The effects of sampling bias and model complexity on the predictive performance of MaxEnt species distribution models.
Species distribution models (SDMs) trained on presence-only data are frequently used in ecological research and conservation planning. However, users of SDM software are faced with a variety of options, and it is not always obvious how selecting one option over another will affect model performance. Working with MaxEnt software and with tree fern presence data from New Zealand, we assessed whether (a) choosing to correct for geographical sampling bias and (b) using complex environmental response curves have strong effects on goodness of fit. SDMs were trained on tree fern data, obtained from an online biodiversity data portal, with two sources that differed in size and geographical sampling bias: a small, widely-distributed set of herbarium specimens and a large, spatially clustered set of ecological survey records. We attempted to correct for geographical sampling bias by incorporating sampling bias grids in the SDMs, created from all georeferenced vascular plants in the datasets, and explored model complexity issues by fitting a wide variety of environmental response curves (known as "feature types" in MaxEnt). In each case, goodness of fit was assessed by comparing predicted range maps with tree fern presences and absences using an independent national dataset to validate the SDMs. We found that correcting for geographical sampling bias led to major improvements in goodness of fit, but did not entirely resolve the problem: predictions made with clustered ecological data were inferior to those made with the herbarium dataset, even after sampling bias correction. We also found that the choice of feature type had negligible effects on predictive performance, indicating that simple feature types may be sufficient once sampling bias is accounted for. Our study emphasizes the importance of reducing geographical sampling bias, where possible, in datasets used to train SDMs, and the effectiveness and essentialness of sampling bias correction within MaxEnt.


Genotype at a promoter polymorphism of the interleukin-6 gene is associated with baseline levels of plasma C-reactive protein.
Baseline concentrations of plasma C-reactive protein (CRP) are associated with coronary heart disease. Interleukin-6 (IL-6) regulates CRP gene expression; a promoter polymorphism (-174G/C) of the IL-6 gene has been shown to influence IL-6 transcription but the relationship between genotype at this polymorphism and circulating levels of inflammatory markers remains unclear. We hypothesised that plasma CRP would be a heritable phenotype that would be influenced by genotype at this polymorphism. We measured baseline plasma CRP and determined genotypes at the -174G/C polymorphism of the IL-6 gene in 588 members of 98 nuclear families. The heritability of plasma CRP and the association of plasma CRP with genotype were determined using variance components methods. Baseline CRP levels were highly heritable (h(2)=0.39, P<0.0000001). Presence of the -174C allele was associated with higher baseline CRP levels, both in the whole population (P=0.01), and in the founders only (n=128, P=0.001). Family-based analyses confirmed the association (P=0.02) suggesting that it arises from chromosomal proximity or identity of the typed polymorphism with a genetic variant influencing baseline CRP levels. Baseline plasma CRP is a significantly heritable cardiovascular risk factor. Levels are associated with genotype at the -174G/C polymorphism of the IL-6 gene.


ELM: the status of the 2010 eukaryotic linear motif resource.
Linear motifs are short segments of multidomain proteins that provide regulatory functions independently of protein tertiary structure. Much of intracellular signalling passes through protein modifications at linear motifs. Many thousands of linear motif instances, most notably phosphorylation sites, have now been reported. Although clearly very abundant, linear motifs are difficult to predict de novo in protein sequences due to the difficulty of obtaining robust statistical assessments. The ELM resource at http://elm.eu.org/ provides an expanding knowledge base, currently covering 146 known motifs, with annotation that includes >1300 experimentally reported instances. ELM is also an exploratory tool for suggesting new candidates of known linear motifs in proteins of interest. Information about protein domains, protein structure and native disorder, cellular and taxonomic contexts is used to reduce or deprecate false positive matches. Results are graphically displayed in a 'Bar Code' format, which also displays known instances from homologous proteins through a novel 'Instance Mapper' protocol based on PHI-BLAST. ELM server output provides links to the ELM annotation as well as to a number of remote resources. Using the links, researchers can explore the motifs, proteins, complex structures and associated literature to evaluate whether candidate motifs might be worth experimental investigation.


Four jointed box 1 promotes angiogenesis and is associated with poor patient survival in colorectal carcinoma.
Angiogenesis, the recruitment and re-configuration of pre-existing vasculature, is essential for tumor growth and metastasis. Increased tumor vascularization often correlates with poor patient outcomes in a broad spectrum of carcinomas. We identified four jointed box 1 (FJX1) as a candidate regulator of tumor angiogenesis in colorectal cancer. FJX1 mRNA and protein are upregulated in human colorectal tumor epithelium as compared with normal epithelium and colorectal adenomas, and high expression of FJX1 is associated with poor patient prognosis. FJX1 mRNA expression in colorectal cancer tissues is significantly correlated with changes in known angiogenesis genes. Augmented expression of FJX1 in colon cancer cells promotes growth of xenografts in athymic mice and is associated with increased tumor cell proliferation and vascularization. Furthermore, FJX1 null mice develop significantly fewer colonic polyps than wild-type littermates after combined dextran sodium sulfate (DSS) and azoxymethane (AOM) treatment. In vitro, conditioned media from FJX1 expressing cells promoted endothelial cell capillary tube formation in a HIF1-α dependent manner. Taken together our results support the conclusion that FJX1 is a novel regulator of tumor progression, due in part, to its effect on tumor vascularization.


Immunogenicity and induction of immunological memory of the heptavalent pneumococcal conjugate vaccine in preterm UK infants.
Data on the immunogenicity and memory induction of pneumococcal conjugate vaccines in very preterm infants is limited. We vaccinated 69 full term and 68 preterm infants (median gestational age (GA) 30 weeks) with a 7-valent pneumococcal conjugate vaccine (PCV7) at 2/3/4 months of age, followed by a plain polysaccharide booster at 12 months of age. IgG-GMC (ELISA) was significantly lower in preterm infants to six vaccine serotypes (ST) at 2 months and 5 months of age, to five ST at 12 months of age and to three ST at 13 months of age. A significantly lower proportion of preterm infants achieved IgG levels>or=0.35 microg/ml to ST 4, 6B and 9V at 5 months and to ST 4, 6B, 18C, 19F and 23F at 12 months of age. Fold rises following the polysaccharide booster were comparable to those of term infants. At least 93% of both cohorts achieved IgG>or=0.35 microg/ml to all STs following booster vaccination. Pneumococcal conjugate vaccine at an accelerated schedule of 2/3/4 months of age is likely to provide protection against pneumococcal disease for preterm infants. Antibody concentrations wane over the first year of life in both preterm and term infants and booster vaccination is therefore likely to be important.


Embryonic stem cell-specific microRNAs promote induced pluripotency.
This report demonstrates that introduction of microRNAs (miRNAs) specific to embryonic stem cells enhances the production of mouse induced pluripotent stem (iPS) cells. The miRNAs miR-291-3p, miR-294 and miR-295 increase the efficiency of reprogramming by Oct4, Sox2 and Klf4, but not by these factors plus cMyc. cMyc binds the promoter of the miRNAs, suggesting that they are downstream effectors of cMyc during reprogramming. However, unlike cMyc, the miRNAs induce a homogeneous population of iPS cell colonies.


Developing a new justification for assent.
Current guidelines do not clearly outline when assent should be attained from paediatric research participants, nor do they detail the necessary elements of the assent process. This stems from the fact that the fundamental justification behind the concept of assent is misunderstood. In this paper, we critically assess three widespread ethical arguments used for assent: children's rights, the best interests of the child, and respect for a child's developing autonomy. We then outline a newly-developed two-fold justification for the assent process: respect for the parent's pedagogical role in teaching their child to become an autonomous being and respect for the child's moral worth. We argue that the ethical grounding for the involvement of young children in medical decision-making does not stem from children's rights, the principle of best interests, or respect for developing autonomy. An alternative strategy is to examine the original motivation to engage with the child. In paediatric settings there are two obligations on the researcher: an obligation to the parents who are responsible for determining when and under what circumstances the child develops his capacity for autonomy and reasoning, and an obligation to the child himself. There is an important distinction between respecting a decision and encouraging a decision. This paper illustrates that the process of assent is an important way in which respect for the child as an individual can be demonstrated, however, the value lies not in the child's response but the fact that his views were solicited in the first place. This paper demonstrates that the common justifications for the process of assent are incomplete. Assent should be understood as playing a pedagogical role for the child, helping to teach him how specific decisions are made and therefore helping him to become a better decision-maker. How the researcher engages with the child supports his obligation to the child's parents, yet why the researcher engages with the child stems from the child's moral worth. Treating a child as having moral worth need not mean doing what they say but it may mean listening, considering, engaging or involving them in the decision.


Adolescents' response to pictorial warnings on the reverse panel of cigarette packs: a repeat cross-sectional study.
The UK (UK) became the third country in the European Union to require pictorial warnings on the back of cigarette packs, in October 2008. A repeat cross-sectional survey was conducted with 11-16-year-olds in the UK between August and September 2008 (N=1401) and August and September 2011 (N=1373). At both waves the same text warnings appeared on the front and back of packs, with the only difference being the inclusion of images on the back of packs to support the text warnings in 2011. Warning related measures assessed were salience (noticing, looking closely at warnings), depth of processing (thinking about warnings, discussing them with others), comprehension and credibility (warning comprehensibility, believability and truthfulness), unaided recall, persuasiveness (warnings as a deterrent to smoking), avoidance techniques (eg, hiding packs) and a behavioural indicator (forgoing cigarettes due to warnings). For never smokers, warning persuasiveness and thinking about what warnings are telling them when the pack is in sight significantly increased from 2008 to 2011, but warning comprehensibility significantly decreased. For experimental smokers, there was a significant increase from 2008 to 2011 for warning persuasiveness, believing warnings and considering them truthful. For regular smokers, there were no significant changes from 2008 to 2011, except for an increase in hiding packs to avoid warnings and a decrease in warning salience. Including pictorial images on the back of cigarette packaging improved warning persuasiveness for never and experimental smokers, but had a negligible impact on regular smokers. The findings have implications for warning design.


