Genetic determinants of co-accessible chromatin regions in activated T cells across humans.

Over 90% of genetic variants associated with complex human traits map to non-coding regions, but little is understood about how they modulate gene regulation in health and disease. One possible mechanism is that genetic variants affect the activity of one or more cis-regulatory elements leading to gene expression variation in specific cell types. To identify such cases, we analyzed ATAC-seq and RNA-seq profiles from stimulated primary CD4+ T cells in up to 105 healthy donors. We found that regions of accessible chromatin (ATAC-peaks) are co-accessible at kilobase and megabase resolution, consistent with the three-dimensional chromatin organization measured by in situ Hi-C in T cells. Fifteen percent of genetic variants located within ATAC-peaks affected the accessibility of the corresponding peak (local-ATAC-QTLs). Local-ATAC-QTLs have the largest effects on co-accessible peaks, are associated with gene expression and are enriched for autoimmune disease variants. Our results provide insights into how natural genetic variants modulate cis-regulatory elements, in isolation or in concert, to influence gene expression

Liquid-gas phase transition in nuclear multifragmentation

The equation of state of nuclear matter suggests that at suitable beam energies the disassembling hot system formed in heavy ion collisions will pass through a liquid-gas coexistence region. Searching for the signatures of the phase transition has been a very important focal point of experimental endeavours in heavy ion collisions, in the last fifteen years. Simultaneously theoretical models have been developed to provide information about the equation of state and reaction mechanisms consistent with the experimental observables. This article is a review of this endeavour.Comment: 63 pages, 27 figures, submitted to Adv. Nucl. Phys. Some typos corrected, minor text change

Metabolic investigations prevent liver transplantation in two young children with citrullinemia type I

Acute liver failure may be caused by a variety of disorders including inborn errors of metabolism. In those cases, rapid metabolic investigations and adequate treatment may avoid the need for liver transplantation. We report two patients who presented with acute liver failure and were referred to our center for liver transplantation work-up. Urgent metabolic investigations revealed citrullinemia type I. Treatment for citrullinemia type I avoided the need for liver transplantation. Acute liver failure as a presentation of citrullinemia type I has not previously been reported in young children. Although acute liver failure has occasionally been described in other urea cycle disorders, these disorders may be underestimated as a cause. Timely diagnosis and treatment of these disorders may avoid liver transplantation and improve clinical outcome. Therefore, urea cycle disorders should be included in the differential diagnosis in young children presenting with acute liver failure

Worldwide Esophageal Cancer Collaboration : clinical staging data

Peer reviewe

Clinical characteristics and therapeutic outcomes of nosocomial super-infection in adult bacterial meningitis

<p>Abstract</p> <p>Background</p> <p>Super-infection in adult bacterial meningitis (ABM) is a condition wherein the cerebrospinal fluid (CSF) grows new pathogen(s) during the therapeutic course of meningitis. It is an uncommon but clinically important condition rarely examined in literature.</p> <p>Methods</p> <p>Twenty-seven episodes of super-infection states in 21 ABM patients collected in a 9.5-year study period (January 2001 to June 2010) were evaluated. The clinical characteristics, implicated pathogens, results of antimicrobial susceptibility tests, and therapeutic outcomes were analyzed.</p> <p>Results</p> <p>Twenty-one patients (13 men, 8 women) aged 25-73 years (median, 45 years) had post-neurosurgical state as the preceding event and nosocomial infection. The post-neurosurgical states included spontaneous intracranial hemorrhage (ICH) with craniectomy or craniotomy with extra-ventricular drainage (EVD) or ventriculo-peritoneal shunt (VPS) in 10 patients, traumatic ICH with craniectomy or craniotomy with EVD or VPS in 6 patients, hydrocephalus s/p VPS in 2 patients, and one patient each with cerebral infarct s/p craniectomy with EVD, meningeal metastasis s/p Omaya implant, and head injury. All 21 patients had EVD and/or VP shunt and/or Omaya implant during the whole course of ABM. Recurrent fever was the most common presentation and the implicated bacterial pathogens were protean, many of which were antibiotic resistant. Most patients required adjustment of antibiotics after the pathogens were identified but even with antimicrobial therapy, 33.3% (7/21) died. Morbidity was also high among survivors.</p> <p>Conclusions</p> <p>Super-infection in ABM is usually seen in patients with preceding neurosurgical event, especially insertion of an external drainage device. Repeat CSF culture is mandatory for diagnostic confirmation because most of the implicated bacterial strains are non-susceptible to common antibiotics used. Unusual pathogens like anaerobic bacteria and fungi may also appear. Despite antimicrobial therapy, prognosis remains poor.</p

MultiMSOAR 2.0: An Accurate Tool to Identify Ortholog Groups among Multiple Genomes

The identification of orthologous genes shared by multiple genomes plays an important role in evolutionary studies and gene functional analyses. Based on a recently developed accurate tool, called MSOAR 2.0, for ortholog assignment between a pair of closely related genomes based on genome rearrangement, we present a new system MultiMSOAR 2.0, to identify ortholog groups among multiple genomes in this paper. In the system, we construct gene families for all the genomes using sequence similarity search and clustering, run MSOAR 2.0 for all pairs of genomes to obtain the pairwise orthology relationship, and partition each gene family into a set of disjoint sets of orthologous genes (called super ortholog groups or SOGs) such that each SOG contains at most one gene from each genome. For each such SOG, we label the leaves of the species tree using 1 or 0 to indicate if the SOG contains a gene from the corresponding species or not. The resulting tree is called a tree of ortholog groups (or TOGs). We then label the internal nodes of each TOG based on the parsimony principle and some biological constraints. Ortholog groups are finally identified from each fully labeled TOG. In comparison with a popular tool MultiParanoid on simulated data, MultiMSOAR 2.0 shows significantly higher prediction accuracy. It also outperforms MultiParanoid, the Roundup multi-ortholog repository and the Ensembl ortholog database in real data experiments using gene symbols as a validation tool. In addition to ortholog group identification, MultiMSOAR 2.0 also provides information about gene births, duplications and losses in evolution, which may be of independent biological interest. Our experiments on simulated data demonstrate that MultiMSOAR 2.0 is able to infer these evolutionary events much more accurately than a well-known software tool Notung. The software MultiMSOAR 2.0 is available to the public for free

