Maternal corticotropin-releasing hormone is associated with LEP DNA methylation at birth and in childhood: an epigenome-wide study in Project Viva

BackgroundCorticotropin-releasing hormone (CRH) plays a central role in regulating the secretion of cortisol which controls a wide range of biological processes. Fetuses overexposed to cortisol have increased risks of disease in later life. DNA methylation may be the underlying association between prenatal cortisol exposure and health effects. We investigated associations between maternal CRH levels and epigenome-wide DNA methylation of cord blood in offsprings and evaluated whether these associations persisted into mid-childhood.MethodsWe investigated mother-child pairs enrolled in the prospective Project Viva pre-birth cohort. We measured DNA methylation in 257 umbilical cord blood samples using the HumanMethylation450 Bead Chip. We tested associations of maternal CRH concentration with cord blood cells DNA methylation, adjusting the model for maternal age at enrollment, education, maternal race/ethnicity, maternal smoking status, pre-pregnancy body mass index, parity, gestational age at delivery, child sex, and cell-type composition in cord blood. We further examined the persistence of associations between maternal CRH levels and DNA methylation in children's blood cells collected at mid-childhood (n = 239, age: 6.7-10.3 years) additionally adjusting for the children's age at blood drawn.ResultsMaternal CRH levels are associated with DNA methylation variability in cord blood cells at 96 individual CpG sites (False Discovery Rate <0.05). Among the 96 CpG sites, we identified 3 CpGs located near the LEP gene. Regional analyses confirmed the association between maternal CRH and DNA methylation near LEP. Moreover, higher maternal CRH levels were associated with higher blood-cell DNA methylation of the promoter region of LEP in mid-childhood (P < 0.05, β = 0.64, SE = 0.30).ConclusionIn our cohort, maternal CRH was associated with DNA methylation levels in newborns at multiple loci, notably in the LEP gene promoter. The association between maternal CRH and LEP DNA methylation levels persisted into mid-childhood

VAMP4 directs synaptic vesicles to a pool that selectively maintains asynchronous neurotransmission

Synaptic vesicles in the brain harbor several soluble N-ethylmaleimide-sensitive-factor attachment protein receptor (SNARE) proteins. With the exception of synaptobrevin2, or VAMP2 (syb2), which is directly involved in vesicle fusion, the role of these SNAREs in neurotransmission is unclear. Here we show that in mice syb2 drives rapid Ca2+-dependent synchronous neurotransmission, whereas the structurally homologous SNARE protein VAMP4 selectively maintains bulk Ca2+-dependent asynchronous release. At inhibitory nerve terminals, up- or downregulation of VAMP4 causes a correlated change in asynchronous release. Biochemically, VAMP4 forms a stable complex with SNAREs syntaxin-1 and SNAP-25 that does not interact with complexins or synaptotagmin-1, proteins essential for synchronous neurotransmission. Optical imaging of individual synapses indicates that trafficking of VAMP4 and syb2 show minimal overlap. Taken together, these findings suggest that VAMP4 and syb2 diverge functionally, traffic independently and support distinct forms of neurotransmission. These results provide molecular insight into how synapses diversify their release properties by taking advantage of distinct synaptic vesicle–associated SNAREs

Mechanisms of T cell organotropism

F.M.M.-B. is supported by the British Heart Foundation, the Medical Research Council of the UK and the Gates Foundation

The Interleukin 3 Gene (IL3) Contributes to Human Brain Volume Variation by Regulating Proliferation and Survival of Neural Progenitors

One of the most significant evolutionary changes underlying the highly developed cognitive abilities of humans is the greatly enlarged brain volume. In addition to being far greater than in most other species, the volume of the human brain exhibits extensive variation and distinct sexual dimorphism in the general population. However, little is known about the genetic mechanisms underlying normal variation as well as the observed sex difference in human brain volume. Here we show that interleukin-3 (IL3) is strongly associated with brain volume variation in four genetically divergent populations. We identified a sequence polymorphism (rs31480) in the IL3 promoter which alters the expression of IL3 by affecting the binding affinity of transcription factor SP1. Further analysis indicated that IL3 and its receptors are continuously expressed in the developing mouse brain, reaching highest levels at postnatal day 1–4. Furthermore, we found IL3 receptor alpha (IL3RA) was mainly expressed in neural progenitors and neurons, and IL3 could promote proliferation and survival of the neural progenitors. The expression level of IL3 thus played pivotal roles in the expansion and maintenance of the neural progenitor pool and the number of surviving neurons. Moreover, we found that IL3 activated both estrogen receptors, but estrogen didn’t directly regulate the expression of IL3. Our results demonstrate that genetic variation in the IL3 promoter regulates human brain volume and reveals novel roles of IL3 in regulating brain development