Effects of Withania somnifera (Ashwagandha) and Terminalia arjuna (Arjuna) on physical performance and cardiorespiratory endurance in healthy young adults.
Several medicinal plants have been described to be beneficial for cardiac ailments in Ayurveda like Ashwagandha and Arjuna. Ashwagandha-categorised as Rasayanas, and described to promote health and longevity and Arjuna primarily for heart ailments. coronary artery disease, heart failure, hypercholesterolemia, anginal pain and can be considered as a useful drug for coronary artery disease, hypertension and ischemic cardiomyopathy. There are no scientific clinical studies showing effect of both these drugs on exercise performance after regular administration when given as supplements The present study was therefore designed and performed to assess the effects of Withania somnifera (Ashwagandha) and Terminalia arjuna (Arjuna) individually and as a combination on maximum velocity, average absolute and relative Power, balance, maximum oxygen consumption (VO2 max) and blood pressure in humans. Forty normal healthy. Subjects (either sex, mean age 20.6 ± 2.5yrs and mean Body Mass Index 21.9 ± 2.2) were recruited after written informed consent was obtained. Institutional Ethics Committee permission was also obtained. Thirty participants were assigned to experimental group of which 10 received standardized root extracts of Withania somnifera, 10 received standardized bark extract of Terminalia arjuna and the rest of the 10 received standardized root extract of Withania somnifera in addition to bark extract of Terminalia arjuna both. Both the drugs were given in the form of capsules (dosage 500mg/day for both the drugs). Ten participants received placebo (capsules filled with flour). All the subjects continued the regimen for 8 weeks. All variables were assessed before and after the course of drug administration Our study showed that Withania somnifera increased velocity, power and VO2 max whereas Terminalia arjuna increased VO2 max and lowered resting systolic blood pressure. When given in combination, the improvement was seen in all parameters except balance and diastolic blood pressure. Withania somnifera may therefore be useful for generalized weakness and to improve speed and lower limb muscular strength and neuro-muscular co-ordination. Terminalia arjuna may prove useful to improve cardio-vascular endurance and lowering systolic blood pressure. Both drugs appear to be safe for young adults when given for mentioned dosage and duration.


Highly discrepant proportions of female and male Scandinavian and British Isles ancestry within the isolated population of the Faroe Islands.
The Faroe Islands in the North Atlantic Ocean are inhabited by a small population, whose origin is thought to date back to the Viking Age. Historical, archaeological and linguistic evidence indicates that the present population of the Faroe Islands may have a mixture of Scandinavian and British Isles ancestry. In the present study we used 122 new and 19 previously published hypervariable region I sequences of the mitochondrial control region to analyse the genetic diversity of the Faroese population and compare it with other populations in the North Atlantic region. The analyses suggested that the Faroese mtDNA pool has been affected by genetic drift, and is among the most homogenous and isolated in the North Atlantic region. This will have implications for attempts to locate genes for complex disorders. To obtain estimates of Scandinavian vs British Isles ancestry proportions, we applied a frequency-based admixture approach taking private haplotypes into account by the use of phylogenetic information. While previous studies have suggested an excess of Scandinavian ancestry among the male settlers of the Faroe Islands, the current study indicates an excess of British Isles ancestry among the female settlers of the Faroe Islands. Compared to other admixed populations of the North Atlantic region, the population of the Faroe Islands appears to have the highest level of asymmetry in Scandinavian vs British Isles ancestry proportions among female and male settlers of the archipelago.


Enhanced localization of genetic samples through linkage-disequilibrium correction.
Characterizing the spatial patterns of genetic diversity in human populations has a wide range of applications, from detecting genetic mutations associated with disease to inferring human history. Current approaches, including the widely used principal-component analysis, are not suited for the analysis of linked markers, and local and long-range linkage disequilibrium (LD) can dramatically reduce the accuracy of spatial localization when unaccounted for. To overcome this, we have introduced an approach that performs spatial localization of individuals on the basis of their genetic data and explicitly models LD among markers by using a multivariate normal distribution. By leveraging external reference panels, we derive closed-form solutions to the optimization procedure to achieve a computationally efficient method that can handle large data sets. We validate the method on empirical data from a large sample of European individuals from the POPRES data set, as well as on a large sample of individuals of Spanish ancestry. First, we show that by modeling LD, we achieve accuracy superior to that of existing methods. Importantly, whereas other methods show decreased performance when dense marker panels are used in the inference, our approach improves in accuracy as more markers become available. Second, we show that accurate localization of genetic data can be achieved with only a part of the genome, and this could potentially enable the spatial localization of admixed samples that have a fraction of their genome originating from a given continent. Finally, we demonstrate that our approach is resistant to distortions resulting from long-range LD regions; such distortions can dramatically bias the results when unaccounted for.


Robust Gag-specific T cell responses characterize viremia control in HIV-2 infection.
HIV-2 infection in the majority of infected subjects follows an attenuated disease course that distinguishes it from infection with HIV-1. Antigen-specific T cells are pivotal in the management of chronic viral infections but are not sufficient to control viral replication in HIV-1-positive subjects, and their function in HIV-2 infection is not fully established. In a community-based cohort of HIV-2 long-term nonprogressors in rural Guinea-Bissau, we performed what we believe is the first comprehensive analysis of HIV-2-specific immune responses. We demonstrate that Gag is the most immunogenic protein. The magnitude of the IFN-gamma immune response to the HIV-2 proteome was inversely correlated with HIV-2 viremia, and this relationship was specifically due to the targeting of Gag. Furthermore, patients with undetectable viremia had greater Gag-specific responses compared with patients with high viral replication. The most frequently recognized peptides clustered within a defined region of Gag, and responses to a single peptide in this region were associated with low viral burden. The consistent relationship between Gag-specific immune responses and viremia control suggests that T cell responses are vital in determining the superior outcome of HIV-2 infection. A better understanding of how HIV-2 infection is controlled may identify correlates of effective protective immunity essential for the design of HIV vaccines.


Profits and pandemics: prevention of harmful effects of tobacco, alcohol, and ultra-processed food and drink industries.
The 2011 UN high-level meeting on non-communicable diseases (NCDs) called for multisectoral action including with the private sector and industry. However, through the sale and promotion of tobacco, alcohol, and ultra-processed food and drink (unhealthy commodities), transnational corporations are major drivers of global epidemics of NCDs. What role then should these industries have in NCD prevention and control? We emphasise the rise in sales of these unhealthy commodities in low-income and middle-income countries, and consider the common strategies that the transnational corporations use to undermine NCD prevention and control. We assess the effectiveness of self-regulation, public-private partnerships, and public regulation models of interaction with these industries and conclude that unhealthy commodity industries should have no role in the formation of national or international NCD policy. Despite the common reliance on industry self-regulation and public-private partnerships, there is no evidence of their effectiveness or safety. Public regulation and market intervention are the only evidence-based mechanisms to prevent harm caused by the unhealthy commodity industries.


Epidemiology of hip and knee pain and its impact on overall health status in older adults.
To obtain prevalence rates of hip and knee pain in elderly people and compare combinations of symptoms with overall health status. We performed a cross-sectional postal survey of a random sample of 5500 Oxfordshire residents aged 65 yr and older. Prevalence estimates were based on the screening question: 'During the past 12 months, have you had pain in or around either of your hip/knee joints on most days for one month or longer?' Overall health status was assessed with the SF-36 questionnaire. The response rate was 66.3% (3341/5039 eligible people), and was highest (approximately reverse similar 72%) for the 65-74 yr age-group. The percentage reporting hip pain was 19.2% [95% confidence interval (CI) 17.9-20.6], and 32.6% (95% CI 31.0-34.3) reported knee pain. The percentage reporting hip and knee pain was 11.3%, and 40.7% reported hip or knee pain. Less than half (48%) of the symptomatic respondents had unilateral problems affecting one hip or knee joint only. SF-36 scores worsened as the number of symptomatic hip and knee joints increased (P<0.001 for physical function, physical role limitation and bodily pain). Patterns of hip and knee symptoms are complex in older people. Amongst the symptomatic, most have more than one hip/knee affected. This has implications for treatment and health status measurement. In the absence of hip and knee symptoms, general health status scores of elderly people are similar to those of people aged under 65 yr.


Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2V617F-positive myeloproliferative neoplasms.
V617F driver mutation of JAK2 is the leading cause of the Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs). Although thrombosis is a leading cause of mortality and morbidity in MPNs, the mechanisms underlying their pathogenesis are unclear. Here, we identified pleckstrin-2 (Plek2) as a downstream target of the JAK2/STAT5 pathway in erythroid and myeloid cells, and showed that it is upregulated in a JAK2V617F-positive MPN mouse model and in patients with MPNs. Loss of Plek2 ameliorated JAK2V617F-induced myeloproliferative phenotypes including erythrocytosis, neutrophilia, thrombocytosis, and splenomegaly, thereby reverting the widespread vascular occlusions and lethality in JAK2V617F-knockin mice. Additionally, we demonstrated that a reduction in red blood cell mass was the main contributing factor in the reversion of vascular occlusions. Thus, our study identifies Plek2 as an effector of the JAK2/STAT5 pathway and a key factor in the pathogenesis of JAK2V617F-induced MPNs, pointing to Plek2 as a viable target for the treatment of MPNs.


