Pain Acceptance Among Retired National Football League Athletes: Implications for Clinical Intervention.
Over 80% of National Football League (NFL) retirees experience daily pain. Pain acceptance is an important psychological construct implicated in the intensity of chronic pain, though these findings have not been extended to NFL retirees. Therefore, the current study examined the association between pain acceptance and pain intensity among former NFL athletes. NFL retirees (N = 90) recruited from 2018 to 2019 completed questionnaires that assessed pain, substance use, and NFL career information. Multiple linear regression examined the association between current pain acceptance and pain intensity while adjusting for other risk factors of pain. NFL retirees reported average scores of 33.31 (SD = 10.00), and 2.18 (SD = 2.40) on measures of pain acceptance and pain intensity, respectively. After covariate adjustment, greater pain acceptance (β = -0.538, p < .001) was associated with lower pain intensity. These findings can further inform the behavioral and mental health care of retired NFL athletes.


Discovery of novel GPVI receptor antagonists by structure-based repurposing.
Inappropriate platelet aggregation creates a cardiovascular risk that is largely managed with thienopyridines and aspirin. Although effective, these drugs carry risks of increased bleeding and drug 'resistance', underpinning a drive for new antiplatelet agents. To discover such drugs, one strategy is to identify a suitable druggable target and then find small molecules that modulate it. A good and unexploited target is the platelet collagen receptor, GPVI, which promotes thrombus formation. To identify inhibitors of GPVI that are safe and bioavailable, we docked a FDA-approved drug library into the GPVI collagen-binding site in silico. We now report that losartan and cinanserin inhibit GPVI-mediated platelet activation in a selective, competitive and dose-dependent manner. This mechanism of action likely underpins the cardioprotective effects of losartan that could not be ascribed to its antihypertensive effects. We have, therefore, identified small molecule inhibitors of GPVI-mediated platelet activation, and also demonstrated the utility of structure-based repurposing.


A population-based study of hospital care costs during 5 years after transient ischemic attack and stroke.
Few studies have evaluated long-term costs after stroke onset, with almost no cost data for transient ischemic attack (TIA). We studied hospital costs during the 5 years after TIA or stroke in a population-based study. Patients from a United Kingdom population-based cohort study (Oxford Vascular Study) were recruited from 2002 to 2007. Analysis was based on follow-up until 2010. Hospital resource usage was obtained from patient hospital records and valued using 2008/2009 unit costs. Because not all patients had full 5-year follow-up, we used nonparametric censoring techniques. Among 485 TIA and 729 stroke patients ascertained and included, mean censor-adjusted 5-year hospital costs after index stroke were $25,741 (95% confidence interval, 23,659-27,914), with costs varying considerably by severity: $21,134 after minor stroke; $33,119 after moderate stroke; and $28,552 after severe stroke. For the 239 surviving stroke patients who had reached final follow-up, mean costs were $24,383 (95% confidence interval, 20,156-28,595), with more than half of costs ($12,972) being incurred in the first year after the event. After index TIA, the mean censor-adjusted 5-year costs were $18,091 (95% confidence interval, 15,947-20,258). A multivariate analysis showed that event severity, recurrent stroke, and coronary events after the index event were independent predictors of 5-year costs. Differences by stroke subtype were mostly explained by stroke severity and subsequent events. Long-term hospital costs after TIA and stroke are considerable, but they are mainly incurred during the first year after the index event. Event severity and experiencing subsequent stroke and coronary events after the index event accounted for much of the increase in costs.


Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7.
To further resolve the genetic architecture of the inflammatory bowel diseases ulcerative colitis and Crohn's disease, we sequenced the whole genomes of 4,280 patients at low coverage and compared them to 3,652 previously sequenced population controls across 73.5 million variants. We then imputed from these sequences into new and existing genome-wide association study cohorts and tested for association at ∼12 million variants in a total of 16,432 cases and 18,843 controls. We discovered a 0.6% frequency missense variant in ADCY7 that doubles the risk of ulcerative colitis. Despite good statistical power, we did not identify any other new low-frequency risk variants and found that such variants explained little heritability. We detected a burden of very rare, damaging missense variants in known Crohn's disease risk genes, suggesting that more comprehensive sequencing studies will continue to improve understanding of the biology of complex diseases.


To leave an area after disaster: how evacuees from the WTC buildings left the WTC area following the attacks.
How people leave a devastated area after a disaster is critical to understanding their ability to cope with risks they face while evacuating. Knowledge of their needs for communications about these risks is particularly crucial in planning for emergency responses. A convenience sample of 1,444 persons who survived the World Trade Center (WTC) attacks on September 11, 2001 were surveyed to ascertain their initial and ultimate destinations once they had left the buildings, how they arrived there, the role of types of obstacles they encountered, and the need for information and the seeking of other people as potential factors in influencing the process of leaving immediately. This survey was part of a larger, original survey. Results showed differences in how people traveled by mode to initial and ultimate destinations, how immediately they left the area, and factors associated with when they left. How they traveled and when they left were associated with where people lived, their tendency in times of stress to seek out other people including who they knew in the immediate area (e.g., co-workers or friends), the physical conditions surrounding them, and the importance to some of waiting for more information. Many people indicated they did not leave immediately because they had no information about where to go or what services would be available to them. Perceptions and communications about risks they were facing were reflected in the choices they considered in how and when to leave the area. These findings have numerous ramifications for understanding and guiding personal behavior in catastrophic situations.


Reported frequency of physical activity in a large epidemiological study: relationship to specific activities and repeatability over time.
How overall physical activity relates to specific activities and how reported activity changes over time may influence interpretation of observed associations between physical activity and health. We examine the relationships between various physical activities self-reported at different times in a large cohort study of middle-aged UK women. At recruitment, Million Women Study participants completed a baseline questionnaire including questions on frequency of strenuous and of any physical activity. About 3 years later 589,896 women also completed a follow-up questionnaire reporting the hours they spent on a range of specific activities. Time spent on each activity was used to estimate the associated excess metabolic equivalent hours (MET-hours) and this value was compared across categories of physical activity reported at recruitment. Additionally, 18,655 women completed the baseline questionnaire twice, at intervals of up to 4 years; repeatability over time was assessed using the weighted kappa coefficient (κweighted) and absolute percentage agreement. The average number of hours per week women reported doing specific activities was 14.0 for housework, 4.5 for walking, 3.0 for gardening, 0.2 for cycling, and 1.4 for all strenuous activity. Time spent and the estimated excess MET-hours associated with each activity increased with increasing frequency of any or strenuous physical activity reported at baseline (tests for trend, P < 0.003), although the associations for housework were by far the weakest (Spearman correlations, 0.01 and -0.03 respectively for housework, and 0.11-0.37 for all other activities). Repeatability of responses to physical activity questions on the baseline questionnaire declined significantly over time. For strenuous activity, absolute agreement was 64% (κweighted = 0.71) for questionnaires administered less than 6 months apart, and 52% (κweighted = 0.51) for questionnaires more than 2 years apart. Corresponding values for any physical activity were 57% (κweighted = 0.67) and 47% (κweighted = 0.58). In this cohort, responses to simple questions on the frequency of any physical activity and of strenuous activity asked at baseline were associated with hours spent on specific activities and the associated estimated excess MET-hours expended, reported 3 years later. The weakest associations were with housework. Agreement for identical questions asked on two occasions about the frequency of physical activity decreased over time.


Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade.
To examine the mechanism by which free fatty acids (FFAs) induce insulin resistance in vivo, awake chronically catheterized rats underwent a hyperinsulinemic-euglycemic clamp with or without a 5-h preinfusion of lipid/heparin to raise plasma FFA concentrations. Increased plasma FFAs resulted in insulin resistance as reflected by a approximately 35% reduction in the glucose infusion rate (P < 0.05 vs. control). The insulin resistance was associated with a 40-50% reduction in 13C nuclear magnetic resonance (NMR)-determined rates of muscle glycogen synthesis (P < 0.01 vs. control) and muscle glucose oxidation (P < 0.01 vs. control), which in turn could be attributed to a approximately 25% reduction in glucose transport activity as assessed by 2-[1,2-3H]deoxyglucose uptake in vivo (P < 0.05 vs. control). This lipid-induced decrease in insulin-stimulated muscle glucose metabolism was associated with 1) a approximately 50% reduction in insulin-stimulated insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase activity (P < 0.05 vs. control), 2) a blunting in insulin-stimulated IRS-1 tyrosine phosphorylation (P < 0.05, lipid-infused versus glycerol-infused), and 3) a four-fold increase in membrane-bound, or active, protein kinase C (PKC) theta (P < 0.05 vs. control). We conclude that acute elevations of plasma FFA levels for 5 h induce skeletal muscle insulin resistance in vivo via a reduction in insulin-stimulated muscle glycogen synthesis and glucose oxidation that can be attributed to reduced glucose transport activity. These changes are associated with abnormalities in the insulin signaling cascade and may be mediated by FFA activation of PKC theta.


How a vicinal layer of solvent modulates the dynamics of proteins.
The dynamics of a folded protein is studied in water and glycerol at a series of temperatures below and above their respective dynamical transition. The system is modeled in two distinct states whereby the protein is decoupled from the bulk solvent at low temperatures, and communicates with it through a vicinal layer at physiological temperatures. A linear viscoelastic model elucidates the less-than-expected increase in the relaxation times observed in the backbone dynamics of the protein. The model further explains the increase in the flexibility of the protein once the transition takes place and the differences in the flexibility under the different solvent environments. Coupling between the vicinal layer and the protein fluctuations is necessary to interpret these observations. The vicinal layer is postulated to form once a threshold for the volumetric fluctuations in the protein to accommodate solvents of different sizes is reached. Compensation of entropic-energetic contributions from the protein-coupled vicinal layer quantifies the scaling of the dynamical transition temperatures in various solvents. The protein adapts different conformational routes for organizing the required coupling to a specific solvent, which is achieved by adjusting the amount of conformational jumps in the surface-group dihedrals.


