Humanized H19/Igf2 locus reveals diverged imprinting mechanism between mouse and human and reflects Silver–Russell syndrome phenotypes

Genomic imprinting is essential for mammalian development. Curiously, elements that regulate genomic imprinting, the imprinting control regions (ICRs), often diverge across species. To understand whether the diverged ICR sequence plays a species-specific role at the H19/insulin-like growth factor 2 (Igf2) imprinted locus, we generated a mouse in which the human ICR (hIC1) sequence replaced the endogenous mouse ICR. We show that the imprinting mechanism has partially diverged between mouse and human, depending on the parental origin of the hIC1 in mouse. We also suggest that our mouse model is optimal for studying the imprinting disorders Beckwith–Wiedemann syndrome when hIC1 is maternally transmitted, and Silver–Russell syndrome when hIC1 is paternally transmitted

Characterization of BRD4 during mammalian post-meiotic sperm development

During spermiogenesis, the post-meiotic phase of mammalian spermatogenesis, transcription is progressively repressed as nuclei of haploid spermatids are compacted through a dramatic chromatin reorganization involving hyper-acetylation and replacement of most histones with protamines. Although BRDT functions in transcription and histone removal in spermatids, it is unknown whether other BET family proteins play a role. Immunofluorescence of spermatogenic cells revealed BRD4 in a ring around the nuclei of spermatids containing hyper-acetylated histones. The ring lies directly adjacent to the acroplaxome, the cytoskeletal base of the acrosome, previously linked to chromatin reorganization. The BRD4 ring does not form in acrosomal mutant mice. ChIP sequencing in spermatids revealed enrichment of BRD4 and acetylated histones at the promoters of active genes. BRD4 and BRDT show distinct and synergistic binding patterns, with a pronounced enrichment of BRD4 at spermatogenesis-specific genes. Direct association of BRD4 with acetylated H4 decreases in late spermatids as acetylated histones are removed from the condensing nucleus in a wave following the progressing acrosome. These data provide evidence for a prominent transcriptional role of BRD4 and suggest a possible removal mechanism for chromatin components from the genome via the progressing acrosome as transcription is repressed in response to chromatin condensation during spermiogenesis

A Research and Development (R&D) roadmap for influenza vaccines: Looking toward the future

Improved influenza vaccines are urgently needed to reduce the burden of seasonal influenza and to ensure a rapid and effective public-health response to future influenza pandemics. The Influenza Vaccines Research and Development (R&D) Roadmap (IVR) was created, through an extensive international stakeholder engagement process, to promote influenza vaccine R&D. The roadmap covers a 10-year timeframe and is organized into six sections: virology; immunology; vaccinology for seasonal influenza vaccines; vaccinology for universal influenza vaccines; animal and human influenza virus infection models; and policy, finance, and regulation. Each section identifies barriers, gaps, strategic goals, milestones, and additional R&D priorities germane to that area. The roadmap includes 113 specific R&D milestones, 37 of which have been designated high priority by the IVR expert taskforce. This report summarizes the major issues and priority areas of research outlined in the IVR. By identifying the key issues and steps to address them, the roadmap not only encourages research aimed at new solutions, but also provides guidance on the use of innovative tools to drive breakthroughs in influenza vaccine R&D.publishedVersio

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Epidemic Microclusters of Blood-Culture Proven Sepsis in Very-Low-Birth Weight Infants: Experience of the German Neonatal Network