Enhancing Biomedical Text Summarization Using Semantic Relation Extraction

Automatic text summarization for a biomedical concept can help researchers to get the key points of a certain topic from large amount of biomedical literature efficiently. In this paper, we present a method for generating text summary for a given biomedical concept, e.g., H1N1 disease, from multiple documents based on semantic relation extraction. Our approach includes three stages: 1) We extract semantic relations in each sentence using the semantic knowledge representation tool SemRep. 2) We develop a relation-level retrieval method to select the relations most relevant to each query concept and visualize them in a graphic representation. 3) For relations in the relevant set, we extract informative sentences that can interpret them from the document collection to generate text summary using an information retrieval based method. Our major focus in this work is to investigate the contribution of semantic relation extraction to the task of biomedical text summarization. The experimental results on summarization for a set of diseases show that the introduction of semantic knowledge improves the performance and our results are better than the MEAD system, a well-known tool for text summarization

Intraoperative radiotherapy electron boost in advanced and recurrent epithelial ovarian carcinoma: a retrospective study

<p>Abstract</p> <p>Background</p> <p>Relapses of epithelial ovarian carcinoma (EOC) have a poor prognosis and are almost always fatal. The aim of this study was to evaluate the clinical outcome and toxicity of intraoperative electron beam radiation therapy (IOERT) in advanced and recurrent EOC.</p> <p>Methods</p> <p>Forty-five women with EOC were treated with IOERT. Twenty-five patients had primary disease (PD) without distant metastasis at IOERT, and 20 patients had an isolated local recurrence (ILR) after surgery. All 45 patients in this series underwent optimal cytoreductive (≤ 1 cm) surgery. The whole pelvic (WP) radiotherapy was intraoperatively delivered using 12 Mev electron beam; 43 patients received 18-20 Gy and two patients received 10 Gy. Thirty-three patients received postoperateive intraperitoneal (IP) chemotherapy, while seven patients received intravenous (IV) chemotherapy. Five patients refused concurrent chemotherapy. Overall survival (OS) rates were analyzed using the Kaplan-Meier method.</p> <p>Results</p> <p>Tumor recurrence and metastasis were observed in 16 patients (35.6%). Of those, 14 patients (31.1%) relapsed and two patients (4.4%) had distant metastasis alone. Eight of 25 (32%) local failures were observed in the PD group, as compared to 6/20 (30%) in the ILR group (<it>P </it>= 0.885). Actuarial local control at five year follow-up was 31/45 (68.9%). Seventeen of the total 45 (37.8%) patients died. Nine of 25 (36%) in the PD group died, as compared to 8 of 20 (40%) in the ILR group. The 5-year OS and disease-free survival (DFS) rates were 28/45 (62.2%) and 25/45 (55.6%), respectively. In the PD group, the 5-year OS and DFS rates were 16/25 (64%) and 14/25 (56%) (<it>P </it>> 0.05, <it>vs</it>. the ILR group at 12/20 and 11/20, respectively). The OS and DFS in the IOERT plus IP group were 25/33 (75.8%) and 23/33 (69.7%), respectively, which were superior to the rates achieved with IOERT plus IV chemotherapy (<it>P </it>< 0.05, 2/7 and 1/7, respectively). The major complication of IOERT was neuropathy. Five (11.1%) patients developed peripheral neurotoxicity.</p> <p>Conclusions</p> <p>IOERT may be feasible and effective as a boosting technique for advanced and recurrent ovarian cancer. IOERT plus IP chemotherapy may achieve high locoregional disease control and survival benefit with a low risk of toxicity. Peripheral nerves in the IOERT field are dose-limiting structures requiring nerve protection policies or a dose compromise to ensure against severe neurological damage.</p

Increased proportion of nitric oxide synthase immunoreactive neurons in rat ileal myenteric ganglia after severe acute pancreatitis