Attribution, cognition and psychopathology in persistent insomnia disorder: outcome and mediation analysis from a randomized placebo-controlled trial of online cognitive behavioural therapy.
Insomnia patients complain that mental events keep them awake. This study investigates how cognitive behavioural therapy (CBT) affects such events and considers how attributional, cognitive and psychopathological symptoms may mediate sleep improvement. A pragmatic, parallel-group randomized controlled trial of 164 adults (120 F: (mean 49 years (18-78 years)) meeting Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for insomnia disorder, assigned to CBT (n=55; 40 F), imagery relief therapy (IRT placebo; n=55; 42 F), or treatment as usual (TAU; n=54; 38 F), was conducted. CBT/IRT comprised six online sessions delivered by an animated therapist, with automated web/e-mail support. CBT users had access to a moderated community. TAU comprised 'usual care'. Participants completed the Sleep Disturbance Questionnaire (SDQ), Glasgow Content of Thoughts Inventory (GCTI), Depression Anxiety and Stress Scales (DASS) and Sleep Condition Indicator (SCI) at baseline, post treatment and 8-week follow-up. The sample was characterised by mental arousal, notably 'trying too hard' to sleep (SDQ), and by 'sleep and sleeplessness' and 'rehearsal and planning' thoughts (GCTI). Treatment effects were observed for all SDQ domains (e.g., CBT vs. IRT: d=0.76 for 'trying too hard'). CBT was also superior to IRT on the GCTI (e.g., 'rehearsal and planning', d=0.62; 'sleep and sleeplessness', d=0.74). CBT vs. TAU comparisons yielded larger effects, whereas placebo effects (IRT vs. TAU) were small to moderate. Hierarchical regression demonstrated partial mediation of SCI improvement by attributional and cognitive factors (R2 = 21-27%) following CBT. Improvement in sleep efficiency appears to be independent of such factors. Online CBT modifies sleep-related attributions, night-time thought content and psychopathology. This process partly mediates improvement in DSM-5-defined insomnia.


Cavemen were better at depicting quadruped walking than modern artists: erroneous walking illustrations in the fine arts from prehistory to today.
The experts of animal locomotion well know the characteristics of quadruped walking since the pioneering work of Eadweard Muybridge in the 1880s. Most of the quadrupeds advance their legs in the same lateral sequence when walking, and only the timing of their supporting feet differ more or less. How did this scientific knowledge influence the correctness of quadruped walking depictions in the fine arts? Did the proportion of erroneous quadruped walking illustrations relative to their total number (i.e. error rate) decrease after Muybridge? How correctly have cavemen (upper palaeolithic Homo sapiens) illustrated the walking of their quadruped prey in prehistoric times? The aim of this work is to answer these questions. We have analyzed 1000 prehistoric and modern artistic quadruped walking depictions and determined whether they are correct or not in respect of the limb attitudes presented, assuming that the other aspects of depictions used to determine the animals gait are illustrated correctly. The error rate of modern pre-Muybridgean quadruped walking illustrations was 83.5%, much more than the error rate of 73.3% of mere chance. It decreased to 57.9% after 1887, that is in the post-Muybridgean period. Most surprisingly, the prehistoric quadruped walking depictions had the lowest error rate of 46.2%. All these differences were statistically significant. Thus, cavemen were more keenly aware of the slower motion of their prey animals and illustrated quadruped walking more precisely than later artists.


Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort.
To examine the hypothesis that risk of oesophageal, but not of gastric or colorectal, cancer is increased in users of oral bisphosphonates. Nested case-control analysis within a primary care cohort of about 6 million people in the UK, with prospectively recorded information on prescribing of bisphosphonates. UK General Practice Research Database cohort. Men and women aged 40 years or over-2954 with oesophageal cancer, 2018 with gastric cancer, and 10 641 with colorectal cancer, diagnosed in 1995-2005; five controls per case matched for age, sex, general practice, and observation time. Relative risks for incident invasive cancers of the oesophagus, stomach, and colorectum, adjusted for smoking, alcohol, and body mass index. The incidence of oesophageal cancer was increased in people with one or more previous prescriptions for oral bisphosphonates compared with those with no such prescriptions (relative risk 1.30, 95% confidence interval 1.02 to1.66; P=0.02). Risk of oesophageal cancer was significantly higher for 10 or more prescriptions (1.93, 1.37 to 2.70) than for one to nine prescriptions (0.93, 0.66 to 1.31) (P for heterogeneity=0.002), and for use for over 3 years (on average, about 5 years: relative risk v no prescription, 2.24, 1.47 to 3.43). Risk of oesophageal cancer did not differ significantly by bisphosphonate type, and risk in those with 10 or more bisphosphonate prescriptions did not vary by age, sex, smoking, alcohol intake, or body mass index; by diagnosis of osteoporosis, fracture, or upper gastrointestinal disease; or by prescription of acid suppressants, non-steroidal anti-inflammatory drugs, or corticosteroids. Cancers of the stomach and colorectum were not associated with prescription of bisphosphonate: relative risks for one or more versus no prescriptions were 0.87 (0.64 to 1.19) and 0.87 (0.77 to 1.00). The specificity of the association for oesophageal cancer argues against methodological problems in the selection of cases and controls or in the analysis. The risk of oesophageal cancer increased with 10 or more prescriptions for oral bisphosphonates and with prescriptions over about a five year period. In Europe and North America, the incidence of oesophageal cancer at age 60-79 is typically 1 per 1000 population over five years, and this is estimated to increase to about 2 per 1000 with five years' use of oral bisphosphonates.


Rates of molecular evolution in RNA viruses: a quantitative phylogenetic analysis.
The study of rates of nucleotide substitution in RNA viruses is central to our understanding of their evolution. Herein we report a comprehensive analysis of substitution rates in 50 RNA viruses using a recently developed maximum likelihood phylogenetic method. This analysis revealed a significant relationship between genetic divergence and isolation time for an extensive array of RNA viruses, although more rate variation was usually present among lineages than would be expected under the constraints of a molecular clock. Despite the lack of a molecular clock, the range of statistically significant variation in overall substitution rates was surprisingly narrow for those viruses where a significant relationship between genetic divergence and time was found, as was the case when synonymous sites were considered alone, where the molecular clock was rejected less frequently. An analysis of the ecological and genetic factors that might explain this rate variation revealed some evidence of significantly lower substitution rates in vector-borne viruses, as well as a weak correlation between rate and genome length. Finally, a simulation study revealed that our maximum likelihood estimates of substitution rates are valid, even if the molecular clock is rejected, provided that sufficiently large data sets are analyzed.


Chromatin and transcriptional signatures for Nodal signaling during endoderm formation in hESCs.
The first stages of embryonic differentiation are driven by signaling pathways hardwired to induce particular fates. Endoderm commitment is controlled by the TGF-β superfamily member, Nodal, which utilizes the transcription factors, SMAD2/3, SMAD4 and FOXH1, to drive target gene expression. While the role of Nodal is well defined within the context of endoderm commitment, mechanistically it is unknown how this signal interacts with chromatin on a genome wide scale to trigger downstream responses. To elucidate the Nodal transcriptional network that governs endoderm formation, we used ChIP-seq to identify genomic targets for SMAD2/3, SMAD3, SMAD4, FOXH1 and the active and repressive chromatin marks, H3K4me3 and H3K27me3, in human embryonic stem cells (hESCs) and derived endoderm. We demonstrate that while SMAD2/3, SMAD4 and FOXH1 associate with DNA in a highly dynamic fashion, there is an optimal bivalent signature at 32 gene loci for driving endoderm commitment. Initially, this signature is marked by both H3K4me3 and H3K27me3 as a very broad bivalent domain in hESCs. Within the first 24h, SMAD2/3 accumulation coincides with H3K27me3 reduction so that these loci become monovalent marked by H3K4me3. JMJD3, a histone demethylase, is simultaneously recruited to these promoters, suggesting a conservation of mechanism at multiple promoters genome-wide. The correlation between SMAD2/3 binding, monovalent formation and transcriptional activation suggests a mechanism by which SMAD proteins coordinate with chromatin at critical promoters to drive endoderm specification.


Optimising beamformer regions of interest analysis.
Beamforming is a spatial filtering based source reconstruction method for EEG and MEG that allows the estimation of neuronal activity at a particular location within the brain. The computation of the location specific filter depends solely on an estimate of the data covariance matrix and on the forward model. Increasing the number of M/EEG sensors, increases the quantity of data required for accurate covariance matrix estimation. Often however we have a prior hypothesis about the site of, or the signal of interest. Here we show how this prior specification, in combination with optimal estimations of data dimensionality, can give enhanced beamformer performance for relatively short data segments. Specifically we show how temporal (Bayesian Principal Component Analysis) and spatial (lead field projection) methods can be combined to produce improvements in source estimation over and above employing the approaches individually.


Adapted Physical Education Teachers' Job Satisfaction.
Grounded in occupational socialization theory, the authors examined adapted physical education (APE) teachers' job satisfaction. Twelve (nine female and three male) APE teachers who had 3-43 years of teaching experience participated in the study. A semistructured interview was employed. The interviews focused on the participants' roles and responsibilities. The following questions guided this study: (a) What social agents positively impact APE teachers' job satisfaction? (b) what APE teachers' roles and responsibilities are related to job satisfaction? and (c) what type of working conditions are linked to APE teachers' job satisfaction? Thematic analysis was employed to analyze the data. The following four themes emerged from the analysis: (a) support from administrators, physical education teachers, and colleagues; (b) relevant and meaningful professional development; (c) itinerant working conditions; and (d) seeing students' progress and achievement. The results of this study provide several implications to enhance APE teachers' job satisfaction.


