Changes of the intestinal microbiota along the gut of Japanese Eel (Anguilla japonica).

Fish intestine contains different types of microbiomes, and bacteria are the dominant microbiota in fishes. Studies have identified various core gut bacteria in fishes. However, little is known about the composition and their relative functions of gut microbial community along the intestine. To explore this, the current study investigated the microbial community distribution along the gut in Anguilla japonica. By 16S rRNA gene sequencing, we profiled the gut microbiota in eel along the three regions (anterior intestine (AI), the middle intestine (MI) and the posterior intestine (PI)). Results suggested that the three regions did not have significant differences on the observed species and diversities. The cluster tree analysis showed that the bacteria community in MI was closer to PI than the AI. The dominant bacteria in AI were the Proteobacteria, in which the majority was graduated replaced by Bacteroidetes along the gut to PI region. Through PICRUSt analysis, shifts in the bacterial community along the gut were found to affect the genetic information processing pathways. Higher levels of translation and transcriptional pathway activities were found in MI and PI than in AI. The dominant bacterial species were different among the regions and contributed to various biological functions along the gut.

What do psychiatrists think about primary mental health competencies among family doctors? A WPA-WONCA global survey.

People with common mental disorders often seek medical attention from their family doctors. Thus, it is essential for family doctors to possess primary mental health knowledge. The aim of this study was to understand whether psychiatrists endorse the primary mental health competencies identified by the World Organization of Family Doctors and whether they agree that family doctors are demonstrating these competencies. A questionnaire was constructed based on 32 core competencies. Presidents of all World Psychiatric Association member societies were invited to complete the questionnaire or to forward it to local experts. According to the respondents, these competencies are considered relevant yet not sufficiently possessed by typical primary care doctors. Proposals are made to bridge this assumed competency gap.

Ancestral whole-genome duplication in the marine chelicerate horseshoe crabs.

This corrects the article DOI: 10.1038/hdy.2015.89.

Oncogenic mutations and dysregulated pathways in obesity-associated hepatocellular carcinoma.

Epidemiological studies showed that obesity and its related non-alcoholic fatty liver disease (NAFLD) promote hepatocellular carcinoma (HCC) development. We aimed to uncover the genetic alterations of NAFLD-HCC using whole-exome sequencing. We compared HCC development in genetically obese mice and dietary obese mice with wild-type lean mice fed a normal chow after treatment with diethylnitrosamine. HCC tumor and adjacent normal samples from obese and lean mice were then subjected to whole-exome sequencing. Functional and mechanistic importance of the identified mutations in Carboxyl ester lipase (Cel) gene and Harvey rat sarcoma virus oncogene 1 (Hras) was further elucidated. We demonstrated significantly higher incidences of HCC in both genetic and dietary obese mice with NAFLD development as compared with lean mice without NAFLD. The mutational signatures of NAFLD-HCC and lean HCC were distinct, with <3% overlapped. Eight metabolic or oncogenic pathways were found to be significantly enriched by mutated genes in NAFLD-HCC, but only two of these pathways were dysregulated by mutations in lean HCC. In particular, Cel was mutated significantly more frequently in NAFLD-HCC than in lean HCC. The multiple-site mutations in Cel are loss-of-function mutations, with effects similar to Cel knock-down. Mutant Cel caused accumulation of cholesteryl ester in liver cells, which led to induction of endoplasmic reticulum stress and consequently activated the IRE1α/c-Jun N-terminal kinase (JNK)/c-Jun/activating protein-1 (AP-1) signaling cascade to promote liver cell growth. In addition, single-site mutations in Hras at codon 61 were found in NAFLD-HCC but none in lean HCC. The gain-of-function mutations in Hras (Q61R and Q61K) significantly promoted liver cell growth through activating the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt pathways. In conclusion, we have identified mutation signature and pathways in NAFLD-associated HCC. Mutations in Cel and Hras have important roles in NAFLD-associated hepatocellular carcinogenesis.

Ancestral whole-genome duplication in the marine chelicerate horseshoe crabs.

Whole-genome duplication (WGD) results in new genomic resources that can be exploited by evolution for rewiring genetic regulatory networks in organisms. In metazoans, WGD occurred before the last common ancestor of vertebrates, and has been postulated as a major evolutionary force that contributed to their speciation and diversification of morphological structures. Here, we have sequenced genomes from three of the four extant species of horseshoe crabs-Carcinoscorpius rotundicauda, Limulus polyphemus and Tachypleus tridentatus. Phylogenetic and sequence analyses of their Hox and other homeobox genes, which encode crucial transcription factors and have been used as indicators of WGD in animals, strongly suggests that WGD happened before the last common ancestor of these marine chelicerates >135 million years ago. Signatures of subfunctionalisation of paralogues of Hox genes are revealed in the appendages of two species of horseshoe crabs. Further, residual homeobox pseudogenes are observed in the three lineages. The existence of WGD in the horseshoe crabs, noted for relative morphological stasis over geological time, suggests that genomic diversity need not always be reflected phenotypically, in contrast to the suggested situation in vertebrates. This study provides evidence of ancient WGD in the ecdysozoan lineage, and reveals new opportunities for studying genomic and regulatory evolution after WGD in the Metazoa.

Genome-wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4.

AIMS/HYPOTHESIS: Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians. METHODS: We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations. RESULTS: We identified CDKN2A/B and four novel type 2 diabetes association signals with p < 1 × 10(-5) from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (p meta = 2.6 × 10(-8); OR [95% CI] 1.18 [1.11, 1.25]). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (p meta = 2.3 × 10(-10)) and a population of European descent (p = 8.6 × 10(-3)). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians. CONCLUSIONS/INTERPRETATION: Our study identifies rs10229583 near PAX4 as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes.

