and accuracy of a program of pulse oximetry screening of asymptomatic newborns for critical congenital cardiovascular malformation (CCVM). Pulse oximetry was performed on asymptomatic newborns in the well-infant nurseries of 2 hospitals. Cardiac ultrasound was performed on infants with positive screens (saturation <or=95% at >24 hours). Data regarding true and false positives as well as negatives were collected and analyzed. Oximetry was performed on 11 281 asymptomatic newborns, and 3 cases of CCVM were detected (total anomalous pulmonary venous return x2, truncus arteriosus). During the study interval, there were 9 live births of infants with CCVM from a group of 15 fetuses with CCVM detected by fetal echocardiography. Six infants with CCVM were symptomatic before screening. There was 1 false-positive screen. Two infants with negative screens were readmitted (coarctation, hypoplastic left pulmonary artery with aorto-pulmonary collaterals). Other cardiac diagnoses in the database search were nonurgent, including cases of patent foramen ovale, peripheral pulmonic stenosis, and ventricular septal defect. The prevalence of critical CCVM among all live births was 1 in 564 and among the screened population was 1 in 2256 (sensitivity: 60%; specificity: 99.95%; positive predictive value: 75%; negative predictive value: 99.98%; accuracy: 99.97%). This screening test is simple, noninvasive, and inexpensive and can be administered in conjunction with state-mandated screening. The false-negative screen patients had lesions not amenable to detection by oximetry. The sensitivity, specificity, and predictive value in this population are satisfactory, indicating that screening should be applied to larger populations, particularly where lower rates of fetal detection result in increased CCVM prevalence in asymptomatic newborns.


KCNJ10 gene mutations causing EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function.
Mutations of the KCNJ10 (Kir4.1) K(+) channel underlie autosomal recessive epilepsy, ataxia, sensorineural deafness, and (a salt-wasting) renal tubulopathy (EAST) syndrome. We investigated the localization of KCNJ10 and the homologous KCNJ16 in kidney and the functional consequences of KCNJ10 mutations found in our patients with EAST syndrome. Kcnj10 and Kcnj16 were found in the basolateral membrane of mouse distal convoluted tubules, connecting tubules, and cortical collecting ducts. In the human kidney, KCNJ10 staining was additionally observed in the basolateral membrane of the cortical thick ascending limb of Henle's loop. EM of distal tubular cells of a patient with EAST syndrome showed reduced basal infoldings in this nephron segment, which likely reflects the morphological consequences of the impaired salt reabsorption capacity. When expressed in CHO and HEK293 cells, the KCNJ10 mutations R65P, G77R, and R175Q caused a marked impairment of channel function. R199X showed complete loss of function. Single-channel analysis revealed a strongly reduced mean open time. Qualitatively similar results were obtained with coexpression of KCNJ10/KCNJ16, suggesting a dominance of KCNJ10 function in native renal KCNJ10/KCNJ16 heteromers. The decrease in the current of R65P and R175Q was mainly caused by a remarkable shift of pH sensitivity to the alkaline range. In summary, EAST mutations of KCNJ10 lead to impaired channel function and structural changes in distal convoluted tubules. Intriguingly, the metabolic alkalosis present in patients carrying the R65P mutation possibly improves residual function of KCNJ10, which shows higher activity at alkaline pH.


The neurobiology of food intake in an obesogenic environment.
The objective of this non-systematic review of the literature is to highlight some of the neural systems and pathways that are affected by the various intake-promoting aspects of the modern food environment and explore potential modes of interaction between core systems such as hypothalamus and brainstem primarily receptive to internal signals of fuel availability and forebrain areas such as the cortex, amygdala and meso-corticolimbic dopamine system, primarily processing external signals. The modern lifestyle with its drastic changes in the way we eat and move puts pressure on the homoeostatic system responsible for the regulation of body weight, which has led to an increase in overweight and obesity. The power of food cues targeting susceptible emotions and cognitive brain functions, particularly of children and adolescents, is increasingly exploited by modern neuromarketing tools. Increased intake of energy-dense foods high in fat and sugar is not only adding more energy, but may also corrupt neural functions of brain systems involved in nutrient sensing as well as in hedonic, motivational and cognitive processing. It is concluded that only long-term prospective studies in human subjects and animal models with the capacity to demonstrate sustained over-eating and development of obesity are necessary to identify the critical environmental factors as well as the underlying neural systems involved. Insights from these studies and from modern neuromarketing research should be increasingly used to promote consumption of healthy foods.


Proactive dairy cattle disease control in the UK: veterinary surgeons' involvement and associated characteristics.
Characteristics of 94 veterinary surgeons associated with delivering preventive herd-level strategies to control mastitis, lameness and Johne's disease were investigated using two multinomial models. The response variables were 'Gold Standard Monitoring' (including on-going data analysis, risk assessments and laboratory testing), and a lower level of involvement called 'Regular Control Advice'. Although the sample was biased towards those who spend the majority of their time with dairy cows, 69 per cent currently had no involvement in Gold Standard Monitoring for lameness, 60 per cent no involvement with Johne's, and 52 per cent no involvement with mastitis. The final model predicted that an assistant without a postgraduate cattle qualification, who had spent no time on dairy cattle continuous professional development (CPD) in the last year, had an 88 per cent chance of having no involvement with Gold Standard Monitoring for any disease, versus <5 per cent chance for a CPD 'enriched' partner with a postgraduate cattle qualification; there was <1 per cent chance this assistant would be involved with Gold Standard Monitoring of all three diseases on one or more farms, versus a 58 per cent chance for this partner. CPD and employment status were also associated with markedly different probabilities for delivering Regular Control Advice. Increased postgraduate education may further veterinary involvement of this nature.