<p>Abstract</p> <p>Background</p> <p>Severe acute pancreatitis (SAP) remains a potentially life-threatening disease. Gastrointestinal motility disturbance such as intestinal ileus is seen in every case. By now, the mechanisms of pancreatitis-induced ileus are largely unknown. The main purpose of the present study was to observe changes of nitric oxide synthase-immunoreactive (NOS-IR) neurons in ileal myenteric ganglia in SAP rats with gastrointestinal dysmotility, trying to explore underlying nervous mechanisms of pancreatitis-induced ileus.</p> <p>Methods</p> <p>Twenty Sprague Dawley rats were randomly divided into sham operated group and SAP group. SAP was induced by retrograde cholangiopancreatic duct injection of 5% sodium taurocholate. Abdominal X-ray and intestinal transit were performed to detect the existence of paralytic ileus and intestinal dysmotility. Pathological damage of pancreas was evaluated. Double-immunolabeling was employed for the whole-mount preparations of ileal myenteric ganglia. The morphology of NOS-IR neurons were observed and the percentage of NOS-IR neurons was calculated based on the total Hu-immunoreactive neurons. Total RNA of ileum was extracted according to Trizol reagent protocol. Neuronal NOS (nNOS) mRNA expression was evaluated by RT-PCR.</p> <p>Results</p> <p>The small intestinal transit index in the SAP group was significantly lower compared with the sham operated group (29.21 ± 3.68% vs 52.48 ± 6.76%, <it>P <</it>0.01). The percentage of NOS-IR neurons in ileal myenteric ganglia in the SAP group was significantly higher than that in the sham operated group (37.5 ± 12.28% vs 26.32 ± 16.15%, <it>P <</it>0.01). nNOS mRNA expression in ileum of SAP group was significantly higher than that in the sham operated group (1.02 ± 0.10 vs 0.70 ± 0.06, <it>P </it>< 0.01).</p> <p>Conclusions</p> <p>The increased quantity of NOS-IR neurons in ileal myenteric ganglia and increased nNOS mRNA expression may suggest nNOS over expression as one of the nervous mechanisms of gastrointestinal dysmotility in SAP rat.</p

No Interaction of Barrier-to-Autointegration Factor (BAF) with HIV-1 MA, Cone-Rod Homeobox (Crx) or MAN1-C in Absence of DNA

Barrier-to-autointegration factor is a cellular protein that protects retroviral DNA from autointegration. Its cellular role is not well understood, but genetic studies show that it is essential and depletion or knockout results in lethal nuclear defects. In addition to binding DNA, BAF interacts with the LEM domain, a domain shared among a family of lamin-associated polypeptides. BAF has also been reported to interact with several other viral and cellular proteins suggesting that these interactions may be functionally relevant. We find that, contrary to previous reports, BAF does not interact with HIV-1 MA, cone-rod homeobox (Crx) or MAN1-C. The reported interactions can be explained by indirect association through DNA binding and are unlikely to be biologically relevant. A mutation that causes a premature aging syndrome lies on the previously reported MAN1-C binding surface of BAF. The absence of direct binding of BAF to MAN1-C eliminates disruption of this interaction as the cause of the premature aging phenotype

Age groups and spread of influenza: implications for vaccination strategy

<p>Abstract</p> <p>Background</p> <p>The unpredictable nature of the potentially devastating impact of 2009 pH1N1 influenza pandemic highlights the need for pandemic preparedness planning, where modeling studies could be most useful for simulations of possible future scenarios.</p> <p>Methods</p> <p>A compartmental model with pre-symptomatic and asymptomatic influenza infections is proposed which incorporates age groups as well as intervention measures such as age-specific vaccination, in order to study spread of influenza in a community.</p> <p>Results</p> <p>We derive the basic reproduction number and other effective reproduction numbers under various intervention measures. For illustration, we make use of the Pneumonia and Influenza (P&I) mortality data and vaccination data of the very young (age 0-2) and the very old (age >64) during 2004-2005 Taiwan winter influenza season to fit our model and to compute the relevant reproduction numbers. The reproduction number for this winter flu season is estimated to be slightly above one (~1.0001).</p> <p>Conclusions</p> <p>Comparatively large errors in fitting the P&I mortality data of the elderly (>64) were observed shortly after winter school closings in January, which may indicate the impact of younger, more active age groups transmitting influenza to other age groups outside of the school settings; in particular, to the elderly in the households. Pre-symptomatic infections seemed to have little effect on the model fit, while asymptomatic infection by asymptomatic infectives has a more pronounced impact on the model fit for the elderly mortality, perhaps indicating a larger role in disease transmission by asymptomatic infection. Simulations indicate that the impact of vaccination on the disease incidence might not be fully revealed in the change (or the lack thereof) in the effective reproduction number with interventions, but could still be substantial. The estimated per contact transmission probability for susceptible elderly is significantly higher than that of any other age group, perhaps highlighting the vulnerability of the elderly due to close contacts with their caretakers from other age groups. The relative impact of targeting the very young and the very old for vaccination was weakened by their relative inactivity, thus giving evidence of the lack of impact of vaccinating these two groups on the overall transmissibility of the disease in the community. This further underscores the need for morbidity-based strategy to prevent elderly mortality.</p