Hyperglycemia in bacterial meningitis: a prospective cohort study

ABSTRACT: BACKGROUND: Hyperglycemia has been associated with unfavorable outcome in several disorders, but few data are available in bacterial meningitis. We assessed the incidence and significance of hyperglycemia in adults with bacterial meningitis. METHODS: We collected data prospectively between October 1998 and April 2002, on 696 episodes of community-acquired bacterial meningitis, confirmed by culture of CSF in patients >16 years. Patients were dichotomized according to blood glucose level on admission. A cutoff random non-fasting blood glucose level of 7.8 mmol/L (140 mg/dL) was used to define hyperglycemia, and a cutoff random non-fasting blood glucose level of 11.1 mmol/L (200 mg/dL) was used to define severe hyperglycemia. Unfavorable outcome was defined on the Glasgow outcome scale as a score <5. We also evaluated characteristics of patients with a preadmission diagnosis of diabetes mellitus. RESULTS: 69% of patients were hyperglycemic and 25% severely hyperglycemic on admission. Compared with non-hyperglycemic patients, hyperglycemia was related with advanced age (median, 55 yrs vs. 44 yrs, P<0.0001), preadmission diagnosis of diabetes (9% vs. 3%, P=0.005), and distant focus of infection (37% vs. 28%, P=0.02). They were more often admitted in coma (16% vs. 8%; P=0.004) and with pneumococcal meningitis (55% vs. 42%, P=0.007). These differences remained significant after exclusion of patients with known diabetes. Hyperglycemia was related with unfavorable outcome (in a hockey stick-shaped curve) but this relation did not remain robust in a multivariate analysis. Factors predictive for neurologic compromise were related with higher blood glucose levels, whereas factors predictive for systemic compromise were related with lower blood glucose levels. Only a minority of severely hyperglycemic patients were known diabetics (19%). The vast majority of these known diabetic patients had meningitis due to Streptococcus pneumoniae (67%) or Listeria monocytogenes (13%) and they were at high risk for unfavorable outcome (52%). CONCLUSIONS: The majority of patients with bacterial meningitis have hyperglycemic blood glucose levels on admission. Hyperglycemia can be explained by a physical stress reaction, the central nervous system insult leading to disturbed blood-glucose regulation mechanisms, and preponderance of diabetics for pneumococcal meningitis. Patients with diabetes and bacterial meningitis are at high risk for unfavorable outcom

Plio-Pleistocene sea level and temperature fluctuations in the northwestern Pacific promoted speciation in the globally-distributed flathead mullet Mugil cephalus

<p>Abstract</p> <p>Background</p> <p>The study of speciation in the marine realm is challenging because of the apparent absence of physical barriers to dispersal, which are one of the main drivers of genetic diversity. Although phylogeographic studies using mitochondrial DNA (mtDNA) information often reveal significant genetic heterogeneity within marine species, the evolutionary significance of such diversity is difficult to interpret with these markers. In the northwestern (NW) Pacific, several studies have emphasised the potential importance of sea-level regression during the most recent glaciations as a driver of genetic diversity in marine species. These studies have failed, however, to determine whether the period of isolation was long enough for divergence to attain speciation. Among these marine species, the cosmopolitan estuarine-dependent fish <it>Mugil cephalus </it>represents an interesting case study. Several divergent allopatric mtDNA lineages have been described in this species worldwide, and three occur in sympatry in the NW Pacific.</p> <p>Results</p> <p>Ten nuclear microsatellites were surveyed to estimate the level of genetic isolation of these lineages and determine the role of sea-level fluctuation in the evolution of NW Pacific <it>M. cephalus</it>. Three cryptic species of <it>M. cephalus </it>were identified within this region (NWP1, 2 and 3) using an assignment test on the microsatellite data. Each species corresponds with one of the three mtDNA lineages in the COI phylogenetic tree. NWP3 is the most divergent species, with a distribution range that suggests tropical affinities, while NWP1, with a northward distribution from Taiwan to Russia, is a temperate species. NWP2 is distributed along the warm Kuroshio Current. The divergence of NWP1 from NWP2 dates back to the Pleistocene epoch and probably corresponds to the separation of the Japan and China Seas when sea levels dropped. Despite their subsequent range expansion since this period of glaciation, no gene flow was observed among these three lineages, indicating that speciation has been achieved.</p> <p>Conclusions</p> <p>This study successfully identified three cryptic species in <it>M. cephalus </it>inhabiting the NW Pacific, using a combination of microsatellites and mitochondrial genetic markers. The current genetic architecture of the <it>M. cephalus </it>species complex in the NW Pacific is the result of a complex interaction of contemporary processes and historical events. Sea level and temperature fluctuations during Plio-Pleistocene epochs probably played a major role in creating the marine species diversity of the NW Pacific that is found today.</p