Electroweak Higgs boson production in the standard model effective field theory beyond leading order in QCD

We study the impact of dimension-six operators of the standard model effective field theory relevant for vector-boson fusion and associated Higgs boson production at the LHC. We present predictions at the next-to-leading order accuracy in QCD that include matching to parton showers and that rely on fully automated simulations. We show the importance of the subsequent reduction of the theoretical uncertainties in improving the possible discrimination between effective field theory and standard model results, and we demonstrate that the range of the Wilson coefficient values allowed by a global fit to LEP and LHC Run I data can be further constrained by LHC Run II future results

Integrated Epigenome Profiling of Repressive Histone Modifications, DNA Methylation and Gene Expression in Normal and Malignant Urothelial Cells

Epigenetic regulation of gene expression is commonly altered in human cancer. We have observed alterations of DNA methylation and microRNA expression that reflect the biology of bladder cancer. This common disease arises by distinct pathways with low and high-grade differentiation. We hypothesized that epigenetic gene regulation reflects an interaction between histone and DNA modifications, and differences between normal and malignant urothelial cells represent carcinogenic events within bladder cancer. To test this we profiled two repressive histone modifications (H3K9m3 and H3K27m3) using ChIP-Seq, cytosine methylation using MeDIP and mRNA expression in normal and malignant urothelial cell lines. In genes with low expression we identified H3K27m3 and DNA methylation each in 20–30% of genes and both marks in 5% of genes. H3K9m3 was detected in 5–10% of genes but was not associated with overall expression. DNA methylation was more closely related to gene expression in malignant than normal cells. H3K27m3 was the epigenetic mark most specifically correlated to gene silencing. Our data suggest that urothelial carcinogenesis is accompanied by a loss of control of both DNA methylation and H3k27 methylation. From our observations we identified a panel of genes with cancer specific-epigenetic mediated aberrant expression including those with reported carcinogenic functions and members potentially mediating a positive epigenetic feedback loop. Pathway enrichment analysis revealed genes marked by H3K9m3 were involved with cell homeostasis, those marked by H3K27m3 mediated pro-carcinogenic processes and those marked with cytosine methylation were mixed in function. In 150 normal and malignant urothelial samples, our gene panel correctly estimated expression in 65% of its members. Hierarchical clustering revealed that this gene panel stratified samples according to the presence and phenotype of bladder cancer

Human Skeletal Muscle Possesses an Epigenetic Memory of Hypertrophy

It is unknown if adult human skeletal muscle has an epigenetic memory of earlier encounters with growth. We report, for the first time in humans, genome-wide DNA methylation (850,000 CpGs) and gene expression analysis after muscle hypertrophy (loading), return of muscle mass to baseline (unloading), followed by later hypertrophy (reloading). We discovered increased frequency of hypomethylation across the genome after reloading (18,816 CpGs) versus earlier loading (9,153 CpG sites). We also identified AXIN1, GRIK2, CAMK4, TRAF1 as hypomethylated genes with enhanced expression after loading that maintained their hypomethylated status even during unloading where muscle mass returned to control levels, indicating a memory of these genes methylation signatures following earlier hypertrophy. Further, UBR5, RPL35a, HEG1, PLA2G16, SETD3 displayed hypomethylation and enhanced gene expression following loading, and demonstrated the largest increases in hypomethylation, gene expression and muscle mass after later reloading, indicating an epigenetic memory in these genes. Finally, genes; GRIK2, TRAF1, BICC1, STAG1 were epigenetically sensitive to acute exercise demonstrating hypomethylation after a single bout of resistance exercise that was maintained 22 weeks later with the largest increase in gene expression and muscle mass after reloading. Overall, we identify an important epigenetic role for a number of largely unstudied genes in muscle hypertrophy/memory

Parasite fate and involvement of infected cells in the induction of CD4+ and CD8+ T cell responses to Toxoplasma gondii

During infection with the intracellular parasite Toxoplasma gondii, the presentation of parasite-derived antigens to CD4+ and CD8+ T cells is essential for long-term resistance to this pathogen. Fundamental questions remain regarding the roles of phagocytosis and active invasion in the events that lead to the processing and presentation of parasite antigens. To understand the most proximal events in this process, an attenuated non-replicating strain of T. gondii (the cpsII strain) was combined with a cytometry-based approach to distinguish active invasion from phagocytic uptake. In vivo studies revealed that T. gondii disproportionately infected dendritic cells and macrophages, and that infected dendritic cells and macrophages displayed an activated phenotype characterized by enhanced levels of CD86 compared to cells that had phagocytosed the parasite, thus suggesting a role for these cells in priming naïve T cells. Indeed, dendritic cells were required for optimal CD4+ and CD8+ T cell responses, and the phagocytosis of heat-killed or invasion-blocked parasites was not sufficient to induce T cell responses. Rather, the selective transfer of cpsII-infected dendritic cells or macrophages (but not those that had phagocytosed the parasite) to naïve mice potently induced CD4+ and CD8+ T cell responses, and conferred protection against challenge with virulent T. gondii. Collectively, these results point toward a critical role for actively infected host cells in initiating T. gondii-specific CD4+ and CD8+ T cell responses