Bioreduction of idarubicin and formation of ROS responsible for DNA cleavage by NADPH-cytochrome P450 reductase and its potential role in the antitumor effect.
Idarubicin is a clinically effective synthetic anthracycline analog used in the treatment of several human neoplasms. Anthracyclines have the potential to undergo bioactivation by flavoenzymes to free radicals and thus exert their cytotoxic actions. In this study, our main objective was to investigate the possible involvement of NADPH-cytochrome P450 reductase in the bioreductive activation of idarubicin to DNA-damaging species. A pBR322 plasmid DNA damage assay was used as a sensitive method for detecting strand breaks in DNA exposed to idarubicin in the presence of P450 reductase and cofactor NADPH under various incubation conditions. In addition, the rates of idarubicin reduction by P450 reductases purified from phenobarbital-treated rabbit liver, beef liver and sheep lung microsomes were determined by measuring NADPH oxidation at 340 nm. The plasmid DNA experiments demonstrated that idarubicin could undergo bioreduction by P450 reductase with the resulting formation of DNA strand breaks. The antioxidant enzymes SOD and catalase, and hydroxyl radical scavengers, DMSO and thiourea, afforded significant levels of protection against idarubicin-induced DNA strand breaks. These findings suggested that DNA damage by idarubicin occurs through a mechanism which involves its redox cycling with P450 reductase to generate reactive oxygen species (ROS). The extent of DNA damage by idarubicin was found to increase with increasing concentrations of drug or enzyme as well as with increasing incubation time. The capacity of idarubicin to induce DNA damage under above incubation conditions was compared with that of a model compound, mitomycin C. Finally, enzyme assays carried out with purified P450 reductases revealed that idarubicin exhibited about two-fold higher rate of reduction than mitomycin C. Our findings implicated bioreduction of idarubicin by P450 reductase and subsequent redox cycling under aerobic conditions as being one mode of idarubicin action potentially contributing to its antitumor effect.


The effects of medication and current mood upon facial emotion recognition: findings from a large bipolar disorder cohort study.
Emotional processing abnormalities have been implicated in bipolar disorder (BD) but studies are typically small and uncontrolled. Here, facial expression recognition was explored in a large and naturalistically recruited cohort of BD patients. 271 patients with BD completed the facial expression recognition task. The effects of current medication together with the influence of current mood state and diagnostic subtype were assessed whilst controlling for the effects of demographic variables. Patients who were currently receiving treatment with lithium demonstrated significantly poorer accuracy in recognising angry faces, an effect that held in a monotherapy sub-analysis comparing those participants on lithium only and those who were medication-free. Accuracy in recognising angry faces was also lower amongst participants currently taking dopamine antagonists (antipsychotics). Higher levels of current depressive symptoms were linked to poorer accuracy at identifying happy faces. Use of lithium and possibly dopamine antagonists may be associated with reduced processing of anger cues in BD. Findings support the existence of mood-congruent negative biases associated with depressive symptoms in BD. Observational cohort studies provide opportunities to explore the substantial effects of demographic, psychometric and clinical variables on cognitive performance and emotional processing.


Effect of inhaled acetone concentrations on exhaled breath acetone concentrations at rest and during exercise.
Real-time measurements of the differences in inhaled and exhaled, unlabeled and fully deuterated acetone concentration levels, at rest and during exercise, have been conducted using proton transfer reaction mass spectrometry. A novel approach to continuously differentiate between the inhaled and exhaled breath acetone concentration signals is used. This leads to unprecedented fine grained data of inhaled and exhaled concentrations. The experimental results obtained are compared with those predicted using a simple three compartment model that theoretically describes the influence of inhaled concentrations on exhaled breath concentrations for volatile organic compounds with high blood:air partition coefficients, and hence is appropriate for acetone. An agreement between the predicted and observed concentrations is obtained. Our results highlight that the influence of the upper airways cannot be neglected for volatiles with high blood:air partition coefficients, i.e. highly water soluble volatiles.


Empirical explorations of mindfulness: conceptual and methodological conundrums.
This commentary reflects on the articles in this Special Issue. The appearance of this group of articles underscores the important idea that a major target of mindfulness practice is on emotion. Transformation in trait affect is a key goal of all contemplative traditions. This commentary addresses several key methodological and conceptual issues in the empirical study of mindfulness. The many ways in which the term "mindfulness" is used in the articles in this Special Issue are noted, and they include its reference to states, traits, and independent variables that are manipulated in an experimental context. How the term "mindfulness" is conceptualized and operationalized is crucial, and for progress to be made it is essential that we qualify the use of this term by reference to how it is being operationalized in each context. Other methodological issues are considered, such as the duration of training and how it should be measured, and the nature of control and comparison groups in studies of mindfulness-based interventions. Finally, the commentary ends with a consideration of the targets within emotion processing that are likely to be impacted by mindfulness. This collection of articles underscores the substantial progress that has occurred in the empirical study of mindfulness and it is a harbinger of a very promising future in this area.


Hepatic encephalopathy: a central neuroinflammatory disorder?
Encephalopathy and brain edema are serious central nervous system complications of liver failure. Recent studies using molecular probes and antibodies to cell-specific marker proteins have demonstrated the activation of microglial cells in the brain during liver failure and confirmed a central neuroinflammatory response. In animal models of ischemic or toxic liver injury, microglial activation and concomitantly increased expression of genes coding for proinflammatory cytokines in the brain occur early in the progression of encephalopathy and brain edema. Moreover, the prevention of these complications with mild hypothermia or N-acetylcysteine (two treatments known to manifest both peripheral and central cytoprotective properties) averts central neuroinflammation due to liver failure. Recent studies using anti-inflammatory agents such as ibuprofen and indomethacin have shown promise for the treatment of mild encephalopathy in patients with cirrhosis, whereas treatment with minocycline, a potent inhibitor of microglial activation, attenuates the encephalopathy grade and prevents brain edema in experimental acute liver failure. The precise nature of the signaling mechanisms between the failing liver and central neuroinflammation has yet to be fully elucidated; mechanisms involving blood-brain cytokine transfer and receptor-mediated cytokine signal transduction as well as a role for liver-related toxic metabolites such as ammonia have been proposed. The prevention of central proinflammatory processes will undoubtedly herald a new chapter in the development of agents for the prevention and treatment of the central nervous system complications of liver failure.


Estimating hepatitis B virus cccDNA persistence in chronic infection.
Hepatitis B virus (HBV) infection is a major global health problem with over 240 million infected individuals at risk of developing progressive liver disease and hepatocellular carcinoma. HBV is an enveloped DNA virus that establishes its genome as an episomal, covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. Currently, available standard-of-care treatments for chronic hepatitis B (CHB) include nucleos(t)ide analogues (NAs) that suppress HBV replication but do not target the cccDNA and hence rarely cure infection. There is considerable interest in determining the lifespan of cccDNA molecules to design and evaluate new curative treatments. We took a novel approach to this problem by developing a new mathematical framework to model changes in evolutionary rates during infection which, combined with previously determined within-host evolutionary rates of HBV, we used to determine the lifespan of cccDNA. We estimate that during HBe-antigen positive (HBeAgPOS) infection the cccDNA lifespan is 61 (36-236) days, whereas during the HBeAgNEG phase of infection it is only 26 (16-81) days. We found that cccDNA replicative capacity declined by an order of magnitude between HBeAgPOS and HBeAgNEG phases of infection. Our estimated lifespan of cccDNA is too short to explain the long durations of chronic infection observed in patients on NA treatment, suggesting that either a sub-population of long-lived hepatocytes harbouring cccDNA molecules persists during therapy, or that NA therapy does not suppress all viral replication. These results provide a greater understanding of the biology of the cccDNA reservoir and can aid the development of new curative therapeutic strategies for treating CHB.


Honey as a source of dietary antioxidants: structures, bioavailability and evidence of protective effects against human chronic diseases.
In the long human tradition honey has been used not only as a nutrient but also as a medicine. Its composition is rather variable and depends on the floral source and on external factors, such as seasonal, environmental conditions and processing. In this review, specific attention is focused on absorption, metabolism, and beneficial biological activities of honey compounds in human. Honey is a supersaturated solution of sugars, mainly composed of fructose (38%) and glucose (31%), containing also minerals, proteins, free amino acids, enzymes, vitamins and polyphenols. Among polyphenols, flavonoids are the most abundant and are closely related to its biological functions. Honey positively affects risk factors for cardiovascular diseases by inhibiting inflammation, improving endothelial function, as well as the plasma lipid profile, and increasing low-density lipoprotein resistance to oxidation. Honey also displays an important antitumoral capacity, where polyphenols again are considered responsible for its complementary and overlapping mechanisms of chemopreventive activity in multistage carcinogenesis, by inhibiting mutagenesis or inducing apoptosis. Moreover, honey positively modulates the glycemic response by reducing blood glucose, serum fructosamine or glycosylated hemoglobin concentrations and exerts antibacterial properties caused by its consistent amount of hydrogen peroxide and non-peroxide factors as flavonoids, methylglyoxal and defensin-1 peptide. In conclusion, the evidence of the biological actions of honey can be ascribed to its polyphenolic contents which, in turn, are usually associated to its antioxidant and anti-inflammatory actions, as well as to its cardiovascular, antiproliferative and antimicrobial benefits.


Clinical and individual factors associated with smoking quit attempts among adults with COPD: do factors vary with regard to race?
Only half of adults with chronic obstructive pulmonary disease (COPD) report a smoking quit attempt in the past year. Adults with COPD have frequent encounters with the healthcare system that are opportunities for health behavior interventions that support quit attempts. The purpose of this research was to examine individual- and clinical-level factors associated with smoking quit attempts in adults with COPD. Cross-sectional data were from the 2011 Behavioral Risk Factor Surveillance System. Race-stratified, weighted logistic regression examined factors associated with quit attempt among current smokers with COPD. Overall, quit attempt was reported by 65% (95% confidence interval (CI): 61.9, 67.5) of adults and was more likely among blacks than whites (p < 0.0001). Among whites with COPD quit attempt was associated with: Female gender (adjusted odds ratio (AOR) = 1.3; CI: 1.0, 1.7), exercise (AOR = 2.0; CI: 1.5, 2.5), and medications for COPD (AOR = 1.6; CI: 1.3, 2.2). Among black adults with COPD quit attempt was associated with: Having a partner (AOR = 4.5; CI: 1.3, 15.0), exercise (AOR = 3.7; CI: 1.6, 8.7), spirometry (AOR = 9.5; CI: 3.2, 28.7), and having a personal doctor (AOR = 6.4; CI: 1.8, 22.5). Individual and clinical-factors associated with quit attempt varied by race. These findings suggest an impact of the healthcare system that supports quit attempts in blacks but not whites with COPD.