INTRODUCTION: We evaluated blood culture-proven sepsis episodes occurring in microclusters in very-low-birth-weight infants born in the German Neonatal Network (GNN) during 2009-2010. METHODS: Thirty-seven centers participated in GNN; 23 centers enrolled ≥50 VLBW infants in the study period. Data quality was approved by on-site monitoring. Microclusters of sepsis were defined as occurrence of at least two blood-culture proven sepsis events in different patients of one center within 3 months with the same bacterial species. For microcluster analysis, we selected sepsis episodes with typically cross-transmitted bacteria of high clinical significance including gram-negative rods and Enterococcus spp. RESULTS: In our cohort, 12/2110 (0.6%) infants were documented with an early-onset sepsis and 235 late-onset sepsis episodes (≥72 h of age) occurred in 203/2110 (9.6%) VLBW infants. In 182/235 (77.4%) late-onset sepsis episodes gram-positive bacteria were documented, while coagulase negative staphylococci were found to be the most predominant pathogens (48.5%, 95%CI: 42.01-55.01). Candida spp. and gram-negative bacilli caused 10/235 (4.3%, 95%CI: 1.68% -6.83%) and 43/235 (18.5%) late-onset sepsis episodes, respectively. Eleven microclusters of blood-culture proven sepsis were detected in 7 hospitals involving a total 26 infants. 16/26 cluster patients suffered from Klebsiella spp. sepsis. The median time interval between the first patient's Klebsiella spp. sepsis and cluster cases was 14.1 days (interquartile range: 1-27 days). First patients in the cluster, their linked cases and sporadic sepsis events did not show significant differences in short term outcome parameters. DISCUSSION: Microclusters of infection are an important phenomenon for late-onset sepsis. Most gram-negative cluster infections occur within 30 days after the first patient was diagnosed and Klebsiella spp. play a major role. It is essential to monitor epidemic microclusters of sepsis in surveillance networks to adapt clinical practice, inform policy and further improve quality of care

Test performance of faecal occult blood testing for the detection of bowel cancer in people with chronic kidney disease (DETECT) protocol

<p>Abstract</p> <p>Background</p> <p>Cancer is a major cause of mortality and morbidity in patients with chronic kidney disease (CKD). In patients without kidney disease, screening is a major strategy for reducing the risk of cancer and improving the health outcomes for those who developed cancers by detecting treatable cancers at an early stage. Among those with CKD, the effectiveness, the efficacy and patients' preferences for cancer screening are unknown.</p> <p>Methods/Design</p> <p>This work describes the protocol for the DETECT study examining the effectiveness, efficiency and patient's perspectives of colorectal cancer screening using immunochemical faecal occult blood testing (iFOBT) for people with CKD. The aims of the DETECT study are 1) to determine the test performance characteristics of iFOBT screening in individuals with CKD, 2) to estimate the incremental costs and health benefits of iFOBT screening in CKD compared to no screening and 3) to elicit patients' perspective for colorectal cancer screening in the CKD population. Three different study designs will be used to explore the uncertainties surrounding colorectal cancer screening in CKD. A diagnostic test accuracy study of iFOBT screening will be conducted across all stages of CKD in patients ages 35-70. Using individually collected direct healthcare costs and outcomes from the diagnostic test accuracy study, cost-utility and cost-effective analyses will be performed to estimate the costs and health benefits of iFOBT screening in CKD. Qualitative in-depth interviews will be undertaken in a subset of participants from the diagnostic test accuracy study to investigate the perspectives, experiences, attitudes and beliefs about colorectal cancer screening among individuals with CKD.</p> <p>Discussion</p> <p>The DETECT study will target the three major unknowns about early cancer detection in CKD. Findings from our study will provide accurate and definitive estimates of screening efficacy and efficiency for colorectal cancer, and will allow better service planning and budgeting for early cancer detection in this at-risk population.</p> <p>The DETECT study is also registered with the Australia New Zealand Clinical Trials Registry <a href="http://www.anzctr.org.au/ACTRN12611000538943.aspx">ACTRN12611000538943</a></p

Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA): Cerebrovascular disease and the failure of elimination of Amyloid-β from the brain and retina with age and Alzheimer's disease-Opportunities for Therapy.