BSM W W production with a jet veto

We consider the impact on W W production of the unique dimension-six operator coupling gluons to the Higgs field. In order to study this process, we have to appropriately model the effect of a veto on additional jets. This requires the resummation of large logarithms of the ratio of the maximum jet transverse momentum and the invariant mass of the W boson pair. We have performed such resummation at the appropriate accuracy for the Standard Model (SM) background and for a signal beyond the SM (BSM), and devised a simple method to interface jet-veto resummations with fixed-order event generators. This resulted in the fast numerical code MCFM-RE, the Resummation Edition of the fixed-order code MCFM. We compared our resummed predictions with parton-shower event generators and assessed the size of effects, such as limited detector acceptances, hadronisation and the underlying event, that were not included in our resummation. We have then used the code to compare the sensitivity of W W and Z Z production at the HL-LHC to the considered higher-dimension operator. We have found that W W can provide complementary sensitivity with respect to Z Z, provided one is able to control theory uncertainties at the percent-level. Our method is general and can be applied to the production of any colour singlet, both within and beyond the SM

Helicobacter pylori regulates iNOS promoter by histone modifications in human gastric epithelial cells. [R. Pero* corresponding author]

Inducible nitric oxide synthase (iNOS) expression is altered in gastrointestinal diseases. Helicobacter pylori (Hp) infection may have a critical role in iNOS disregulation. We undertook this study to investigate possible chromatin changes occurring early during iNOS gene activation as a direct consequence of Hp???gastric cells interaction. We show that Hp infection is followed by different expression and chromatin modifications in gastric cells including (1) activation of iNOS gene expression, (2) chromatin changes at iNOS promoter including decreased H3K9 methylation and increased H3 acetylation and H3K4 methylation levels, (3) selective release of methyl-CpG-binding protein 2 from the iNOS promoter. Moreover, we show that Hp-induced activation of iNOS is delayed, but not eliminated, by the treatment with LSD1 inhibitors. Our data suggest a role for specific chromatin-based mechanisms in the control of human iNOS gene expression upon Hp exposure

A preliminary investigation to explore the cognitive resources of physicians experiencing difficulty in training

Background Treating patients is complex, and research shows that there are differences in cognitive resources between physicians who experience difficulties, and those who do not. It is possible that differences in some cognitive resources could explain the difficulties faced by some physicians. In this study, we explore differences in cognitive resources between different groups of physicians (that is, between native (UK) physicians and International Medical Graduates (IMG); those who continue with training versus those who were subsequently removed from the training programme); and also between physicians experiencing difficulties compared with the general population. Methods A secondary evaluation was conducted on an anonymised dataset provided by the East Midlands Professional Support Unit (PSU). One hundred and twenty one postgraduate trainee physicians took part in an Educational Psychology assessment through PSU. Referrals to the PSU were mainly on the basis of problems with exam progression and difficulties in communication skills, organisation and confidence. Cognitive resources were assessed using the Wechsler Adult Intelligence Scale (WAIS-IV). Physicians were categorised into three PSU outcomes: ‘Continued in training’, ‘Removed from training’ and ‘Active’ (currently accessing the PSU). Results Using a one-sample Z test, we compared the referred physician sample to a UK general population sample on the WAIS-IV and found the referred sample significantly higher in Verbal Comprehension (VCI; z = 8.78) and significantly lower in Working Memory (WMI; z = −4.59). In addition, the native sample were significantly higher in Verbal Comprehension than the UK general population sample (VCI; native physicians: z = 9.95, p < .001, d = 1.25), whilst there was a lesser effect for the difference between the IMG sample and the UK general population (z = 2.13, p = .03, d = 0.29). Findings also showed a significant difference in VCI scores between those physicians who were ‘Removed from training’ and those who ‘Continued in training’. Conclusions Our results suggest it is important to understand the cognitive resources of physicians to provide a more focussed explanation of those who experience difficulties in training. This will help to implement more targeted interventions to help physicians develop compensatory strategies

Age-Specific Epigenetic Drift in Late-Onset Alzheimer's Disease

Despite an enormous research effort, most cases of late-onset Alzheimer's disease (LOAD) still remain unexplained and the current biomedical science is still a long way from the ultimate goal of revealing clear risk factors that can help in the diagnosis, prevention and treatment of the disease. Current theories about the development of LOAD hinge on the premise that Alzheimer's arises mainly from heritable causes. Yet, the complex, non-Mendelian disease etiology suggests that an epigenetic component could be involved. Using MALDI-TOF mass spectrometry in post-mortem brain samples and lymphocytes, we have performed an analysis of DNA methylation across 12 potential Alzheimer's susceptibility loci. In the LOAD brain samples we identified a notably age-specific epigenetic drift, supporting a potential role of epigenetic effects in the development of the disease. Additionally, we found that some genes that participate in amyloid-β processing (PSEN1, APOE) and methylation homeostasis (MTHFR, DNMT1) show a significant interindividual epigenetic variability, which may contribute to LOAD predisposition. The APOE gene was found to be of bimodal structure, with a hypomethylated CpG-poor promoter and a fully methylated 3′-CpG-island, that contains the sequences for the ε4-haplotype, which is the only undisputed genetic risk factor for LOAD. Aberrant epigenetic control in this CpG-island may contribute to LOAD pathology. We propose that epigenetic drift is likely to be a substantial mechanism predisposing individuals to LOAD and contributing to the course of disease

DNA methylation, the early-life social environment and behavioral disorders

One of the outstanding questions in behavioral disorders is untangling the complex relationship between nurture and nature. Although epidemiological data provide evidence that there is an interaction between genetics (nature) and the social and physical environments (nurture) in a spectrum of behavioral disorders, the main open question remains the mechanism. Emerging data support the hypothesis that DNA methylation, a covalent modification of the DNA molecule that is a component of its chemical structure, serves as an interface between the dynamic environment and the fixed genome. We propose that modulation of DNA methylation in response to environmental cues early in life serves as a mechanism of life-long genome adaptation. Under certain contexts, this adaptation can turn maladaptive resulting in behavioral disorders. This hypothesis has important implications on understanding, predicting, preventing, and treating behavioral disorders including autism that will be discussed