Ribosomal oxygenases are structurally conserved from prokaryotes to humans.
2-Oxoglutarate (2OG)-dependent oxygenases have important roles in the regulation of gene expression via demethylation of N-methylated chromatin components and in the hydroxylation of transcription factors and splicing factor proteins. Recently, 2OG-dependent oxygenases that catalyse hydroxylation of transfer RNA and ribosomal proteins have been shown to be important in translation relating to cellular growth, TH17-cell differentiation and translational accuracy. The finding that ribosomal oxygenases (ROXs) occur in organisms ranging from prokaryotes to humans raises questions as to their structural and evolutionary relationships. In Escherichia coli, YcfD catalyses arginine hydroxylation in the ribosomal protein L16; in humans, MYC-induced nuclear antigen (MINA53; also known as MINA) and nucleolar protein 66 (NO66) catalyse histidine hydroxylation in the ribosomal proteins RPL27A and RPL8, respectively. The functional assignments of ROXs open therapeutic possibilities via either ROX inhibition or targeting of differentially modified ribosomes. Despite differences in the residue and protein selectivities of prokaryotic and eukaryotic ROXs, comparison of the crystal structures of E. coli YcfD and Rhodothermus marinus YcfD with those of human MINA53 and NO66 reveals highly conserved folds and novel dimerization modes defining a new structural subfamily of 2OG-dependent oxygenases. ROX structures with and without their substrates support their functional assignments as hydroxylases but not demethylases, and reveal how the subfamily has evolved to catalyse the hydroxylation of different residue side chains of ribosomal proteins. Comparison of ROX crystal structures with those of other JmjC-domain-containing hydroxylases, including the hypoxia-inducible factor asparaginyl hydroxylase FIH and histone N(ε)-methyl lysine demethylases, identifies branch points in 2OG-dependent oxygenase evolution and distinguishes between JmjC-containing hydroxylases and demethylases catalysing modifications of translational and transcriptional machinery. The structures reveal that new protein hydroxylation activities can evolve by changing the coordination position from which the iron-bound substrate-oxidizing species reacts. This coordination flexibility has probably contributed to the evolution of the wide range of reactions catalysed by oxygenases.


Animal Magnetism: Metaphoric Cues Alter Perceptions of Romantic Partners and Relationships.
The psychological state of love is difficult to define, and we often rely on metaphors to communicate about this state and its constituent experiences. Commonly, these metaphors liken love to a physical force-it sweeps us off our feet, causes sparks to fly, and ignites flames of passion. Even the use of "attraction" to refer to romantic interest, commonplace in both popular and scholarly discourse, implies a force propelling two objects together. The present research examined the effects of exposing participants to a physical force (magnetism) on subsequent judgments of romantic outcomes. Across two studies, participants exposed to magnets reported greater levels of satisfaction, attraction, intimacy, and commitment.


Global burden of 87 risk factors in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019.
Rigorous analysis of levels and trends in exposure to leading risk factors and quantification of their effect on human health are important to identify where public health is making progress and in which cases current efforts are inadequate. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a standardised and comprehensive assessment of the magnitude of risk factor exposure, relative risk, and attributable burden of disease. GBD 2019 estimated attributable mortality, years of life lost (YLLs), years of life lived with disability (YLDs), and disability-adjusted life-years (DALYs) for 87 risk factors and combinations of risk factors, at the global level, regionally, and for 204 countries and territories. GBD uses a hierarchical list of risk factors so that specific risk factors (eg, sodium intake), and related aggregates (eg, diet quality), are both evaluated. This method has six analytical steps. (1) We included 560 risk-outcome pairs that met criteria for convincing or probable evidence on the basis of research studies. 12 risk-outcome pairs included in GBD 2017 no longer met inclusion criteria and 47 risk-outcome pairs for risks already included in GBD 2017 were added based on new evidence. (2) Relative risks were estimated as a function of exposure based on published systematic reviews, 81 systematic reviews done for GBD 2019, and meta-regression. (3) Levels of exposure in each age-sex-location-year included in the study were estimated based on all available data sources using spatiotemporal Gaussian process regression, DisMod-MR 2.1, a Bayesian meta-regression method, or alternative methods. (4) We determined, from published trials or cohort studies, the level of exposure associated with minimum risk, called the theoretical minimum risk exposure level. (5) Attributable deaths, YLLs, YLDs, and DALYs were computed by multiplying population attributable fractions (PAFs) by the relevant outcome quantity for each age-sex-location-year. (6) PAFs and attributable burden for combinations of risk factors were estimated taking into account mediation of different risk factors through other risk factors. Across all six analytical steps, 30 652 distinct data sources were used in the analysis. Uncertainty in each step of the analysis was propagated into the final estimates of attributable burden. Exposure levels for dichotomous, polytomous, and continuous risk factors were summarised with use of the summary exposure value to facilitate comparisons over time, across location, and across risks. Because the entire time series from 1990 to 2019 has been re-estimated with use of consistent data and methods, these results supersede previously published GBD estimates of attributable burden. The largest declines in risk exposure from 2010 to 2019 were among a set of risks that are strongly linked to social and economic development, including household air pollution; unsafe water, sanitation, and handwashing; and child growth failure. Global declines also occurred for tobacco smoking and lead exposure. The largest increases in risk exposure were for ambient particulate matter pollution, drug use, high fasting plasma glucose, and high body-mass index. In 2019, the leading Level 2 risk factor globally for attributable deaths was high systolic blood pressure, which accounted for 10·8 million (95% uncertainty interval [UI] 9·51-12·1) deaths (19·2% [16·9-21·3] of all deaths in 2019), followed by tobacco (smoked, second-hand, and chewing), which accounted for 8·71 million (8·12-9·31) deaths (15·4% [14·6-16·2] of all deaths in 2019). The leading Level 2 risk factor for attributable DALYs globally in 2019 was child and maternal malnutrition, which largely affects health in the youngest age groups and accounted for 295 million (253-350) DALYs (11·6% [10·3-13·1] of all global DALYs that year). The risk factor burden varied considerably in 2019 between age groups and locations. Among children aged 0-9 years, the three leading detailed risk factors for attributable DALYs were all related to malnutrition. Iron deficiency was the leading risk factor for those aged 10-24 years, alcohol use for those aged 25-49 years, and high systolic blood pressure for those aged 50-74 years and 75 years and older. Overall, the record for reducing exposure to harmful risks over the past three decades is poor. Success with reducing smoking and lead exposure through regulatory policy might point the way for a stronger role for public policy on other risks in addition to continued efforts to provide information on risk factor harm to the general public. Bill & Melinda Gates Foundation.


The cost-effectiveness of adjuvant chemotherapy for early breast cancer: A comparison of no chemotherapy and first, second, and third generation regimens for patients with differing prognoses.
The risk of recurrence following surgery in women with early breast cancer varies, depending upon prognostic factors. Adjuvant chemotherapy reduces this risk; however, increasingly effective regimens are associated with higher costs and toxicity profiles, making it likely that different regimens may be cost-effective for women with differing prognoses. To investigate this we performed a cost-effectiveness analysis of four treatment strategies: (1) no chemotherapy, (2) chemotherapy using cyclophosphamide, methotrexate, and fluorouracil (CMF) (a first generation regimen), (3) chemotherapy using Epirubicin-CMF (E-CMF) or fluorouracil, epirubicin, and cyclophosphamide (FEC60) (a second generation regimens), and (4) chemotherapy with FEC60 followed by docetaxel (FEC-D) (a third generation regimen). These adjuvant chemotherapy regimens were used in three large UK-led randomised controlled trials (RCTs). A Markov model was used to simulate the natural progression of early breast cancer and the impact of chemotherapy on modifying this process. The probability of a first recurrent event within the model was estimated for women with different prognostic risk profiles using a parametric regression-based survival model incorporating established prognostic factors. Other probabilities, treatment effects, costs and quality of life weights were estimated primarily using data from the three UK-led RCTs, a meta-analysis of all relevant RCTs, and other published literature. The model predicted the lifetime costs, quality adjusted life years (QALYs) and cost-effectiveness of the four strategies for women with differing prognoses. Sensitivity analyses investigated the impact of uncertain parameters and model assumptions. For women with an average to high risk of recurrence (based upon prognostic factors and any other adjuvant therapies received), FEC-D appeared most cost-effective assuming a threshold of £20,000 per QALY for the National Health Service (NHS). For younger low risk women, E-CMF/FEC60 tended to be the optimal strategy and, for some older low risk women, the model suggested a policy of no chemotherapy was cost-effective. For no patient group was CMF chemotherapy the preferred option. Sensitivity analyses demonstrated cost-effectiveness results to be particularly sensitive to the treatment effect estimate for FEC-D and the future price of docetaxel. To our knowledge, this analysis is the first cost-effectiveness comparison of no chemotherapy, and first, second, and third generation adjuvant chemotherapy regimens for early breast cancer patients with differing prognoses. The results demonstrate the potential for different treatment strategies to be cost-effective for different types of patients. These findings may prove useful for policy makers attempting to formulate cost-effective treatment guidelines in the field of early breast cancer.