Revised direct radiocarbon dating of the Vindija G1 Upper Paleolithic Neandertals.
The 1998/1999 direct dating of two Neandertal specimens from level G(1) of Vindija Cave in Croatia to approximately 28,000 and approximately 29,000 radiocarbon ((14)C) years ago has led to interpretations concerning the late survival of Neandertals in south-central Europe, patterns of interaction between Neandertals and in-dispersing early modern humans in Europe, and complex biocultural scenarios for the earlier phases of the Upper Paleolithic. Given improvements, particularly in sample pretreatment techniques for bone radiocarbon samples, especially ultrafiltration of collagen samples, these Vindija G(1) Neandertal fossils are redated to approximately 32,000-33,000 (14)C years ago and possibly earlier. These results and the recent redating of a number of purportedly old modern human skeletal remains in Europe to younger time periods highlight the importance of fine chronological control when studying this biocultural time period and the tenuous nature of monolithic scenarios for the establishment of modern humans and earlier phases of the Upper Paleolithic in Europe.


Measurement of kT splitting scales in W→ℓν events at [Formula: see text] with the ATLAS detector.
A measurement of splitting scales, as defined by the kT clustering algorithm, is presented for final states containing a W boson produced in proton-proton collisions at a centre-of-mass energy of 7 TeV. The measurement is based on the full 2010 data sample corresponding to an integrated luminosity of 36 pb-1 which was collected using the ATLAS detector at the CERN Large Hadron Collider. Cluster splitting scales are measured in events containing W bosons decaying to electrons or muons. The measurement comprises the four hardest splitting scales in a kT cluster sequence of the hadronic activity accompanying the W boson, and ratios of these splitting scales. Backgrounds such as multi-jet and top-quark-pair production are subtracted and the results are corrected for detector effects. Predictions from various Monte Carlo event generators at particle level are compared to the data. Overall, reasonable agreement is found with all generators, but larger deviations between the predictions and the data are evident in the soft regions of the splitting scales.


Effect of hydroalcoholic extract of Sphaeranthus indicus against experimentally induced anxiety, depression and convulsions in rodents.
To investigate the effects of a hydroalcoholic extract of the Sphaeranthus indicus (SIE) against experimentally induced anxiety, depression and convulsions in rodents. The SIE (100, 200, 500 mg/kg, p.o.) was used in elevated plus maze, open field, forced swimming, and tail suspension tests in mice. The same doses were also used to evaluate its anticonvulsant effect on pentylenetetrazole (PTZ)-induced convulsions in mice and maximal electroshock (MES)-induced convulsions in rats. SIE was found to increase the number of entries and the time spent in the open arms of the maze at a dose of 100 mg/kg, p.o., indicating its anxiolytic activity. On the other hand, higher doses of SIE (200 and 500 mg/kg, p.o.) decreased open arm entries and time spent in the open arms of the maze in the elevated plus maze test indicating an absence of anxiolytic activity. However, this effect could have been related to a decrease in the locomotor activity of the mice and not to an anxiogenic effect, as indicated by the reduction in the total number of entries in the elevated plus maze. SIE also (at doses of 200 and 500 mg/kg, p.o.) decreased locomotor activity but did not affect emotional activity parameters in the open field test, suggesting a possible central nervous depressant activity. SIE also increased the immobility time in the forced swimming test at an oral dose of 500 mg/kg but did not significantly modify the activity in the tail suspension test. SIE protected rats against MES-induced convulsions and mice against PTZ-induced convulsions. Sphaeranthus indicus demonstrated anxiolytic, central nervous depressant, and anticonvulsant activities in rodents, thus supporting the folk medicinal use of this plant in nervous disorders.


Prism adaptation aftereffects in stroke patients with spatial neglect: pathological effects on subjective straight ahead but not visual open-loop pointing.
Prism adaptation to rightward optical shifts during visually guided pointing is considered a promising intervention in right-hemisphere stroke patients with left spatial neglect. Conventionally, prism adaptation is assessed via aftereffects, on subjective straight ahead (SSA) pointing with eyes closed; or by visual open-loop pointing (VOL), i.e. pointing to a visual target without seeing the hand. Previous data suggest indirectly that prism aftereffects in neglect patients may be larger (pathologically so) when assessed by SSA than by VOL. But these measures have never been directly compared within the same patients after identical prism exposure. Accordingly we implemented both measures here within the same group of 13 neglect patients and 13 controls. Prism aftereffects were much larger for SSA than VOL in neglect patients, falling outside the normative range only for SSA. This may arise because the SSA task can itself involve aspects of neglect that may be ameliorated by the prism intervention, hence showing abnormal changes after prisms. The extent of SSA change after prisms varied between patients, and correlated with improvements on a standard cancellation measure for neglect. The lesions of patients who did versus did not show neglect improvement immediately after prisms provide an initial indication that lack of improvement may potentially relate to cortical damage in right intraparietal sulcus and white matter damage in inferior parietal lobe and middle frontal gyrus. Future studies of possible rehabilitative impact from prisms upon neglect may need to consider carefully how to measure prism adaptation per se, separately from any impact of such adaptation upon manifestations of neglect.


On the accuracy of framing-rate measurements in ultra-high speed rotating mirror cameras.
Rotating mirror systems based on the Miller Principle are a mainstay modality for ultra-high speed imaging within the range 1-25 million frames per second. Importantly, the true temporal accuracy of observations recorded in such cameras is sensitive to the framing rate that the system directly associates with each individual data acquisition. The purpose for the present investigation was to examine the validity of such system-reported frame rates in a widely used commercial system (a Cordin 550-62 model) by independently measuring the framing rate at the instant of triggering. Here, we found a small but significant difference between such measurements: the average discrepancy (over the entire spectrum of frame rates used) was found to be 0.66 ± 0.48%, with a maximum difference of 2.33%. The principal reason for this discrepancy was traced to non-optimized sampling of the mirror rotation rate within the system protocol. This paper thus serves three purposes: (i) we highlight a straightforward diagnostic approach to facilitate scrutiny of rotating-mirror system integrity; (ii) we raise awareness of the intrinsic errors associated with data previously acquired with this particular system and model; and (iii), we recommend that future control routines address the sampling issue by implementing real-time measurement at the instant of triggering.


Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.
A modifier variant can abrogate the risk of a monogenic disorder. DFNM1 is a locus on chromosome 1 encoding a dominant suppressor of human DFNB26 recessive, profound deafness. Here, we report that DFNB26 is associated with a substitution (p.Gly116Glu) in the pleckstrin homology domain of GRB2-associated binding protein 1 (GAB1), an essential scaffold in the MET proto-oncogene, receptor tyrosine kinase/HGF (MET/HGF) pathway. A dominant substitution (p.Arg544Gln) of METTL13, encoding a predicted methyltransferase, is the DFNM1 suppressor of GAB1-associated deafness. In zebrafish, human METTL13 mRNA harboring the modifier allele rescued the GAB1-associated morphant phenotype. In mice, GAB1 and METTL13 colocalized in auditory sensory neurons, and METTL13 coimmunoprecipitated with GAB1 and SPRY2, indicating at least a tripartite complex. Expression of MET-signaling genes in human lymphoblastoid cells of individuals homozygous for p.Gly116Glu GAB1 revealed dysregulation of HGF, MET, SHP2, and SPRY2, all of which have reported variants associated with deafness. However, SPRY2 was not dysregulated in normal-hearing humans homozygous for both the GAB1 DFNB26 deafness variant and the dominant METTL13 deafness suppressor, indicating a plausible mechanism of suppression. Identification of METTL13-based modification of MET signaling offers a potential therapeutic strategy for a wide range of associated hearing disorders. Furthermore, MET signaling is essential for diverse functions in many tissues including the inner ear. Therefore, identification of the modifier of MET signaling is likely to have broad clinical implications.


Assessment of body surface potential mapping in diabetic patients with recognized depression.
Parameters of body surface potential mapping (BSPM) in DM II patients are significantly different comparing with healthy non-diabetic subjects. Hypothesis that these changes are more pronounced in DM II patients with depression was tested in the present study. For this purpose, analysis of the relationship between the Int-QRST (isointegral) maps distribution and the depressive symptoms intensification, as well interrelation between depressive and diabetic symptoms were performed. BSPM registrations were obtained from the three study groups (aged 37-52 years), namely 40 diabetic patients with clinically documented depression, 30 depressive patient without DM and 90 normal subjects. BSPM recordings were displayed in a form of the Int-QRST maps. Examination with BDI and HbA1c test were also performed in all investigated subjects. Isointegral QRST maps turned out to display abnormal, i.e. non-dipolar distribution. Moreover, extent of Int-QRST maps multipolarity increased in the examined diabetic patients along with DM II duration, BDI scores and HbA1c level. Non-dipolar distribution of Int-QRST maps, more pronounced in diabetic patients with depression, can be a specific indicator of the increased risk of severe ventricular arrhythmias occurring prior to abnormalities detectable on the standard 12-lead ECG recordings, which is of great importance especially in prevention of life-threatening arrhythmias.


The vitamin D receptor: contemporary genomic approaches reveal new basic and translational insights.
The vitamin D receptor (VDR) is the single known regulatory mediator of hormonal 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] in higher vertebrates. It acts in the nucleus of vitamin D target cells to regulate the expression of genes whose products control diverse, cell type-specific biological functions that include mineral homeostasis. In this Review we describe progress that has been made in defining new cellular sites of action of this receptor, the mechanisms through which this mediator controls the expression of genes, the biology that ensues, and the translational impact of this receptor on human health and disease. We conclude with a brief discussion of what comes next in understanding vitamin D biology and the mechanisms that underlie its actions.