Two of the key functions of arteries in the brain are (1) the well-recognized supply of blood via the vascular lumen and (2) the emerging role for the arterial walls as routes for the elimination of interstitial fluid (ISF) and soluble metabolites, such as amyloid beta (Aβ), from the brain and retina. As the brain and retina possess no conventional lymphatic vessels, fluid drainage toward peripheral lymph nodes is mediated via transport along basement membranes in the walls of capillaries and arteries that form the intramural peri-arterial drainage (IPAD) system. IPAD tends to fail as arteries age but the mechanisms underlying the failure are unclear. In some people this is reflected in the accumulation of Aβ plaques in the brain in Alzheimer's disease (AD) and deposition of Aβ within artery walls as cerebral amyloid angiopathy (CAA). Knowledge of the dynamics of IPAD and why it fails with age is essential for establishing diagnostic tests for the early stages of the disease and for devising therapies that promote the clearance of Aβ in the prevention and treatment of AD and CAA. This editorial is intended to introduce the rationale that has led to the establishment of the Clearance of Interstitial Fluid (ISF) and CSF (CLIC) group, within the Vascular Professional Interest Area of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment

Your Resting Brain CAREs about Your Risky Behavior

Research on the neural correlates of risk-related behaviors and personality traits has provided insight into mechanisms underlying both normal and pathological decision-making. Task-based neuroimaging studies implicate a distributed network of brain regions in risky decision-making. What remains to be understood are the interactions between these regions and their relation to individual differences in personality variables associated with real-world risk-taking.We employed resting state functional magnetic resonance imaging (R-fMRI) and resting state functional connectivity (RSFC) methods to investigate differences in the brain's intrinsic functional architecture associated with beliefs about the consequences of risky behavior. We obtained an individual measure of expected benefit from engaging in risky behavior, indicating a risk seeking or risk-averse personality, for each of 21 participants from whom we also collected a series of R-fMRI scans. The expected benefit scores were entered in statistical models assessing the RSFC of brain regions consistently implicated in both the evaluation of risk and reward, and cognitive control (i.e., orbitofrontal cortex, nucleus accumbens, lateral prefrontal cortex, dorsal anterior cingulate). We specifically focused on significant brain-behavior relationships that were stable across R-fMRI scans collected one year apart. Two stable expected benefit-RSFC relationships were observed: decreased expected benefit (increased risk-aversion) was associated with 1) stronger positive functional connectivity between right inferior frontal gyrus (IFG) and right insula, and 2) weaker negative functional connectivity between left nucleus accumbens and right parieto-occipital cortex.Task-based activation in the IFG and insula has been associated with risk-aversion, while activation in the nucleus accumbens and parietal cortex has been associated with both risk seeking and risk-averse tendencies. Our results suggest that individual differences in attitudes toward risk-taking are reflected in the brain's functional architecture and may have implications for engaging in real-world risky behaviors

Nano-Crystalline &Amorphous Silicon PhotoTransistor Performance Analysis

In this thesis, we compared electrical performance and stability of a novel nanocrystalline Si (nc-Si) thin film phototransistor (TFT) phototransistor and a regular amorphous silicon (a-Si:H) TFT phototransistor for large area imaging applications. The electrical performance parameters of nc-Si TFT phototransistor were extracted from the electrical (current-voltage) testing in dark and under illumination. The field-effect mobility is found to be around 1.2 cm2V-1s-1, the threshold voltage around 3.9V and the sub-threshold voltage slope around 0.47V/Dec. Optical properties of nc-Si TFT phototransistor have been evaluated under the green light illumination in the range of 1014 – 1017 lum, and the photocurrent gain and the external quantum efficiency were extracted from the experimental results. By comparing the results with those for a-Si:H TFTs measured under the same conditions, we found that nc-Si TFT has higher photo current gain under low illumination intensity, 5 ×1014 to 7 ×1015 lum. This thesis shows the relations bewteen the photo current gain, the external quantum efficiency, TFT drain and TFT gate bias; the photo current gain and the external quantum efficiency can be controlled by the Vds and the Vgs