Zidovudine, didanosine, and zalcitabine in the treatment of HIV infection: meta-analyses of the randomised evidence. HIV Trialists' Collaborative Group.
To assess the effects of zidovudine, didanosine, and zalcitabine on HIV disease progression and survival, we undertook meta-analyses of individual patient data and tabular data from all randomised trials that compared these agents. Individual patient data were available for 7722 participants without AIDS in the nine randomised trials of immediate versus deferred zidovudine, and 7700 participants with or without AIDS in the six trials comparing zidovudine plus didanosine, zidovudine plus zalcitabine, or zidovudine alone. The main outcomes were mortality and disease progression (new AIDS-defining event or death before any such event). In the comparison of immediate versus deferred zidovudine, during a median follow-up of 50 months, 1908 individuals progressed, of whom 1351 died. In the deferred group, 61% started antiretroviral therapy (median time to therapy 28 months, which was zidovudine monotherapy in 94%). During the first year of follow-up, immediate zidovudine halved the rate of disease progression (p<0.0001), increasing the probability of AIDS-free survival at 1 year from 96% to 98%. This early delay did not persist: after 6 years, AIDS-free survival was 54% in both groups. At no time was there any difference in overall survival, which at 6 years was 64% with immediate and 65% with deferred zidovudine (rate ratio 1.04 [95% CI 0.94-1.15]). In the comparison of zidovudine plus didanosine or zalcitabine versus zidovudine alone, during a median follow-up of 29 months, 2904 individuals progressed, of whom 1850 died. The addition of didanosine to zidovudine delayed both progression (rate ratio 0.74 [0.67-0.82], p<0.0001) and death (0.72 [0.64-0.82], p<0.0001). Similarly, the addition of zalcitabine to zidovudine also delayed progression (0.86 [0.78-0.94], p=0.001) and death (0.87 [0.77-0.98], p=0.02). After 3 years, the estimated percentages alive and without a new AIDS event were 53% for zidovudine plus didanosine, 49% for zidovudine plus zalcitabine, and 44% for zidovudine alone; the percentages alive were 68%, 63%, and 59%, respectively. Five of the six trials involved randomised comparisons of zidovudine plus didanosine versus zidovudine plus zalcitabine: in these, the zidovudine plus didanosine regimen had greater effects on disease progression (p=0.004) and death (p=0.009). Although immediate use of zidovudine halved disease progression during the first year, this effect was not sustained, and there was no improvement in survival in the short or long term. However, the use of didanosine and, to a lesser extent, zalcitabine delayed both disease progression and death, at least when added to zidovudine. The comparative effects of these different nucleoside analogues on long-term survival should inform the choice of which to combine with other types of drug, such as protease inhibitors.


Adiposity and risk of ischaemic and haemorrhagic stroke in 0·5 million Chinese men and women: a prospective cohort study.
China has high stroke rates despite the population being relatively lean. Uncertainty persists about the relevance of adiposity to risk of stroke types. We aimed to assess the associations of adiposity with incidence of stroke types and effect mediation by blood pressure in Chinese men and women. The China Kadoorie Biobank enrolled 512 891 adults aged 30-79 years from ten areas (five urban and five rural) during 2004-08. During a median 9 years (IQR 8-10) of follow-up, 32 448 strokes (about 90% confirmed by neuroimaging) were recorded among 489 301 participants without previous cardiovascular disease. Cox regression analysis was used to produce adjusted hazard ratios (HRs) for ischaemic stroke (n=25 210) and intracerebral haemorrhage (n=5380) associated with adiposity. Mean baseline body-mass index (BMI) was 23·6 kg/m2 (SD 3·2), and 331 723 (67·8%) participants had a BMI of less than 25 kg/m2. Throughout the range examined (mean 17·1 kg/m2 [SD 0·9] to 31·7 kg/m2 [2·0]), each 5 kg/m2 higher BMI was associated with 8·3 mm Hg (SE 0·04) higher systolic blood pressure. BMI was positively associated with ischaemic stroke, with an HR of 1·30 (95% CI 1·28-1·33 per 5 kg/m2 higher BMI), which was generally consistent with that predicted by equivalent differences in systolic blood pressure (1·25 [1·24-1·26]). The HR for intracerebral haemorrhage (1·11 [1·07-1·16] per 5 kg/m2 higher BMI) was less extreme, and much weaker than that predicted by the corresponding difference in systolic blood pressure (1·48 [1·46-1·50]). Other adiposity measures showed similar associations with stroke types. After adjustment for usual systolic blood pressure, the positive associations with ischaemic stroke were attenuated (1·05 [1·03-1·07] per 5 kg/m2 higher BMI); for intracerebral haemorrhage, they were reversed (0·73 [0·70-0·77]). High adiposity (BMI >23 kg/m2) accounted for 14·7% of total stroke (16·5% of ischaemic stroke and 6·7% of intracerebral haemorrhage). In Chinese adults, adiposity was strongly positively associated with ischaemic stroke, chiefly through its effect on blood pressure. For intracerebral haemorrhage, leanness, either per se or through some other factor (or factors), might increase risk, offsetting the protective effects of lower blood pressure. UK Wellcome Trust, UK Medical Research Council, British Heart Foundation, Cancer Research UK, Kadoorie Charitable Foundation, Chinese Ministry of Science and Technology, Chinese National Natural Science Foundation.


Targeted peptide measurements in biology and medicine: best practices for mass spectrometry-based assay development using a fit-for-purpose approach.
Adoption of targeted mass spectrometry (MS) approaches such as multiple reaction monitoring (MRM) to study biological and biomedical questions is well underway in the proteomics community. Successful application depends on the ability to generate reliable assays that uniquely and confidently identify target peptides in a sample. Unfortunately, there is a wide range of criteria being applied to say that an assay has been successfully developed. There is no consensus on what criteria are acceptable and little understanding of the impact of variable criteria on the quality of the results generated. Publications describing targeted MS assays for peptides frequently do not contain sufficient information for readers to establish confidence that the tests work as intended or to be able to apply the tests described in their own labs. Guidance must be developed so that targeted MS assays with established performance can be made widely distributed and applied by many labs worldwide. To begin to address the problems and their solutions, a workshop was held at the National Institutes of Health with representatives from the multiple communities developing and employing targeted MS assays. Participants discussed the analytical goals of their experiments and the experimental evidence needed to establish that the assays they develop work as intended and are achieving the required levels of performance. Using this "fit-for-purpose" approach, the group defined three tiers of assays distinguished by their performance and extent of analytical characterization. Computational and statistical tools useful for the analysis of targeted MS results were described. Participants also detailed the information that authors need to provide in their manuscripts to enable reviewers and readers to clearly understand what procedures were performed and to evaluate the reliability of the peptide or protein quantification measurements reported. This paper presents a summary of the meeting and recommendations.


An alternative conformation of the T-cell receptor alpha constant region.
Alphabeta T-cell receptors (TcRs) play a central role in cellular immune response. They are members of the Ig superfamily, with extracellular regions of the alpha and beta chains each comprising a V-type domain and a C-type domain. We have determined the ectodomain structure of an alphabeta TcR, which recognizes the autoantigen myelin basic protein. The 2.0-A-resolution structure reveals canonical main-chain conformations for the V(alpha), V(beta), and C(beta) domains, but the C(alpha) domain exhibits a main-chain conformation remarkably different from those previously reported for TcR crystal structures. The global IgC-like fold is maintained, but a piston-like rearrangement between BC and DE beta-turns results in beta-strand slippage. This substantial conformational change may represent a signaling intermediate. Our structure is the first example for the Ig fold of the increasingly recognized concept of "metamorphic proteins."


Plaque features associated with increased cerebral infarction after minor stroke and TIA: a prospective, case-control, 3-T carotid artery MR imaging study.
The goal of this study was to determine whether a 3-T magnetic resonance imaging (MRI) protocol combining carotid atherosclerotic plaque and brain imaging can identify features of high-risk acutely symptomatic plaque that correlate with brain injury. It has previously been demonstrated that, in asymptomatic patients, MRI can identify features of carotid plaque that are associated with stroke, such as the presence of a large lipid core. We hypothesized that the early phase (<7 days) after a cerebrovascular event, when risk of recurrence is highest, may be associated with particular plaque characteristics that associate with cerebral injury. Eighty-one patients (41 presenting acutely with transient ischemic attack [TIA] or minor stroke and 40 asymptomatic controls) underwent multicontrast carotid artery MRI on 2 separate occasions, each accompanied by diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) imaging of the brain. Complex (American Heart Association [AHA] type VI) plaques were seen in 22 of 41 patients (54%) in the symptomatic group versus 8 of 40 (20%) in the asymptomatic group (p < 0.05). They were caused by intraplaque hemorrhage (34% vs. 18%; p = 0.08), surface rupture (24% vs. 5%; p = 0.03), or luminal thrombus (7% vs. 0%; p = 0.24). Noticeably, 17 of 30 (57%) cases of AHA type VI plaque were in vessels with <70% stenosis. At follow-up scanning (>6 weeks later), only 2 cases of symptomatic AHA type VI plaque showed evidence of full healing. The presence of fibrous cap rupture was associated with higher DWI brain injury at presentation and higher total cerebral FLAIR signal at follow-up (p < 0.05). Early carotid wall MRI in patients experiencing minor stroke or TIA showed a higher proportion of "complex" plaques compared with asymptomatic controls; a majority were in arteries of <70% stenosis. Fibrous cap rupture was associated with increases in DWI and FLAIR lesions in the brain. Combined carotid plaque and brain MRI may aid risk stratification and treatment selection in acute stroke and TIA.


Growth strategy of heterotrophic bacterial population along successional sequence on spoil of brown coal colliery substrate.
The bacterial population of brown coal colliery spoil (Sokolov coal mining district, Czechia) was characterized by measuring viable bacterial biomass, the culturable to total cell ratio (C : T), colony-forming curve (CFC) analysis and species and/or biotype diversity. Bacterial representatives that differed in colony-forming growth (fast and/or slow growers) were used for growth-strategy investigation of heterotrophic bacteria. Spoil substrates from the surface (0-50 mm) and the mineral (100-150 mm) layers were sampled on 4 sites undergoing spontaneous succession corresponding to 1, 11, 21 and 43 years after deposition (initial, early, mid and late stages). The bacterial biomass of the surface layer increased during the initial and early stages with a maximum at mid stage and stabilized in the late stage while mineral layer biomass increased throughout the succession. The maxima of C : T ratios were at the early stage, minima at the late stage. Depending on the succession stage the C : T ratio was 1.5-2 times higher in the mineral than the surface layer of soil. An increase in the fraction of nonculturable bacteria was associated with the late succession stage. CFC analysis of the surface layer during a 3-d incubation revealed that the early-succession substrate contained more (75%) rapidly colonizing bacteria (opportunists, r-strategists) than successively older substrates. The culturable bacterial community of the mineral layer maintained a high genera and species richness of fast growers along the succession line in contrast to the surface layer community, where there was a maximum in the abundance of fast growers in the early stage. There was a balanced distribution of Gram-positive and Gram-negative representatives of fast growers in both layers. A markedly lower abundance of slow growers was observed in the mineral in contrast to the surface layer. Gram-positive species dominated the slow growers at the surface as well as in the mineral layers. The growth strategy of the heterotrophic bacterial population along four successional stages on spoil of brown coal colliery substrate in the surface layer displayed a trend indicative of a r-K continuum in contrast to the mineral layer, where an r-strategy persisted.