Do humans produce the speed-accuracy trade-off that maximizes reward rate?
In this paper we investigate trade-offs between speed and accuracy that are produced by humans when confronted with a sequence of choices between two alternatives. We assume that the choice process is described by the drift diffusion model, in which the speed-accuracy trade-off is primarily controlled by the value of the decision threshold. We test the hypothesis that participants choose the decision threshold that maximizes reward rate, defined as an average number of rewards per unit of time. In particular, we test four predictions derived on the basis of this hypothesis in two behavioural experiments. The data from all participants of our experiments provide support only for some of the predictions, and on average the participants are slower and more accurate than predicted by reward rate maximization. However, when we limit our analysis to subgroups of 30-50% of participants who earned the highest overall rewards, all the predictions are satisfied by the data. This suggests that a substantial subset of participants do select decision thresholds that maximize reward rate. We also discuss possible reasons why the remaining participants select thresholds higher than optimal, including the possibility that participants optimize a combination of reward rate and accuracy or that they compensate for the influence of timing uncertainty, or both.


Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S)
To assess in diabetic patients with coronary heart disease (CHD) the effect of cholesterol lowering with simvastatin on mortality and the risk of CHD and other atherosclerotic events. A post hoc subgroup analysis was carried out on data from 202 diabetic patients and 4,242 nondiabetic patients with previous myocardial infarction or angina pectoris, serum total cholesterol 5.5-8.0 mmol/l, and serum triglycerides < or = 2.5 mmol/l who were participating in the Scandinavian Simvastatin Survival Study (4S). Participants in the 4S were randomly assigned to double-blind treatment with simvastatin, 20 mg daily, with blinded dosage titration up to 40 mg daily, according to cholesterol response during the first 6-18 weeks, or placebo. Endpoints were 1) total mortality, 2) major CHD events (CHD death or nonfatal myocardial infarction), 3) other acute atherosclerotic events, 4) myocardial revascularization procedures. Over the 5.4-year median follow-up period, simvastatin treatment produced mean changes in serum lipids in diabetic patients similar to those observed in nondiabetic patients. The relative risks (RRs) of main endpoints in simvastatin-treated diabetic patients were as follows: total mortality 0.57 (95% CI, 0.30-1.08; P = 0.087), major CHD events 0.45 (95% CI, 0.27-0.74; P = 0.002), and any atherosclerotic event 0.63 (95% CI, 0.43-0.92; P = 0.018). The corresponding RRs in nondiabetic patients were the following: 0.71 (95% CI, 0.58-0.87; P = 0.001), 0.68 (95% CI, 0.60-0.77; P < 0.0001), and 0.74 (95% CI, 0.68-0.82; P < 0.0001). The results strongly suggest that cholesterol lowering with simvastatin improves the prognosis of diabetic patients with CHD. The absolute clinical benefit achieved by cholesterol lowering may be greater in diabetic than in nondiabetic patients with CHD because diabetic patients have a higher absolute risk of recurrent CHD events and other atherosclerotic events.


EphA4 as an effector of Twist1 in the guidance of osteogenic precursor cells during calvarial bone growth and in craniosynostosis.
Heterozygous loss of Twist1 function causes coronal synostosis in both mice and humans. We showed previously that in mice this phenotype is associated with a defect in the neural crest-mesoderm boundary within the coronal suture, as well as with a reduction in the expression of ephrin A2 (Efna2), ephrin A4 (Efna4) and EphA4 in the coronal suture. We also demonstrated that mutations in human EFNA4 are a cause of non-syndromic coronal synostosis. Here we investigate the cellular mechanisms by which Twist1, acting through Eph-ephrin signaling, regulates coronal suture development. We show that EphA4 mutant mice exhibit defects in the coronal suture and neural crest-mesoderm boundary that phenocopy those of Twist1(+/-) mice. Further, we demonstrate that Twist1 and EphA4 interact genetically: EphA4 expression in the coronal suture is reduced in Twist1 mutants, and compound Twist1-EphA4 heterozygotes have suture defects of greater severity than those of individual heterozygotes. Thus, EphA4 is a Twist1 effector in coronal suture development. Finally, by DiI labeling of migratory osteogenic precursor cells that contribute to the frontal and parietal bones, we show that Twist1 and EphA4 are required for the exclusion of such cells from the coronal suture. We suggest that the failure of this process in Twist1 and EphA4 mutants is the cause of craniosynostosis.


Nonoperative management of primary colorectal cancer in patients with stage IV disease.
Traditional teaching maintains that patients with primary colorectal adenocarcinoma require timely resection to prevent bleeding, perforation, or obstruction. The true benefits of primary tumor resection remain undocumented for patients presenting with metastatic disease, however. We postulated that resection of primary colorectal tumors could be avoided safely in a select population of asymptomatic colorectal cancer patients presenting with incurable stage IV disease. A retrospective review of the Vanderbilt University Hospital tumor registry was performed for the years 1985 to 1997. During this period, 955 patients presented for management of primary colorectal cancer. From this group, all patients with stage IV disease at the time of diagnosis were identified. Patients who initially underwent resection of their primary lesion were included in the resection group; those who underwent initial nonoperative primary tumor management were included in the nonresection group. Data were obtained regarding age, extent of disease, nonsurgical therapy, tumor-specific complications, and palliative surgical procedures. Surgery-free survival and overall survival were analyzed using the Kaplan-Meier method. For patients with liver metastases, hepatic tumor burden was defined as either H1 (<25% parenchymal replacement), H2 (25% to 50%), or H3 (>50%) disease. Sixty-six patients were included in the resection group, and 23 patients with intact asymptomatic primary colorectal lesions were included in the nonresection group. Among patients with hepatic metastases, most of the patients in both groups had H1 disease. Ten patients in the resection group and 3 patients in the nonresection group presented with exclusively extrahepatic metastases. In the nonresection group, primary therapy included chemotherapy in 13 patients, external beam radiation therapy in 1 patient, and combination chemoradiation in 9 patients. The median survival in the nonresection group was 16.6 months. The 2-year actuarial survival was 18%, and the surgery-free survival was 91.3%. Only 2 of 23 patients (8.7%) managed without resection eventually developed obstruction at the primary tumor site requiring emergent diversion. There were no episodes of tumor-related hemorrhage or perforation. For the resection group, the operative morbidity was 30.3%, and the perioperative mortality rate was 4.6%. The median survival in the resection group was 14.5 months (P = 0.59, log-rank test vs. nonresection group). Selected patients with asymptomatic primary colorectal tumors who present with incurable metastatic disease may safely avoid resection of their primary lesions, with an anticipated low rate of hemorrhage, perforation, or obstruction before death from systemic disease. No survival advantage is gained by resection of an asymptomatic primary lesion in the setting of incurable stage IV colorectal cancer.


Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia.
Although the role of Hedgehog (Hh) signalling in embryonic pattern formation is well established, its functions in adult tissue renewal and maintenance remain unclear, and the relationship of these functions to cancer development has not been determined. Here we show that the loss of Smoothened (Smo), an essential component of the Hh pathway, impairs haematopoietic stem cell renewal and decreases induction of chronic myelogenous leukaemia (CML) by the BCR-ABL1 oncoprotein. Loss of Smo causes depletion of CML stem cells--the cells that propagate the leukaemia--whereas constitutively active Smo augments CML stem cell number and accelerates disease. As a possible mechanism for Smo action, we show that the cell fate determinant Numb, which depletes CML stem cells, is increased in the absence of Smo activity. Furthermore, pharmacological inhibition of Hh signalling impairs not only the propagation of CML driven by wild-type BCR-ABL1, but also the growth of imatinib-resistant mouse and human CML. These data indicate that Hh pathway activity is required for maintenance of normal and neoplastic stem cells of the haematopoietic system and raise the possibility that the drug resistance and disease recurrence associated with imatinib treatment of CML might be avoided by targeting this essential stem cell maintenance pathway.


Determining which automatic digital blood pressure device performs adequately: a systematic review.
The aim of this study is to systematically examine the proportion of accurate readings attained by automatic digital blood pressure (BP) devices in published validation studies. We included studies of automatic digital BP devices using recognized protocols. We summarized the data as mean and s.d. of differences between measured and observed BP, and proportion of measurements within 5 mm Hg. We included 79 articles (10,783 participants) reporting 113 studies from 22 different countries. Overall, 25/31 (81%), 37/41 (90%) and 34/35 (97%) devices passed the relevant protocols [BHS, AAMI and ESH international protocol (ESH-IP), respectively]. For devices that passed the BHS protocol, the proportion of measured values within 5 mm Hg of the observed value ranged from 60 to 86% (AAMI protocol 47-94% and ESH-IP 54-89%). The results for the same device varied significantly when a different protocol was used (Omron HEM-907 80% of readings were within 5 mm Hg using the AAMI protocol compared with 62% with the ESH-IP). Even devices with a mean difference of zero show high variation: a device with 74% of BP measurements within 5 mm Hg would require six further BP measurements to reduce variation to 95% of readings within 5 mm Hg. Current protocols for validating BP monitors give no guarantee of accuracy in clinical practice. Devices may pass even the most rigorous protocol with as few as 60% of readings within 5 mm Hg of the observed value. Multiple readings are essential to provide clinicians and patients with accurate information on which to base diagnostic and treatment decisions.


A general framework for the analysis of vessel encoded arterial spin labeling for vascular territory mapping.
Vessel encoded arterial spin labeling provides a way to perform non-invasive vascular territory imaging. By uniquely encoding the blood within feeding arteries over a number of images, the territories of each can be identified. Here, a new approach for the analysis of vessel encoded arterial spin labeling data is presented. The method includes a full description of how the geometry of arteries and spatial label modulation affects the measured signal. It also incorporates an artery-based classification that considers multiple arteries in each class, explicitly permitting a voxel to be supplied by multiple arteries. The developed framework is cast within a Bayesian inference procedure allowing both flow contributions and the locations of the arteries in the labeling plane to be inferred. By using simulated data, the method was shown to provide more accurate estimates of blood contribution in areas of mixed supply, such as would be found in watershed regions, than conventional methods. It was also able to estimate the location of arteries within the labeling plane, accounting for motion between sequence prescription and acquisition. Similar performance was found for data acquired using a pseudo-continuous labeling scheme both in the neck and above the Circle of Willis.


Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release: an observational study in three cohorts.
It has been proposed that individual genetic variation contributes to the course of severe infections and sepsis. Recent studies of single nucleotide polymorphisms (SNPs) within the endotoxin receptor and its signaling system showed an association with the risk of disease development. This study aims to examine the response associated with genetic variations of TLR4, the receptor for bacterial LPS, and a central intracellular signal transducer (TIRAP/Mal) on cytokine release and for susceptibility and course of severe hospital acquired infections in distinct patient populations. Three intensive care units in tertiary care university hospitals in Greece and Germany participated. 375 and 415 postoperative patients and 159 patients with ventilator associated pneumonia (VAP) were included. TLR4 and TIRAP/Mal polymorphisms in 375 general surgical patients were associated with risk of infection, clinical course and outcome. In two prospective studies, 415 patients following cardiac surgery and 159 patients with newly diagnosed VAP predominantly caused by Gram-negative bacteria were studied for cytokine levels in-vivo and after ex-vivo monocyte stimulation and clinical course. Patients simultaneously carrying polymorphisms in TIRAP/Mal and TLR4 and patients homozygous for the TIRAP/Mal SNP had a significantly higher risk of severe infections after surgery (odds ratio (OR) 5.5; confidence interval (CI): 1.34 - 22.64; P = 0.02 and OR: 7.3; CI: 1.89 - 28.50; P < 0.01 respectively). Additionally we found significantly lower circulating cytokine levels in double-mutant individuals with ventilator associated pneumonia and reduced cytokine production in an ex-vivo monocyte stimulation assay, but this difference was not apparent in TIRAP/Mal-homozygous patients. In cardiac surgery patients without infection, the cytokine release profiles were not changed when comparing different genotypes. Carriers of mutations in sequential components of the TLR signaling system may have an increased risk for severe infections. Patients with this genotype showed a decrease in cytokine release when infected which was not apparent in patients with sterile inflammation following cardiac surgery.


Persistent microglial activation and synaptic loss with behavioral abnormalities in mouse offspring exposed to CASPR2-antibodies in utero.
Gestational transfer of maternal antibodies against fetal neuronal proteins may be relevant to some neurodevelopmental disorders, but until recently there were no proteins identified. We recently reported a fivefold increase in CASPR2-antibodies in mid-gestation sera from mothers of children with intellectual and motor disabilities. Here, we exposed mice in utero to purified IgG from patients with CASPR2-antibodies (CASPR2-IgGs) or from healthy controls (HC-IgGs). CASPR2-IgG but not HC-IgG bound to fetal brain parenchyma, from which CASPR2-antibodies could be eluted. CASPR2-IgG exposed neonates achieved milestones similarly to HC-IgG exposed controls but, when adult, the CASPR2-IgG exposed progeny showed marked social interaction deficits, abnormally located glutamatergic neurons in layers V-VI of the somatosensory cortex, a 16% increase in activated microglia, and a 15-52% decrease in glutamatergic synapses in layers of the prefrontal and somatosensory cortices. Thus, in utero exposure to CASPR2-antibodies led to permanent behavioral, cellular, and synaptic abnormalities. These findings support a pathogenic role for maternal antibodies in human neurodevelopmental conditions, and CASPR2 as a potential target.


Does aquaculture add resilience to the global food system?
Aquaculture is the fastest growing food sector and continues to expand alongside terrestrial crop and livestock production. Using portfolio theory as a conceptual framework, we explore how current interconnections between the aquaculture, crop, livestock, and fisheries sectors act as an impediment to, or an opportunity for, enhanced resilience in the global food system given increased resource scarcity and climate change. Aquaculture can potentially enhance resilience through improved resource use efficiencies and increased diversification of farmed species, locales of production, and feeding strategies. However, aquaculture's reliance on terrestrial crops and wild fish for feeds, its dependence on freshwater and land for culture sites, and its broad array of environmental impacts diminishes its ability to add resilience. Feeds for livestock and farmed fish that are fed rely largely on the same crops, although the fraction destined for aquaculture is presently small (∼4%). As demand for high-value fed aquaculture products grows, competition for these crops will also rise, as will the demand for wild fish as feed inputs. Many of these crops and forage fish are also consumed directly by humans and provide essential nutrition for low-income households. Their rising use in aquafeeds has the potential to increase price levels and volatility, worsening food insecurity among the most vulnerable populations. Although the diversification of global food production systems that includes aquaculture offers promise for enhanced resilience, such promise will not be realized if government policies fail to provide adequate incentives for resource efficiency, equity, and environmental protection.


Indirect moxibustion (CV4 and CV8) ameliorates chronic fatigue: a randomized, double-blind, controlled study.
The antifatigue effect of indirect moxibustion and its antioxidant properties were investigated. A randomized, double-blind, controlled clinical trial was performed with 44 patients who had idiopathic chronic fatigue. The subjects were treated with a placebo or moxibustion (indirect moxibustion on CV4 and CV8 3 times per week for 4 weeks), and their fatigue severity was monitored using a self-rating numeric scale (NRS) and a visual analog scale (VAS). Serum level of reactive oxygen species and malondialdehyde (MDA), total antioxidant capacity, the activity of catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase and total glutathione content, were determined before initial moxibustion therapy and after the 12th moxibustion treatment. The moxibustion group had a significantly lower fatigue severity score compared to the control for both the NRS (p<0.05) and VAS scores (p<0.01). The level of serum MDA was significantly lower in the moxibustion group than in the placebo group (p<0.05), whereas glutathione reductase activity and total glutathione content increased significantly following moxibustion (p<0.05). The results provide clinical evidence for an antifatigue effect of indirect moxibustion at CV4 and CV8 and suggest that the effect is due to the antioxidant properties of moxibustion.


Recourse to alternative medicine during pregnancy: motivations of women and impact of research findings.
The aims of this study were to gain a better understanding of the motivations of pregnant women utilizing moxibustion for breech presentation and to measure the impact of research results on these patients' treatment decisions regarding this alternative medicine technique. The study involved a statistical analysis of two self-administered questionnaires to 212 women who had previously participated in a randomized clinical trial on the efficacy of moxibustion; in addition, a qualitative thematic content analysis for open-ended questions was also performed. Most women (69%) reported treating themselves at least once with complementary and alternative medicine (CAM). Higher use of CAM was associated with higher education and Caucasian origin. Pregnancy was associated with a significant reduction in utilization of CAMs. After reading the results of a previous randomized clinical trial, which did not demonstrate efficacy of moxibustion, 60% of the women questioned expressed the intention of resorting to this technique in case of a subsequent pregnancy with a fetus in the breech position. The principal motivation was their desire to try anything that may possibly turn such fetuses to increase the chances of delivering them vaginally. It is important to consider the regard that pregnant women attribute to CAMs for self-care strategies. Despite a lack of scientific evidence supporting the use of moxibustion to address breech presentation, pregnant women consider CAMs, in general, to be safe and effective. Studies investigating the physical and psychologic effects of CAMs will enable clinicians to advise patients better about treatment options.


Influences of history, geography, and religion on genetic structure: the Maronites in Lebanon.
Cultural expansions, including of religions, frequently leave genetic traces of differentiation and in-migration. These expansions may be driven by complex doctrinal differentiation, together with major population migrations and gene flow. The aim of this study was to explore the genetic signature of the establishment of religious communities in a region where some of the most influential religions originated, using the Y chromosome as an informative male-lineage marker. A total of 3139 samples were analyzed, including 647 Lebanese and Iranian samples newly genotyped for 28 binary markers and 19 short tandem repeats on the non-recombinant segment of the Y chromosome. Genetic organization was identified by geography and religion across Lebanon in the context of surrounding populations important in the expansions of the major sects of Lebanon, including Italy, Turkey, the Balkans, Syria, and Iran by employing principal component analysis, multidimensional scaling, and AMOVA. Timing of population differentiations was estimated using BATWING, in comparison with dates of historical religious events to determine if these differentiations could be caused by religious conversion, or rather, whether religious conversion was facilitated within already differentiated populations. Our analysis shows that the great religions in Lebanon were adopted within already distinguishable communities. Once religious affiliations were established, subsequent genetic signatures of the older differentiations were reinforced. Post-establishment differentiations are most plausibly explained by migrations of peoples seeking refuge to avoid the turmoil of major historical events.


The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity.
Multiple sclerosis (MS) is a putative T cell-mediated autoimmune disease. As with many autoimmune diseases, females are more susceptible than males. Sexual dimorphisms may be due to differences in sex hormones, sex chromosomes, or both. Regarding sex chromosome genes, a small percentage of X chromosome genes escape X inactivation and have higher expression in females (XX) compared with males (XY). Here, high-throughput gene expression analysis in CD4+ T cells showed that the top sexually dimorphic gene was Kdm6a, a histone demethylase on the X chromosome. There was higher expression of Kdm6a in females compared with males in humans and mice, and the four core genotypes (FCG) mouse model showed higher expression in XX compared with XY. Deletion of Kdm6a in CD4+ T cells ameliorated clinical disease and reduced neuropathology in the classic CD4+ T cell-mediated autoimmune disease experimental autoimmune encephalomyelitis (EAE). Global transcriptome analysis in CD4+ T cells from EAE mice with a specific deletion of Kdm6a showed upregulation of Th2 and Th1 activation pathways and downregulation of neuroinflammation signaling pathways. Together, these data demonstrate that the X escapee Kdm6a regulates multiple immune response genes, providing a mechanism for sex differences in autoimmune disease susceptibility.