Bayesian deconvolution of mass and ion mobility spectra: from binary interactions to polydisperse ensembles.
Interpretation of mass spectra is challenging because they report a ratio of two physical quantities, mass and charge, which may each have multiple components that overlap in m/z. Previous approaches to disentangling the two have focused on peak assignment or fitting. However, the former struggle with complex spectra, and the latter are generally computationally intensive and may require substantial manual intervention. We propose a new data analysis approach that employs a Bayesian framework to separate the mass and charge dimensions. On the basis of this approach, we developed UniDec (Universal Deconvolution), software that provides a rapid, robust, and flexible deconvolution of mass spectra and ion mobility-mass spectra with minimal user intervention. Incorporation of the charge-state distribution in the Bayesian prior probabilities provides separation of the m/z spectrum into its physical mass and charge components. We have evaluated our approach using systems of increasing complexity, enabling us to deduce lipid binding to membrane proteins, to probe the dynamics of subunit exchange reactions, and to characterize polydispersity in both protein assemblies and lipoprotein Nanodiscs. The general utility of our approach will greatly facilitate analysis of ion mobility and mass spectra.


Comparative study between four ultrasound Shear Waves Elastographic methods for liver fibrosis assessment.
Non-invasive methods to assess the severity of chronic liver diseases have become more and more popular. The aim of our study was to evaluate the correlation of four Shear Waves Elastographic methods in a cohort of patients with chronic liver diseases of mixed etiologies and to compare their performances for liver fibrosis evaluation. A prospective study was conducted on 127 consecutive patients with chronic liver diseases of mixed etiologies. LS measurements were performed in all subjects, in one session, during the same day, by means of 4 elastographic methods: Transient Elastography (TE), Virtual Touch Quantification (VTQ), ElastPQ and 2D-SWE.SSI. The diagnosis accuracies of VTQ, ElastPQ, 2D-SWE.SSI were then compared using TE as reference method. Valid LS measurements by all four shear waves ultrasound elastographic methods were obtained in 116/127 subjects with VTQ, in 108/127 subjects with 2D-SWE.SSI, in 111/127 with TE and in 109/127 with ElastPQ, so the final analysis included 82/127 subjects (64.5%). A good and significant correlation was found between all 4 elastographic methods. The diagnostic accuracy of VTQ, 2D-SWE.SSI and ElastPQ for the diagnosis of significant and severe fibrosis (F2/F3), and liver cirrhosis were similar for all elastographic techniques: VTQ vs 2D-SWE.SSI vs ElastPQ: 84.1% vs 85.3% vs. 84% (p>0.05); 93.9% vs 94% vs 94% (p>0.05). considering TE as the reference method for liver fibrosis evaluation, VTQ, ElastPQ, and 2D-SWE.SSI obtained similar accuracies for diagnosing at least significant fibrosis (F≥2) and liver cirrhosis.


CENTS: cortical enhanced neonatal tissue segmentation.
The acquisition of high-quality magnetic resonance (MR) images of neonatal brains is largely hampered by their characteristically small head size and insufficient tissue contrast. As a result, subsequent image processing and analysis, especially brain tissue segmentation, are often affected. To overcome this problem, a dedicated phased array neonatal head coil is utilized to improve MR image quality by augmenting signal-to-noise ratio and spatial resolution without lengthening data acquisition time. In addition, a specialized hybrid atlas-based tissue segmentation algorithm is developed for the delineation of fine structures in the acquired neonatal brain MR images. The proposed tissue segmentation method first enhances the sheet-like cortical gray matter (GM) structures in the to-be-segmented neonatal image with a Hessian filter for generation of a cortical GM confidence map. A neonatal population atlas is then generated by averaging the presegmented images of a population, weighted by their cortical GM similarity with respect to the to-be-segmented image. Finally, the neonatal population atlas is combined with the GM confidence map, and the resulting enhanced tissue probability maps for each tissue form a hybrid atlas is used for atlas-based segmentation. Various experiments are conducted to compare the segmentations of the proposed method with manual segmentation (on both images acquired with a dedicated phased array coil and a conventional volume coil), as well as with the segmentations of two population-atlas-based methods. Results show the proposed method is capable of segmenting the neonatal brain with the best accuracy, and also preserving the most structural details in the cortical regions.


HLA class I molecules are not transported to the cell surface in cells infected with herpes simplex virus types 1 and 2.
To assess the effect of herpes simplex virus (HSV) on assembly and transport of class I MHC molecules, we compared class I MHC immunoprecipitated from metabolically labeled infected and uninfected human dermal fibroblasts. The immunoprecipitates were analyzed by isoelectric focusing, allowing identification of individual class I alleles and assessment of transport through the Golgi apparatus by the sialation of carbohydrate residues. In cells infected with wild-type HSV, class I synthesis was reduced or abolished because of the host protein synthesis shutoff function of the UL41 gene product. In cells infected with mutant viruses of both HSV-2 strain G and HSV-1 strain 17 that lack the UL41 gene, class I HLA molecules failed to become sialated, suggesting that they were not transported to the Golgi apparatus. In contrast, transferrin receptor was normally sialated in both infected and uninfected cells. Drug treatments of cells to restrict viral gene expression suggested that an early gene or genes were responsible for the effect. A pulse chase showed that class I molecules were synthesized in normal amounts in infected cells, but that heavy chains were retained in a sialyl transferase negative compartment either stably associated with beta 2m or as free heavy chain in a pattern that is characteristic for each class I allele. HSV is thus the fourth example of a DNA virus that interferes with class I assembly or transport.