Evaluating the impact of wind turbine noise on health-related quality of life.
We report a cross-sectional study comparing the health-related quality of life (HRQOL) of individuals residing in the proximity of a wind farm to those residing in a demographically matched area sufficiently displaced from wind turbines. The study employed a nonequivalent comparison group posttest-only design. Self-administered questionnaires, which included the brief version of the World Health Organization quality of life scale, were delivered to residents in two adjacent areas in semirural New Zealand. Participants were also asked to identify annoying noises, indicate their degree of noise sensitivity, and rate amenity. Statistically significant differences were noted in some HRQOL domain scores, with residents living within 2 km of a turbine installation reporting lower overall quality of life, physical quality of life, and environmental quality of life. Those exposed to turbine noise also reported significantly lower sleep quality, and rated their environment as less restful. Our data suggest that wind farm noise can negatively impact facets of HRQOL.


Full-length characterization of hepatitis C virus subtype 3a reveals novel hypervariable regions under positive selection during acute infection.
Hepatitis C virus subtype 3a is a highly prevalent and globally distributed strain that is often associated with infection via injection drug use. This subtype exhibits particular phenotypic characteristics. In spite of this, detailed genetic analysis of this subtype has rarely been performed. We performed full-length viral sequence analysis in 18 patients with chronic HCV subtype 3a infection and assessed genomic viral variability in comparison to other HCV subtypes. Two novel regions of intragenotypic hypervariability within the envelope protein E2, of HCV genotype 3a, were identified. We named these regions HVR495 and HVR575. They consisted of flanking conserved hydrophobic amino acids and central variable residues. A 5-amino-acid insertion found only in genotype 3a and a putative glycosylation site is contained within HVR575. Evolutionary analysis of E2 showed that positively selected sites within genotype 3a infection were largely restricted to HVR1, HVR495, and HVR575. Further analysis of clonal viral populations within single hosts showed that viral variation within HVR495 and HVR575 were subject to intrahost positive selecting forces. Longitudinal analysis of four patients with acute HCV subtype 3a infection sampled at multiple time points showed that positively selected mutations within HVR495 and HVR575 arose early during primary infection. HVR495 and HVR575 were not present in HCV subtypes 1a, 1b, 2a, or 6a. Some variability that was not subject to positive selection was present in subtype 4a HVR575. Further defining the functional significance of these regions may have important implications for genotype 3a E2 virus-receptor interactions and for vaccine studies that aim to induce cross-reactive anti-E2 antibodies.


Suicide note sentiment classification: a supervised approach augmented by web data.
To create a sentiment classification system for the Fifth i2b2/VA Challenge Track 2, which can identify thirteen subjective categories and two objective categories. We developed a hybrid system using Support Vector Machine (SVM) classifiers with augmented training data from the Internet. Our system consists of three types of classification-based systems: the first system uses spanning n-gram features for subjective categories, the second one uses bag-of-n-gram features for objective categories, and the third one uses pattern matching for infrequent or subtle emotion categories. The spanning n-gram features are selected by a feature selection algorithm that leverages emotional corpus from weblogs. Special normalization of objective sentences is generalized with shallow parsing and external web knowledge. We utilize three sources of web data: the weblog of LiveJournal which helps to improve the feature selection, the eBay List which assists in special normalization of information and instructions categories, and the suicide project web which provides unlabeled data with similar properties as suicide notes. The performance is evaluated by the overall micro-averaged precision, recall and F-measure. Our system achieved an overall micro-averaged F-measure of 0.59. Happiness_peacefulness had the highest F-measure of 0.81. We were ranked as the second best out of 26 competing teams. Our results indicated that classifying fine-grained sentiments at sentence level is a non-trivial task. It is effective to divide categories into different groups according to their semantic properties. In addition, our system performance benefits from external knowledge extracted from publically available web data of other purposes; performance can be further enhanced when more training data is available.


Compassionate drug (mis)use during pandemics: lessons for COVID-19 from 2009.
New emerging infections have no known treatment. Assessing potential drugs for safety and efficacy enables clinicians to make evidence-based treatment decisions and contributes to overall outbreak control. However, it is difficult to launch clinical trials in the unpredictable environment of an outbreak. We conducted a bibliometric systematic review for the 2009 influenza pandemic to determine the speed and quality of evidence generation for treatments. This informs approaches to high-quality evidence generation in this and future pandemics. We searched PubMed for all clinical data (including clinical trial, observational and case series) describing treatment for patients with influenza A(H1N1)pdm09 and ClinicalTrials.gov for research that aimed to enrol patients with the disease. Thirty-three thousand eight hundred sixty-nine treatment courses for patients hospitalised with A(H1N1)pdm09 were detailed in 160 publications. Most were retrospective observational studies or case series. Five hundred ninety-two patients received treatment (or placebo) as participants in a registered interventional clinical trial with results publicly available. None of these registered trial results was available during the timeframe of the pandemic, and the median date of publication was 213 days after the Public Health Emergency of International Concern ended. Patients were frequently treated for pandemic influenza with drugs not registered for this indication, but rarely under circumstances of high-quality data capture. The result was a reliance on use under compassionate circumstances, resulting in continued uncertainty regarding the potential benefits and harms of anti-viral treatment. Rapid scaling of clinical trials is critical for generating a quality evidence base during pandemics.


The slip-and-slide algorithm: a refinement protocol for detector geometry.
Geometry correction is traditionally plagued by mis-fitting of correlated parameters, leading to local minima which prevent further improvements. Segmented detectors pose an enhanced risk of mis-fitting: even a minor confusion of detector distance and panel separation can prevent improvement in data quality. The slip-and-slide algorithm breaks down effects of the correlated parameters and their associated target functions in a fundamental shift in the approach to the problem. Parameters are never refined against the components of the data to which they are insensitive, providing a dramatic boost in the exploitation of information from a very small number of diffraction patterns. This algorithm can be applied to exploit the adherence of the spot-finding results prior to indexing to a given lattice using unit-cell dimensions as a restraint. Alternatively, it can be applied to the predicted spot locations and the observed reflection positions after indexing from a smaller number of images. Thus, the indexing rate can be boosted by 5.8% using geometry refinement from only 125 indexed patterns or 500 unindexed patterns. In one example of cypovirus type 17 polyhedrin diffraction at the Linac Coherent Light Source, this geometry refinement reveals a detector tilt of 0.3° (resulting in a maximal Z-axis error of ∼0.5 mm from an average detector distance of ∼90 mm) whilst treating all panels independently. Re-indexing and integrating with updated detector geometry reduces systematic errors providing a boost in anomalous signal of sulfur atoms by 20%. Due to the refinement of decoupled parameters, this geometry method also reaches convergence.


[11C]-L-methionine positron emission tomography in the management of children and young adults with brain tumors.
Only a few Methyl-[11C]-L-methionine (MET) positron emission tomography (PET) studies have focused on children and young adults with brain neoplasm. Due to radiation exposure, long scan acquisition time, and the need for sedation in young children MET-PET studies should be restricted to this group of patients when a decision for further therapy is not possible from routine diagnostic procedures alone, e.g., structural imaging. We investigated the diagnostic accuracy of MET-PET for the differentiation between tumorous and non-tumorous lesions in this group of patients. Forty eight MET-PET scans from 39 patients aged from 2 to 21 years (mean 15 +/- 5.0 years) were analyzed. The MET tumor-uptake relative to a corresponding control region was calculated. A receiver operating characteristic (ROC) was performed to determine the MET-uptake value that best distinguishes tumorous from non-tumorous brain lesions. A differentiation between tumorous (n = 39) and non-tumorous brain lesions (n = 9) was possible at a threshold of 1.48 of relative MET-uptake with a sensitivity of 83% and a specificity of 92%, respectively. A differentiation between high grade malignant lesions (mean MET-uptake = 2.00 +/- 0.46) and low grade tumors (mean MET-uptake = 1.84 +/- 0.31) was not possible. There was a significant difference in MET-uptake between the histologically homogeneous subgroups of astrocytoma WHO grade II and anaplastic astrocytoma WHO grade III (P = 0.02). MET-PET might be a useful tool to differentiate tumorous from non-tumorous lesions in children and young adults when a decision for further therapy is difficult or impossible from routine structural imaging procedures alone.


Diverting tyrosine: Data from untargeted metabolic analysis of tomato fruit accumulating L-DOPA.
L-DOPA, also known as Levodopa or L-3,4-dihydroxyphenylalanine, is synthesised in plants from the amino acid tyrosine, through oxidation. Conversion of tyrosine to L-DOPA constitues the first step of betalain biosynthesis in plants. Recently, the gene responsible for this step was identified in beetroot, BvCYP76AD6, that is the source of yellow and purple betalain pigments. Overexpression of this gene, specifically in tomato fruit, led to accumulation of L-DOPA that otherwise is not detectable [1]. Co-expression of the Arabidopsis transcription factor, AtMYB12, in fruit, increased L-DOPA levels further. To study the metabolic changes in these fruit, we performed untargeted metabolite analysis of ripe fruit: GC-MS was performed to identify changes in primary metabolites, LC-MS analysis was used to identify alterations in specialised metabolites. These data can be used to study the impact of diversion of tyrosine in fruit, accompanied by the accumulation of L-DOPA in planta and to identify new biological roles associated with the accumulation of these metabolites.


Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming.
Prostate cancer is an androgen-dependent disease subject to interactions between the tumor epithelium and its microenvironment. Here, we found that epigenetic changes in prostatic cancer-associated fibroblasts (CAF) initiated a cascade of stromal-epithelial interactions. This facilitated lethal prostate cancer growth and development of resistance to androgen signaling deprivation therapy (ADT). We identified a Ras inhibitor, RASAL3, as epigenetically silenced in human prostatic CAF, leading to oncogenic Ras activity driving macropinocytosis-mediated glutamine synthesis. Interestingly, ADT further promoted RASAL3 epigenetic silencing and glutamine secretion by prostatic fibroblasts. In an orthotopic xenograft model, subsequent inhibition of macropinocytosis and glutamine transport resulted in antitumor effects. Stromal glutamine served as a source of energy through anaplerosis and as a mediator of neuroendocrine differentiation for prostate adenocarcinoma. Antagonizing the uptake of glutamine restored sensitivity to ADT in a castration-resistant xenograft model. In validating these findings, we found that prostate cancer patients on ADT with therapeutic resistance had elevated blood glutamine levels compared with those with therapeutically responsive disease (odds ratio = 7.451, P = 0.02). Identification of epigenetic regulation of Ras activity in prostatic CAF revealed RASAL3 as a sensor for metabolic and neuroendocrine reprogramming in prostate cancer patients failing ADT.


Pay, working conditions, and teacher quality.
Eric Hanushek and Steven Rivkin examine how salary and working conditions affect the quality of instruction in the classroom. The wages of teachers relative to those of other college graduates have fallen steadily since 1940. Today, average wages differ little, however, between urban and suburban districts. In some metropolitan areas urban districts pay more, while in others, suburban districts pay more. But working conditions in urban and suburban districts differ substantially, with urban teachers reporting far less administrator and parental support, worse materials, and greater student problems. Difficult working conditions may drive much of the difference in turnover of teachers and the transfer of teachers across schools. Using rich data from Texas public schools, the authors describe in detail what happens when teachers move from school to school. They examine how salaries and student characteristics change when teachers move and also whether turnover affects teacher quality and student achievement. They note that both wages and student characteristics affect teachers' choices and result in a sorting of teachers across schools, but they find little evidence that teacher transitions are detrimental to student learning. The extent to which variations in salaries and working conditions translate into differences in the quality of instruction depends importantly on the effectiveness of school personnel policies in hiring and retaining the most effective teachers and on constraints on both entry into the profession and the firing of low performers. The authors conclude that overall salary increases for teachers would be both expensive and ineffective. The best way to improve the quality of instruction would be to lower barriers to becoming a teacher, such as certification, and to link compensation and career advancement more closely with teachers' ability to raise student performance.


A critical review of simulation-based medical education research: 2003-2009.
This article reviews and critically evaluates historical and contemporary research on simulation-based medical education (SBME). It also presents and discusses 12 features and best practices of SBME that teachers should know in order to use medical simulation technology to maximum educational benefit. This qualitative synthesis of SBME research and scholarship was carried out in two stages. Firstly, we summarised the results of three SBME research reviews covering the years 1969-2003. Secondly, we performed a selective, critical review of SBME research and scholarship published during 2003-2009. The historical and contemporary research synthesis is reported to inform the medical education community about 12 features and best practices of SBME: (i) feedback; (ii) deliberate practice; (iii) curriculum integration; (iv) outcome measurement; (v) simulation fidelity; (vi) skill acquisition and maintenance; (vii) mastery learning; (viii) transfer to practice; (ix) team training; (x) high-stakes testing; (xi) instructor training, and (xii) educational and professional context. Each of these is discussed in the light of available evidence. The scientific quality of contemporary SBME research is much improved compared with the historical record. Development of and research into SBME have grown and matured over the past 40 years on substantive and methodological grounds. We believe the impact and educational utility of SBME are likely to increase in the future. More thematic programmes of research are needed. Simulation-based medical education is a complex service intervention that needs to be planned and practised with attention to organisational contexts.


A functional role for nicotinic acid adenine dinucleotide phosphate in oxytocin-mediated contraction of uterine smooth muscle from rat.
Conventionally, G protein-coupled receptors are thought to increase calcium via inositol 1,4,5-trisphosphate (InsP(3)). More recent evidence shows that an alternative second messenger, nicotinic acid adenine dinucleotide phosphate (NAADP), also has a role to play, causing researchers to question established calcium releasing pathways. With the recent development, by our group, of cell-permeant NAADP (NAADP-aceteoxymethyl ester) and a selective NAADP receptor antagonist (Ned-19; 1-(3-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid),the ability to investigate this signaling pathway has improved. Therefore, we investigated a role for NAADP in oxytocin-mediated responses in the rat uterus. Oxytocin- and NAADP-mediated effects were investigated by using contractile measurements of whole uterine strips from rat in organ baths. Responses were correlated to calcium release in cultured rat uterine smooth muscle cells measured by fluorescence microscopy. Inhibition of both oxytocin-induced contraction and calcium release by the traditional NAADP-signaling disrupter bafilomycin and the NAADP receptor antagonist Ned-19 clearly demonstrated a role for NAADP in oxytocin-induced signaling. A cell-permeant form of NAADP was able to produce both uterine contractions and calcium release. This response was unaffected by depletion of sarcoplasmic reticulum stores with thapsigargin, but was abolished by both bafilomycin and Ned-19. Crucially, oxytocin stimulated an increase in NAADP in rat uterine tissue. The present study demonstrates directly that NAADP signaling plays a role in rat uterine contractions. Moreover, investigation of this signaling pathway highlights yet another component of oxytocin-mediated signaling, stressing the need to consider the action of new components as they are discovered, even in signaling pathways that are thought to be well established.


Modulation of competing memory systems by distraction.
Different forms of learning and memory depend on functionally and anatomically separable neural circuits [Squire, L. R. (1992) Psychol. Rev. 99, 195-231]. Declarative memory relies on a medial temporal lobe system, whereas habit learning relies on the striatum [Cohen, N. J. & Eichenbaum, H. (1993) Memory, Amnesia, and the Hippocampal System (MIT Press, Cambridge, MA)]. How these systems are engaged to optimize learning and behavior is not clear. Here, we present results from functional neuroimaging showing that the presence of a demanding secondary task during learning modulates the degree to which subjects solve a problem using either declarative memory or habit learning. Dual-task conditions did not reduce accuracy but reduced the amount of declarative learning about the task. Medial temporal lobe activity was correlated with task performance and declarative knowledge after learning under single-task conditions, whereas performance was correlated with striatal activity after dual-task learning conditions. These results demonstrate a fundamental difference in these memory systems in their sensitivity to concurrent distraction. The results are consistent with the notion that declarative and habit learning compete to mediate task performance, and they suggest that the presence of distraction can bias this competition. These results have implications for learning in multitask situations, suggesting that, even if distraction does not decrease the overall level of learning, it can result in the acquisition of knowledge that can be applied less flexibly in new situations.


Management of residual risk after statin therapy.
Cardiovascular disease (CVD) is the leading cause of mortality worldwide. Observational data indicate that low-density lipoprotein cholesterol (LDL-C) levels are strongly positively associated with the risk of coronary heart disease (CHD) whilst the level of high-density lipoprotein cholesterol (HDL-C) is strongly inversely associated, with additional associations being observed for other lipid parameters such as triglycerides, apolipoproteins and lipoprotein(a) (Lp(a)). This has led to an interest in the development of a range of lipid intervention therapies. The most widely used of these interventions are statins, but even with intensive statin therapy some groups of patients remain at significant residual cardiovascular (CV) risk. In addition, some people are intolerant of statin therapy. In these circumstances, additional therapeutic agents may be needed. This review considers the evidence behind and the pros and cons of such additional agents.


Absence of face-specific cortical activity in the complete absence of awareness: converging evidence from functional magnetic resonance imaging and event-related potentials.
In this study, we explored the neural correlates of perceptual awareness during a masked face detection task. To assess awareness more precisely than in previous studies, participants employed a 4-point scale to rate subjective visibility. An event-related fMRI and a high-density ERP study were carried out. Imaging data showed that conscious face detection was linked to activation of fusiform and occipital face areas. Frontal and parietal regions, including the pre-SMA, inferior frontal sulcus, anterior insula/frontal operculum, and intraparietal sulcus, also responded strongly when faces were consciously perceived. In contrast, no brain area showed face-selective activity when participants reported no impression of a face. ERP results showed that conscious face detection was associated with enhanced N170 and also with the presence of a second negativity around 300 msec and a slow positivity around 415 msec. Again, face-related activity was absent when faces were not consciously perceived. We suggest that, under conditions of backward masking, ventral stream and fronto-parietal regions show similar, strong links of face-related activity to conscious perception and stress the importance of a detailed assessment of awareness to examine activity related to unseen stimulus events.


Hippocampal volume across age: Nomograms derived from over 19,700 people in UK Biobank.
Measurement of hippocampal volume has proven useful to diagnose and track progression in several brain disorders, most notably in Alzheimer's disease (AD). For example, an objective evaluation of a patient's hippocampal volume status may provide important information that can assist diagnosis or risk stratification of AD. However, clinicians and researchers require access to age-related normative percentiles to reliably categorise a patient's hippocampal volume as being pathologically small. Here we analysed effects of age, sex, and hemisphere on the hippocampus and neighbouring temporal lobe volumes, in 19,793 generally healthy participants in the UK Biobank. A key finding of the current study is a significant acceleration in the rate of hippocampal volume loss in middle age, more pronounced in females than in males. In this report, we provide normative values for hippocampal and total grey matter volume as a function of age for reference in clinical and research settings. These normative values may be used in combination with our online, automated percentile estimation tool to provide a rapid, objective evaluation of an individual's hippocampal volume status. The data provide a large-scale normative database to facilitate easy age-adjusted determination of where an individual hippocampal and temporal lobe volume lies within the normal distribution.