Epigenetic reprogramming of immune cells in injury, repair, and resolution.
Immune cells are pivotal in the reaction to injury, whereupon, under ideal conditions, repair and resolution phases restore homeostasis following initial acute inflammation. Immune cell activation and reprogramming require transcriptional changes that can only be initiated if epigenetic alterations occur. Recently, accelerated deciphering of epigenetic mechanisms has extended knowledge of epigenetic regulation, including long-distance chromatin remodeling, DNA methylation, posttranslational histone modifications, and involvement of small and long noncoding RNAs. Epigenetic changes have been linked to aspects of immune cell development, activation, and differentiation. Furthermore, genome-wide epigenetic landscapes have been established for some immune cells, including tissue-resident macrophages, and blood-derived cells including T cells. The epigenetic mechanisms underlying developmental steps from hematopoietic stem cells to fully differentiated immune cells led to development of epigenetic technologies and insights into general rules of epigenetic regulation. Compared with more advanced research areas, epigenetic reprogramming of immune cells in injury remains in its infancy. While the early epigenetic mechanisms supporting activation of the immune response to injury have been studied, less is known about resolution and repair phases and cell type-specific changes. We review prominent recent findings concerning injury-mediated epigenetic reprogramming, particularly in stroke and myocardial infarction. Lastly, we illustrate how single-cell technologies will be crucial to understanding epigenetic reprogramming in the complex sequential processes following injury.


The neural basis of flashback formation: the impact of viewing trauma.
Psychological traumatic events, such as war or road traffic accidents, are widespread. A small but significant proportion of survivors develop post-traumatic stress disorder (PTSD). Distressing, sensory-based involuntary memories of trauma (henceforth 'flashbacks') are the hallmark symptom of PTSD. Understanding the development of flashbacks may aid their prevention. This work is the first to combine the trauma film paradigm (as an experimental analogue for flashback development) with neuroimaging to investigate the neural basis of flashback aetiology. We investigated the hypothesis that involuntary recall of trauma (flashback) is determined during the original event encoding. Method A total of 22 healthy volunteers viewed a traumatic film whilst undergoing functional magnetic resonance imaging (fMRI). They kept a 1-week diary to record flashbacks to specific film scenes. Using a novel prospective fMRI design, we compared brain activation for those film scenes that subsequently induced flashbacks with both non-traumatic control scenes and scenes with traumatic content that did not elicit flashbacks ('potentials'). Encoding of scenes that later caused flashbacks was associated with widespread increases in activation, including in the amygdala, striatum, rostral anterior cingulate cortex, thalamus and ventral occipital cortex. The left inferior frontal gyrus and bilateral middle temporal gyrus also exhibited increased activation but only relative to 'potentials'. Thus, these latter regions appeared to distinguish between traumatic content that subsequently flashed back and comparable content that did not. Results provide the first prospective evidence that the brain behaves differently whilst experiencing emotional events that will subsequently become involuntary memories - flashbacks. Understanding the neural basis of analogue flashback memory formation may aid the development of treatment interventions for this PTSD feature.


Occupational stress in human computer interaction.
There have been a variety of research approaches that have examined the stress issues related to human computer interaction including laboratory studies, cross-sectional surveys, longitudinal case studies and intervention studies. A critical review of these studies indicates that there are important physiological, biochemical, somatic and psychological indicators of stress that are related to work activities where human computer interaction occurs. Many of the stressors of human computer interaction at work are similar to those stressors that have historically been observed in other automated jobs. These include high workload, high work pressure, diminished job control, inadequate employee training to use new technology, monotonous tasks, por supervisory relations, and fear for job security. New stressors have emerged that can be tied primarily to human computer interaction. These include technology breakdowns, technology slowdowns, and electronic performance monitoring. The effects of the stress of human computer interaction in the workplace are increased physiological arousal; somatic complaints, especially of the musculoskeletal system; mood disturbances, particularly anxiety, fear and anger; and diminished quality of working life, such as reduced job satisfaction. Interventions to reduce the stress of computer technology have included improved technology implementation approaches and increased employee participation in implementation. Recommendations for ways to reduce the stress of human computer interaction at work are presented. These include proper ergonomic conditions, increased organizational support, improved job content, proper workload to decrease work pressure, and enhanced opportunities for social support. A model approach to the design of human computer interaction at work that focuses on the system "balance" is proposed.


Gamma Knife surgery for skull base chordomas and chondrosarcomas.
The purpose of this study was to evaluate radiosurgical outcomes in skull base chordomas and chondrosarcomas, and to determine which tumors are appropriate for stereotactic radiosurgery as adjuvant therapy following maximum tumor resection. Thirty-seven patients (48 lesions) were treated using Gamma Knife surgery (GKS); 27 had chordomas, seven had chondrosarcomas, and three had radiologically diagnosed chordomas. The mean tumor volume was 20 ml, and the mean maximum and marginal doses were 28 and 14 Gy, respectively. The mean follow-up period was 97 months from diagnosis and 59 months from GKS. The actuarial 5- and 10-year survival rates after GKS were 80 and 53%, respectively. The actuarial 5- and 10-year local tumor control (LTC) rates after single or multiple GKS sessions were 76 and 67%, respectively. All patients with low-grade chondrosarcomas achieved good LTC. A tumor volume of less than 20 ml significantly affected the high rate of LTC (p = 0.0182). No patient had adverse radiation effects, other than one in whom facial numbness worsened despite successful tumor control. As an adjuvant treatment after resection, GKS is a reasonable option for selected patients harboring skull base chordomas or chondrosarcomas with a residual tumor volume of less than 20 ml. Dose planning with a generous treatment volume to avoid marginal treatment failure should be made at a marginal dose of at least 15 Gy to achieve long-term tumor control.


Automated virtual reality (VR) cognitive therapy for patients with psychosis: study protocol for a single-blind parallel group randomised controlled trial (gameChange).
Many patients with psychosis experience everyday social situations as anxiety-provoking. The fears can arise, for example, from paranoia, hallucinations, social anxiety or negative-self beliefs. The fears lead patients to withdraw from activities, and this isolation leads to a cycle of worsening physical and mental health. Breaking this cycle requires highly active treatment directly in the troubling situations so that patients learn that they can safely and confidently enter them. However patients with psychosis seldom receive such life-changing interventions. To solve this problem we have developed an automated psychological treatment delivered in virtual reality (VR). It allows patients to experience computer simulations of the situations that they find anxiety-provoking. A virtual coach guides patients, using cognitive techniques, in how to overcome their fears. Patients are willing to enter VR simulations of anxiety-provoking situations because they know the simulations are not real, but the learning made transfers to the real world. 432 patients with psychosis and anxious avoidance of social situations will be recruited from National Health Service (NHS) secondary care services. In the gameChange trial, they will be randomised (1:1) to the six-session VR cognitive treatment added to treatment as usual or treatment as usual alone. Assessments will be conducted at 0, 6 (post-treatment) and 26 weeks by a researcher blind to allocation. The primary outcome is avoidance and distress in real-life situations, using a behavioural assessment task, at 6 weeks. The secondary outcomes are psychiatric symptoms, activity levels and quality of life. All main analyses will be intention-to-treat. Moderation and mediation will be tested. An economic evaluation will be conducted. The trial has received ethical approval from the NHS South Central - Oxford B Research Ethics Committee (19/SC/0075). A key output will be a high-quality automated VR treatment for patients to overcome anxious avoidance of social situations. ISRCTN17308399.


Identification of close relatives in the HUGO Pan-Asian SNP database.
The HUGO Pan-Asian SNP Consortium has recently released a genome-wide dataset, which consists of 1,719 DNA samples collected from 71 Asian populations. For studies of human population genetics such as genetic structure and migration history, this provided the most comprehensive large-scale survey of genetic variation to date in East and Southeast Asia. However, although considered in the analysis, close relatives were not clearly reported in the original paper. Here we performed a systematic analysis of genetic relationships among individuals from the Pan-Asian SNP (PASNP) database and identified 3 pairs of monozygotic twins or duplicate samples, 100 pairs of first-degree and 161 second-degree of relationships. Three standardized subsets with different levels of unrelated individuals were suggested here for future applications of the samples in most types of population-genetics studies (denoted by PASNP1716, PASNP1640 and PASNP1583 respectively) based on the relationships inferred in this study. In addition, we provided gender information for PASNP samples, which were not included in the original dataset, based on analysis of X chromosome data.


Estimation of insulin secretion rates from C-peptide levels. Comparison of individual and standard kinetic parameters for C-peptide clearance.
Insulin secretion rates can be accurately estimated from plasma C-peptide levels with a two-compartment model for C-peptide distribution and degradation. In previous studies, the kinetic parameters of C-peptide clearance were derived in each subject from the decay curve observed after bolus intravenous injection of biosynthetic human C-peptide. To determine whether standard parameters for C-peptide clearance could be defined and used to calculate insulin secretion without obtaining a decay curve in each subject, we analyzed 200 decay curves of biosynthetic human C-peptide obtained in normal, obese, and non-insulin-dependent diabetes mellitus subjects studied in our laboratory. This analysis showed that the volume of distribution and kinetic parameters of C-peptide distribution and metabolism vary by less than 30% in a population highly heterogeneous in terms of age, sex, degree of obesity, and degree of glucose tolerance. The volume of distribution correlated with the degree of obesity as quantified by body surface area (BSA). This dependence of C-peptide distribution volume on BSA was more marked in men than in women. The long half-life was slightly longer in elderly subjects than in younger adults. When effects of BSA, sex, and age were taken into account, the parameters of C-peptide kinetics were very similar in normal, obese, and diabetic subjects. Based on these findings, a simple procedure to derive standard parameters for C-peptide clearance taking into account degree of obesity, sex, and age was defined. These standard parameters resulted in estimations of mean insulin secretion rates, which differed in each subject by only 10-12% from those obtained with individual parameters. The approach of using standard rather than individual parameters did not systematically underestimate or overestimate insulin secretion so that group values for the fasting secretion rate, the mean 24-h secretion rate, and the number and the amplitude of secretory pulses obtained with standard parameters differed by only 1-2% from the values obtained with individual parameters. Furthermore, the accuracy of measurements based on standard parameters was not different from that associated with replicate determinations of the parameters of C-peptide clearance in the same subject. We conclude that it is possible to estimate insulin secretion rates from plasma C-peptide levels with standard parameters for C-peptide clearance rather than individually derived parameters without significant loss of accuracy.


Quantification of house-dust-mite populations.
Since the proposal that allergen from the mite Dermatophagoides pteronyssinus is identical to the house-dust allergen supposed to cause asthma and allergy, interest in the abundance, species diversity, and frequency of mites in the home has expanded. Surveys and ecologic studies have confirmed the ubiquity of mites in house dust, especially mites of the family Pyroglyphidae, but most do not give an accurate estimate of population size or mite exposure. These are still important issues today in attempts to quantify the exposure to house-dust mite that constitutes a risk, to assess mite-eradication trials, and to determine fluctuations in mite population. The problems encountered with common methods of house-dust sampling. mite extraction, and measuring house-dust allergen are discussed.


Dynamics of ferrofluidic flow in the Taylor-Couette system with a small aspect ratio.
We investigate fundamental nonlinear dynamics of ferrofluidic Taylor-Couette flow - flow confined be-tween two concentric independently rotating cylinders - consider small aspect ratio by solving the ferro-hydrodynamical equations, carrying out systematic bifurcation analysis. Without magnetic field, we find steady flow patterns, previously observed with a simple fluid, such as those containing normal one- or two vortex cells, as well as anomalous one-cell and twin-cell flow states. However, when a symmetry-breaking transverse magnetic field is present, all flow states exhibit stimulated, finite two-fold mode. Various bifurcations between steady and unsteady states can occur, corresponding to the transitions between the two-cell and one-cell states. While unsteady, axially oscillating flow states can arise, we also detect the emergence of new unsteady flow states. In particular, we uncover two new states: one contains only the azimuthally oscillating solution in the configuration of the twin-cell flow state, and an-other a rotating flow state. Topologically, these flow states are a limit cycle and a quasiperiodic solution on a two-torus, respectively. Emergence of new flow states in addition to observed ones with classical fluid, indicates that richer but potentially more controllable dynamics in ferrofluidic flows, as such flow states depend on the external magnetic field.


Paleovirology and virally derived immunity.
Paleovirology, the study of viruses on evolutionary timescales, can exploit information from endogenous viral elements (EVEs), which are the result of heritable horizontal gene transfer (HGT) from viruses to hosts. The availability of genomic data has increased opportunities to study EVEs, and bioinformatics techniques have been crucial in cataloguing EVE diversity and taxonomic coverage. Recent advances show that some EVEs have been co-opted as cellular genes, often as inhibitors of viral infection. These genes are an intriguing strategy in virus-host evolutionary battles in that genetic material is transferred from virus to host, and then used by the host against the virus. In this review, we consider the genes and processes involved in EVE-derived immunity (EDI), assess factors leading to its emergence, and outline how future work will benefit from incorporating evolutionary approaches.


How cannabis causes paranoia: using the intravenous administration of ∆9-tetrahydrocannabinol (THC) to identify key cognitive mechanisms leading to paranoia.
Paranoia is receiving increasing attention in its own right, since it is a central experience of psychotic disorders and a marker of the health of a society. Paranoia is associated with use of the most commonly taken illicit drug, cannabis. The objective was to determine whether the principal psychoactive ingredient of cannabis-∆(9)-tetrahydrocannabinol (THC)-causes paranoia and to use the drug as a probe to identify key cognitive mechanisms underlying paranoia. A randomized, placebo-controlled, between-groups test of the effects of intravenous THC was conducted. A total of 121 individuals with paranoid ideation were randomized to receive placebo, THC, or THC preceded by a cognitive awareness condition. Paranoia was assessed extensively via a real social situation, an immersive virtual reality experiment, and standard self-report and interviewer measures. Putative causal factors were assessed. Principal components analysis was used to create a composite paranoia score and composite causal variables to be tested in a mediation analysis. THC significantly increased paranoia, negative affect (anxiety, worry, depression, negative thoughts about the self), and a range of anomalous experiences, and reduced working memory capacity. The increase in negative affect and in anomalous experiences fully accounted for the increase in paranoia. Working memory changes did not lead to paranoia. Making participants aware of the effects of THC had little impact. In this largest study of intravenous THC, it was definitively demonstrated that the drug triggers paranoid thoughts in vulnerable individuals. The most likely mechanism of action causing paranoia was the generation of negative affect and anomalous experiences.


Myeloid loss of Beclin 1 promotes PD-L1hi precursor B cell lymphoma development.
Beclin 1 (Becn1) is a key molecule in the autophagy pathway and has been implicated in cancer development. Due to the embryonic lethality of homozygous Becn1-deficient mice, the precise mechanisms and cell type-specific roles of Becn1 in regulating inflammation and cancer immunity remain elusive. Here, we report that myeloid-deficient Becn1 (Becn1ΔM) mice developed neutrophilia, were hypersusceptible to LPS-induced septic shock, and had a high risk of developing spontaneous precursor B cell (pre-B cell) lymphoma with elevated expression of immunosuppressive molecules programmed death ligand 1 (PD-L1) and IL-10. Becn1 deficiency resulted in the stabilization of MEKK3 and aberrant p38 activation in neutrophils, and mediated neutrophil-B cell interaction through Cxcl9/Cxcr3 chemotaxis. Neutrophil-B cell interplay further led to the activation of IL-21/STAT3/IRF1 and CD40L/ERK signaling and PD-L1 expression; therefore, it suppressed CD8+ T cell function. Ablation of p38 in Becn1ΔM mice prevented neutrophil inflammation and B cell tumorigenesis. Importantly, the low expression of Becn1 in human neutrophils was significantly correlated with the PD-L1 levels in pre-B acute lymphoblastic lymphoma (ALL) patients. Our findings have identified myeloid Becn1 as a key regulator of cancer immunity and therapeutic target for pre-B cell lymphomas.


Phase informed model for motion and susceptibility.
Field inhomogeneities caused by variations in magnetic susceptibility throughout the head lead to geometric distortions, mainly in the phase-encode direction of echo-planar images (EPI). The magnitude and spatial characteristics of the distortions depend on the orientation of the head in the magnetic field and will therefore vary with head movement. A new method is presented, based on a phase informed model for motion and susceptibility (PIMMS), which estimates the change in geometric distortion associated with head motion. This method fits a model of the head motion parameters and scanner hardware characteristics to EPI phase time series. The resulting maps of the model fit parameters are used to correct for susceptibility artifacts in the magnitude images. Results are shown for EPI-based fMRI time-series acquired at 3T, demonstrating that compared with conventional rigid body realignment, PIMMS removes residual variance associated with motion-related distortion effects. Furthermore, PIMMS can lead to a reduction in false negatives compared with the widely accepted approach which uses standard rigid body realignment and includes the head motion parameters in the statistical model. The PIMMS method can be used with any standard EPI sequence for which accurate phase information is available.


Combined Effects of Early Season Leaf Removal and Climatic Conditions on Aroma Precursors in Sauvignon Blanc Grapes.
Early leaf removal around the cluster zone is a common technique applied in cool climate viticulture, to regulate yield components and improve fruit quality. Despite the increasing amount of information on early leaf removal and its impact on total soluble solids, anthocyanins, and polyphenols, less is known regarding aroma compounds. In order to verify the hypothesis that defoliation, applied before or after flowering, could impact the biosynthesis of thiol precursors, we performed a two year (2013 and 2014) experiment on Sauvignon blanc. We provided evidence that differential accumulation of thiol precursors in berries is affected by the timing of defoliation, and this impact was related to modifications in the biosynthetic pathway. Furthermore, the possible interaction between leaf removal treatment and seasonal weather conditions, and its effect on the biosynthesis of volatile precursors are discussed. Our results suggested that in Sauvignon blanc the relative proportion of 4-S-glutathionyl-4-methylpentan-2-one (G-4MSP) and 3-S-glutathionylhexan-1-ol (G-3SH) precursors can be affected by defoliation, and this could be related to the induction of two specific genes encoding glutathione-S-transferases (VvGST3 and VvGST5), while no significant effects on basic fruit chemical parameters, polyphenols, and methoxypyrazines were ascertained under our experimental conditions.


High prevalence of myositis in a southeastern United States pediatric systemic lupus erythematosus cohort.
Inflammatory myositis is reported in 4-16% of adult systemic lupus erythematosus (SLE) patients. The aim of this study was to determine the prevalence of myositis in a cohort of pediatric SLE patients in the southeastern United States. A retrospective chart review was performed of 55 SLE patients evaluated by Pediatric Rheumatologists in Alabama since January 1, 2008. Patients were defined as having myositis if they satisfied one of the following categories: 1) Proximal muscle weakness on exam with lower extremity muscle edema on MRI; 2) Proximal muscle weakness with elevation in CK, AST, aldolase, or LDH muscle enzymes; or 3) Patient reported weakness or muscle pain and an elevated CK. Inflammatory myositis was present as a feature of SLE in 31% (n = 17) with a 95% confidence interval of 19-45%, statistically different from the reported rates of 4-16% (p < 0.0001). Myositis was positively associated with the presence of anti-ribonucleoprotein antibodies (p = 0.009). Negative associations with myositis were the presence of anti-double stranded DNA antibodies (p = 0.02) and hematologic disorders (p = 0.02). Thus, in the state of Alabama, pediatric SLE myositis is present at a statistically higher rate than previously published values of adult SLE myositis, possibly reflecting geographic (genetic or environmental) and/or age-of-onset related influence(s).