Prevalence, clinical features and treatment outcomes of patients with myasthenia gravis positive for antibodies to muscle-specific kinase in Thailand.
A small but variable subgroup of patients with myasthenia gravis (MG) who have antibodies to muscle-specific kinase (MuSKAb-MG) can present with distinct phenotypes and are often treatment-resistant. The prevalence, clinical phenotypes and outcomes of treatment of patients with MuSKAb-MG in Thailand were determined. Eight (16.3%) of the 49 patients with generalized MG who were negative for acetylcholine receptor antibodies (AChRAb) were positive for muscle-specific kinase antibodies. Most patients had predominant oculobulbar features and respiratory failure occurred in three. At follow up, three out of the seven patients who underwent thymectomy were in complete stable remission and four had improved and were on reduced immunosuppression medication, suggesting a possible benefit of thymectomy.


Anterior hypopituitarism secondary to biopsy-proven IgG4-related hypophysitis in a young man.
IgG4-related disease (IgG4-RD) is an immune-mediated fibro-inflammatory condition which can affect various organs including the pituitary gland. The true annual incidence of this condition remains widely unknown. In addition, it is unclear whether IgG4 antibodies are causative or the end result of a trigger. With no specific biomarkers available, the diagnosis of IgG4-related hypophysitis remains a challenge. Additionally, there is a wide differential diagnosis. We report a case of biopsy-proven IgG4-related hypophysitis in a young man with type 2 diabetes mellitus. Learning points: IgG4-related hypophysitis is part of a spectrum of IgG4-related diseases. Clinical manifestations result from anterior pituitary hormone deficiencies with or without diabetes insipidus, which can be temporary or permanent. A combination of clinical, radiological, serological and histological evidence with careful interpretation is required to make the diagnosis. Tissue biopsy remains the gold standard investigation. Disease monitoring and long-term management of this condition is a challenge as relapses occur frequently.


Robotic goalie with 3 ms reaction time at 4% CPU load using event-based dynamic vision sensor.
Conventional vision-based robotic systems that must operate quickly require high video frame rates and consequently high computational costs. Visual response latencies are lower-bound by the frame period, e.g., 20 ms for 50 Hz frame rate. This paper shows how an asynchronous neuromorphic dynamic vision sensor (DVS) silicon retina is used to build a fast self-calibrating robotic goalie, which offers high update rates and low latency at low CPU load. Independent and asynchronous per pixel illumination change events from the DVS signify moving objects and are used in software to track multiple balls. Motor actions to block the most "threatening" ball are based on measured ball positions and velocities. The goalie also sees its single-axis goalie arm and calibrates the motor output map during idle periods so that it can plan open-loop arm movements to desired visual locations. Blocking capability is about 80% for balls shot from 1 m from the goal even with the fastest-shots, and approaches 100% accuracy when the ball does not beat the limits of the servo motor to move the arm to the necessary position in time. Running with standard USB buses under a standard preemptive multitasking operating system (Windows), the goalie robot achieves median update rates of 550 Hz, with latencies of 2.2 ± 2 ms from ball movement to motor command at a peak CPU load of less than 4%. Practical observations and measurements of USB device latency are provided.


Structural and functional imaging of the hippocampus in young people at familial risk of depression.
Major depression is associated with abnormalities in the function and structure of the hippocampus. However, it is unclear whether these abnormalities might also be present in people 'at risk' of illness. We studied 62 young people (mean age 18.8 years) at familial risk of depression (FH+) but who had never been depressed themselves. Participants underwent magnetic resonance imaging to assess hippocampal structure and neural responses to a task designed to activate hippocampal memory networks. Magnetic resonance spectroscopy was used to measure levels of a combination of glutamine and glutamate (Glx) in the right hippocampus. A total of 59 matched controls with no history of mood disorder in a first-degree relative underwent the same investigations. Hippocampal volume did not differ between FH+ participants and controls; however, relative to controls, during the memory task, FH+ participants showed increased activation in brain regions encompassing the insular cortices, putamen and pallidum as well as the dorsal anterior cingulate cortex (ACC). FH+ participants also had increased hippocampal levels of Glx. Euthymic individuals with a parental history of depression demonstrate increased activation of hippocampal-related neural networks during a memory task, particularly in brain regions involved in processing the salience of stimuli. Changes in the activity of the ACC replicate previous findings in FH+ participants using different psychological tasks; this suggests that task-related abnormalities in the ACC may be a marker of vulnerability to depression. Increased levels of Glx in the hippocampus might also represent a risk biomarker but follow-up studies will be required to test these various possibilities.


Where is crystallography going?
Macromolecular crystallography (MX) has been a motor for biology for over half a century and this continues apace. A series of revolutions, including the production of recombinant proteins and cryo-crystallography, have meant that MX has repeatedly reinvented itself to dramatically increase its reach. Over the last 30 years synchrotron radiation has nucleated a succession of advances, ranging from detectors to optics and automation. These advances, in turn, open up opportunities. For instance, a further order of magnitude could perhaps be gained in signal to noise for general synchrotron experiments. In addition, X-ray free-electron lasers offer to capture fragments of reciprocal space without radiation damage, and open up the subpicosecond regime of protein dynamics and activity. But electrons have recently stolen the limelight: so is X-ray crystallography in rude health, or will imaging methods, especially single-particle electron microscopy, render it obsolete for the most interesting biology, whilst electron diffraction enables structure determination from even the smallest crystals? We will lay out some information to help you decide.


Oxygen metabolism and barrier regulation in the intestinal mucosa.
Mucosal surfaces are lined by epithelial cells and provide an important barrier to the flux of antigens from the outside. This barrier is provided at a number of levels, including epithelial junctional complexes, mucus production, and mucosa-derived antimicrobials. Tissue metabolism is central to the maintenance of homeostasis in the mucosa. In the intestine, for example, baseline pO2 levels are uniquely low due to counter-current blood flow and the presence of large numbers of bacteria. As such, hypoxia and HIF signaling predominates normal intestinal metabolism and barrier regulation during both homeostasis and active inflammation. Contributing factors that elicit important adaptive responses within the mucosa include the transcriptional regulation of tight junction proteins, metabolic regulation of barrier components, and changes in autophagic flux. Here, we review recent literature around the topic of hypoxia and barrier function in health and during disease.


Development of a WHO growth reference for school-aged children and adolescents.
To construct growth curves for school-aged children and adolescents that accord with the WHO Child Growth Standards for preschool children and the body mass index (BMI) cut-offs for adults. Data from the 1977 National Center for Health Statistics (NCHS)/WHO growth reference (1-24 years) were merged with data from the under-fives growth standards' cross-sectional sample (18-71 months) to smooth the transition between the two samples. State-of-the-art statistical methods used to construct the WHO Child Growth Standards (0-5 years), i.e. the Box-Cox power exponential (BCPE) method with appropriate diagnostic tools for the selection of best models, were applied to this combined sample. The merged data sets resulted in a smooth transition at 5 years for height-for-age, weight-for-age and BMI-for-age. For BMI-for-age across all centiles the magnitude of the difference between the two curves at age 5 years is mostly 0.0 kg/m(2) to 0.1 kg/m(2). At 19 years, the new BMI values at +1 standard deviation (SD) are 25.4 kg/m(2) for boys and 25.0 kg/m(2) for girls. These values are equivalent to the overweight cut-off for adults (> or = 25.0 kg/m(2)). Similarly, the +2 SD value (29.7 kg/m(2) for both sexes) compares closely with the cut-off for obesity (> or = 30.0 kg/m(2)). The new curves are closely aligned with the WHO Child Growth Standards at 5 years, and the recommended adult cut-offs for overweight and obesity at 19 years. They fill the gap in growth curves and provide an appropriate reference for the 5 to 19 years age group.


[Comparative characteristics of the gene pool of Teleuts inferred from Y-chromosomal marker data].
The gene pool structure of Teleuts was examined and Y-chromosomal haplogroups composition and frequencies were determined. In the gene pool of Teleuts, five haplogroups, C3xM77, N3a, R1b*, R1b3, and R1a1, were identified. Evaluation of the genetic differentiation of the samples examined using analysis of molecular variance (AMOVA) with two marker systems (frequencies of haplogroups and Y-chromosomal microsatellite haplotypes) showed that Bachat Teleuts were equally distant from Southern and Northern Altaians. In Siberian populations, the frequencies and molecular phylogeny of the YSTR haplotypes within Y-chromosomal haplogroup R1a1 were examined. It was demonstrated that Teleuts and Southern Altaians had very close and overlapping profiles of R1a1 haplotypes. Population cluster analysis of the R1a1 YSTR haplotypes showed that Teleuts and Southern Altaians were closer to one another than to all remaining Siberian ethnic groups. Phylogenetic analysis of N3a haplotypes suggested specificity of Teleut haplotypes and their closeness to those of Tomsk Tatars. Teleuts were characterized by extremely high frequency of haplogroup R1b*, distinguished for highly specific profile of YSTR haplotypes and high haplotype diversity. The results of the comparative analysis suggested that the gene pool of Bachat Teleuts was formed on the basis of at least two heterogeneous genetic components, probably associated with ancient Turkic and Samoyedic ethnic components.


Parkinson-linked genes and toxins that affect neuronal cell death through the Bcl-2 family.
Parkinson's disease (PD) results from the death of specific neuronal populations in the CNS. Potential causative factors include environmental toxins and gene mutations that can combine to dysregulate the processing and degradation of alpha-synuclein. Oxidative stress induced by the neurotoxins MPTP, paraquat, maneb, and rotenone causes lipid peroxidation and protein misfolding that affects cell death through members of the Bcl-2 family. Sufficient activation of Bax and Bak facilitates mitochondrial outer-membrane permeabilization, which releases death-inducing factors that cause apoptotic and nonapoptotic programmed cell death. The formation of alpha-synuclein aggregates is a defining pathologic feature of PD and is induced by these neurotoxins as well as several Parkinson-linked familial mutations. Of the familial mutations identified thus far, two of the loci encode proteins associated with ubiquitin-proteasome degradation of misfolded proteins (Parkin and Uch-L1), and two encode proteins associated with mitochondria and oxidative stress (DJ-1 and PINK1). Both gene and toxin findings indicate that dopaminergic neuron losses in PD are the result of oxidative stress affecting mitochondria function and ubiquitin-proteasome activity. Here we describe how related cell death mechanisms are involved in the pathophysiology of Parkinson's disease.