An observational study of children with sickle cell disease in Kilifi, Kenya.
Globally, sickle cell disease (SCD) has its highest prevalence and worst prognosis in sub-Saharan Africa. Nevertheless, relatively few studies describe the clinical characteristics of children with SCD in this region. We conducted a prospective observational study of children with SCD attending a specialist out-patient clinic in Kilifi, Kenya. A total of 124 children (median age 6.3 years) were included in the study. Splenomegaly was present in 41 (33%) subjects and hepatomegaly in 25 (20%), both being common in all age groups. A positive malaria slide was found at 6% of clinic visits. The mean haemoglobin concentration was 73 g/l, compared to 107 g/l in non-SCD controls (P < 0.001). Liver function tests were elevated; plasma bilirubin concentrations were 46 micromol/l and aspartate aminotransferase was 124 iu/l. Forty-eight (39%) children were admitted to hospital and two died. Children with SCD in Kilifi have a similar degree of anaemia and liver function derangement to patients living in developed countries, but splenomegaly persists into later childhood. The prevalence of malaria was lower than expected given the prevalence in the local community. This study provides valuable data regarding the clinical characteristics of children living with SCD in a rural setting in East Africa.


Dlx5 and Dlx6 regulate the development of parvalbumin-expressing cortical interneurons.
Dlx5 and Dlx6 homeobox genes are expressed in developing and mature cortical interneurons. Simultaneous deletion of Dlx5 and 6 results in exencephaly of the anterior brain; despite this defect, prenatal basal ganglia differentiation appeared largely intact, while tangential migration of Lhx6(+) and Mafb(+) interneurons to the cortex was reduced and disordered. The migration deficits were associated with reduced CXCR4 expression. Transplantation of mutant immature interneurons into a wild-type brain demonstrated that loss of either Dlx5 or Dlx5&6 preferentially reduced the number of mature parvalbumin(+) interneurons; those parvalbumin(+) interneurons that were present had increased dendritic branching. Dlx5/6(+/-) mice, which appear normal histologically, show spontaneous electrographic seizures and reduced power of gamma oscillations. Thus, Dlx5&6 appeared to be required for development and function of somal innervating (parvalbumin(+)) neocortical interneurons. This contrasts with Dlx1, whose function is required for dendrite innervating (calretinin(+), somatostatin(+), and neuropeptide Y(+)) interneurons (Cobos et al., 2005).


The Antibody Light-Chain Linker Is Important for Domain Stability and Amyloid Formation.
The association of light chains (LCs) and heavy chains is the basis for functional antibodies that are essential for adaptive immune responses. However, in some cases, LCs and especially fragments consisting of the LC variable (VL) domain are pathologically deposited in fatal aggregation diseases. The two domains of the LC are connected by a highly conserved linker. We show here that, unexpectedly, the linker residue Arg108 affects the conformational stability and folding of both VLκ and LC constant (CLκ) domains. Interestingly, the extension of VL by Arg108 results in its resistance to amyloid formation, which suggests that the nature of the truncation of the LC plays a crucial role in disease progression. Increased solvation due to the exposed charged C-terminal Arg108 residue explains its stabilizing effects on the VL domain. For the CL domain, the interaction of N-terminal loop residues with Arg108 is important for the integrity of the domain, as the disruption of this interaction results in fluctuation, partial opening of the protein's interior and the exposure of hydrophobic residues that destabilize the domain. This establishes new principles for antibody domain architecture and amyloidogenicity.


Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial.
Lowering of LDL cholesterol reduces major vascular events, but whether more intensive therapy safely produces extra benefits is uncertain. We aimed to establish efficacy and safety of more intensive statin treatment in patients at high cardiovascular risk. We undertook a double-blind randomised trial in 12,064 men and women aged 18-80 years with a history of myocardial infarction. Participants were either currently on or had clear indication for statin therapy, and had a total cholesterol concentration of at least 3·5 mmol/L if already on a statin or 4·5 mmol/L if not. Randomisation to either 80 mg or 20 mg simvastatin daily was done centrally using a minimisation algorithm. Participants were assessed at 2, 4, 8, and 12 months after randomisation and then every 6 months until final follow-up. The primary endpoint was major vascular events, defined as coronary death, myocardial infarction, stroke, or arterial revascularisation. Analysis was by intention to treat. This study is registered, number ISRCTN74348595. 6031 participants were allocated 80 mg simvastatin daily, and 6033 allocated 20 mg simvastatin daily. During a mean follow-up of 6·7 (SD 1·5) years, allocation to 80 mg simvastatin produced an average 0·35 (SE 0·01) mmol/L greater reduction in LDL cholesterol compared with allocation to 20 mg. Major vascular events occurred in 1477 (24·5%) participants allocated 80 mg simvastatin versus 1553 (25·7%) of those allocated 20 mg, corresponding to a 6% proportional reduction (risk ratio 0·94, 95% CI 0·88-1·01; p=0·10). There were no apparent differences in numbers of haemorrhagic strokes (24 [0·4%] vs 25 [0·4%]) or deaths attributed to vascular (565 [9·4%] vs 572 [9·5%]) or non-vascular (399 [6·6%] vs 398 [6·6%]) causes. Compared with two (0·03%) cases of myopathy in patients taking 20 mg simvastatin daily, there were 53 (0·9%) cases in the 80 mg group. The 6% (SE 3·5%) reduction in major vascular events with a further 0·35 mmol/L reduction in LDL cholesterol in our trial is consistent with previous trials. Myopathy was increased with 80 mg simvastatin daily, but intensive lowering of LDL cholesterol can be achieved safely with other regimens. Merck; The Clinical Trial Service Unit also receives funding from the UK Medical Research Council and the British Heart Foundation.


The emerging role of autoimmunity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs).
The World Health Organization classifies myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs) as a nervous system disease. Together with other diseases under the G93 heading, ME/cfs shares a triad of abnormalities involving elevated oxidative and nitrosative stress (O&NS), activation of immuno-inflammatory pathways, and mitochondrial dysfunctions with depleted levels of adenosine triphosphate (ATP) synthesis. There is also abundant evidence that many patients with ME/cfs (up to around 60 %) may suffer from autoimmune responses. A wide range of reported abnormalities in ME/cfs are highly pertinent to the generation of autoimmunity. Here we review the potential sources of autoimmunity which are observed in people with ME/cfs. The increased levels of pro-inflammatory cytokines, e.g., interleukin-1 and tumor necrosis factor-α, and increased levels of nuclear factor-κB predispose to an autoimmune environment. Many cytokine abnormalities conspire to produce a predominance of effector B cells and autoreactive T cells. The common observation of reduced natural killer cell function in ME/cfs is a source of disrupted homeostasis and prolonged effector T cell survival. B cells may be pathogenic by playing a role in autoimmunity independent of their ability to produce antibodies. The chronic or recurrent viral infections seen in many patients with ME/cfs can induce autoimmunity by mechanisms involving molecular mimicry and bystander activation. Increased bacterial translocation, as observed in ME/cfs, is known to induce chronic inflammation and autoimmunity. Low ATP production and mitochondrial dysfunction is a source of autoimmunity by inhibiting apoptosis and stimulating necrotic cell death. Self-epitopes may be damaged by exposure to prolonged O&NS, altering their immunogenic profile and become a target for the host's immune system. Nitric oxide may induce many faces of autoimmunity stemming from elevated mitochondrial membrane hyperpolarization and blockade of the methionine cycle with subsequent hypomethylation of DNA. Here we also outline options for treatment involving rituximab and endotherapia.


Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study.
We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. In patients with sporadic ALS, we identified the repeat expansion in 236 (7·0%) of 3377 white individuals from the USA, Europe, and Australia, two (4·1%) of 49 black individuals from the USA, and six (8·3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39·3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6·0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24·8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases. Full funding sources listed at end of paper (see Acknowledgments).


A risk model for lung cancer incidence.
Risk models for lung cancer incidence would be useful for prioritizing individuals for screening and participation in clinical trials of chemoprevention. We present a risk model for lung cancer built using prospective cohort data from a general population which predicts individual incidence in a given time period. We build separate risk models for current and former smokers using 169,035 ever smokers from the multicenter European Prospective Investigation into Cancer and Nutrition (EPIC) and considered a model for never smokers. The data set was split into independent training and test sets. Lung cancer incidence was modeled using survival analysis, stratifying by age started smoking, and for former smokers, also smoking duration. Other risk factors considered were smoking intensity, 10 occupational/environmental exposures previously implicated with lung cancer, and single-nucleotide polymorphisms at two loci identified by genome-wide association studies of lung cancer. Individual risk in the test set was measured by the predicted probability of lung cancer incidence in the year preceding last follow-up time, predictive accuracy was measured by the area under the receiver operator characteristic curve (AUC). Using smoking information alone gave good predictive accuracy: the AUC and 95% confidence interval in ever smokers was 0.843 (0.810-0.875), the Bach model applied to the same data gave an AUC of 0.775 (0.737-0.813). Other risk factors had negligible effect on the AUC, including never smokers for whom prediction was poor. Our model is generalizable and straightforward to implement. Its accuracy can be attributed to its modeling of lifetime exposure to smoking.


Power corrupts co-operation: cognitive and motivational effects in a double EEG paradigm.
This study investigated the effect of interpersonal power on co-operative performance. We used a paired electro-encephalogram paradigm: pairs of participants performed an attention task, followed by feedback indicating monetary loss or gain on every trial. Participants were randomly allocated to the power-holder, subordinate or neutral group by creating different levels of control over how a joint monetary reward would be allocated. We found that power was associated with reduced behavioural accuracy. Event-related potential analysis showed that power-holders devoted less motivational resources to their targets than did subordinates or neutrals, but did not differ at the level of early conflict detection. Their feedback potential results showed a greater expectation of rewards but reduced subjective magnitude attributed to losses. Subordinates, on the other hand, were asymmetrically sensitive to power-holders' targets. They expected fewer rewards, but attributed greater significance to losses. Our study shows that power corrupts balanced co-operation with subordinates.