Arsenite-induced nitric oxide generation is cell cycle-dependent and aberrant in NBS cells.

Exposure to arsenic has been reported to cause DNA damage and eventually the occurrence of bladder, lung and skin cancers. A previous report has demonstrated that arsenite-induced phosphorylation of Mre11, a protein involved in the repair of DNA double strand breaks (DSBs), is M phase-dependent and requires the Nijmegen breakage syndrome (NBS) protein, NBS1 [DNA Repair 1 (2002) 137]. Furthermore, arsenite treatment arrests cells at the M phase and the cells eventually go through apoptosis [Biochemical Pharmacology 60 (2000) 771]. Here we demonstrate that arsenite treatment enhances the generation of nitric oxide (NO), and that the enhanced NO generation is dominant at the G2/M phase. Arsenite-induced NO generation is impaired in DSB repair-defective NBS cells, but not in NBS1-reconstituted NBS cells, suggesting NBS1 is required for effective NO generation. In summary, our study showed, for the first time, that arsenite-induced NO generation is cell-cycle- and NBS1-dependent.

Preparation of patients for anaesthesia - achieving quality care.

Implementation of anaesthesia begins with a preoperative assessment of the surgical patient and development of an anaesthetic plan. Preparation of the patient includes the preoperative assessment, review of preoperative tests, optimisation of medical conditions, adequate preoperative fasting, appropriate premedication, and the explanation of anaesthetic risk to patients. The goals of preoperative preparation are to reduce the morbidity of surgery, to increase the quality while decreasing the cost of perioperative care, and to return the patient to desirable functioning as quickly as possible. A knowledgeable anaesthesiologist is the 'final clinical gatekeeper', who coordinates perioperative management and ensures that the patient is in the optimal state for anaesthesia and surgery.

Regulation of APG14 expression by the GATA-type transcription factor Gln3p.

Gln3p is a nitrogen catabolite repression-sensitive GATA-type transcription factor. Its nuclear accumulation was recently shown to be under the control of TOR signaling. Gln3p normally resides in the cytoplasm. When cells are starved from nitrogen nutrients or treated with rapamycin, however, Gln3p becomes translocated into the nucleus, thereby activating the expression of genes involved in nitrogen utilization and transport. To identify other genes under the control of Gln3p, we searched for the Gln3p-binding GATAA motifs within 500 base pairs of the promoter sequences upstream of the yeast open reading frames in the Saccharomyces Genome Database. APG14, a gene essential for autophagy, was found to have the most GATAA motifs. We show that nitrogen starvation or rapamycin treatment rapidly causes a more than 20-fold induction of APG14. The expression of APG14 is dependent on Gln3p; deletion of Gln3p severely reduced its induction by rapamycin, whereas depletion of Ure2p caused its constitutive expression. However, overexpression of APG14 led to only a slight increase in autophagy in nitrogen-rich medium. Therefore, these results define a signaling cascade leading to the expression of APG14 in response to the availability of nitrogen nutrients and suggest that the regulated expression of APG14 contributes to but is not sufficient for the control of autophagy.

The digital TV filter and nonlinear denoising.

Motivated by the classical TV (total variation) restoration model, we propose a new nonlinear filter-the digital TV filter for denoising and enhancing digital images, or more generally, data living on graphs. The digital TV filter is a data dependent lowpass filter, capable of denoising data without blurring jumps or edges. In iterations, it solves a global total variational (or L(1)) optimization problem, which differs from most statistical filters. Applications are given in the denoising of one dimensional (1-D) signals, two-dimensional (2-D) data with irregular structures, gray scale and color images, and nonflat image features such as chromaticity.

Active contours without edges.

We propose a new model for active contours to detect objects in a given image, based on techniques of curve evolution, Mumford-Shah (1989) functional for segmentation and level sets. Our model can detect objects whose boundaries are not necessarily defined by the gradient. We minimize an energy which can be seen as a particular case of the minimal partition problem. In the level set formulation, the problem becomes a "mean-curvature flow"-like evolving the active contour, which will stop on the desired boundary. However, the stopping term does not depend on the gradient of the image, as in the classical active contour models, but is instead related to a particular segmentation of the image. We give a numerical algorithm using finite differences. Finally, we present various experimental results and in particular some examples for which the classical snakes methods based on the gradient are not applicable. Also, the initial curve can be anywhere in the image, and interior contours are automatically detected.

A chemical genomics approach toward understanding the global functions of the target of rapamycin protein (TOR).

The target of rapamycin protein (TOR) is a highly conserved ataxia telangiectasia-related protein kinase essential for cell growth. Emerging evidence indicates that TOR signaling is highly complex and is involved in a variety of cellular processes. To understand its general functions, we took a chemical genomics approach to explore the genetic interaction between TOR and other yeast genes on a genomic scale. In this study, the rapamycin sensitivity of individual deletion mutants generated by the Saccharomyces Genome Deletion Project was systematically measured. Our results provide a global view of the rapamycin-sensitive functions of TOR. In contrast to conventional genetic analysis, this approach offers a simple and thorough analysis of genetic interaction on a genomic scale and measures genetic interaction at different possible levels. It can be used to study the functions of other drug targets and to identify novel protein components of a conserved core biological process such as DNA damage checkpoint/repair that is interfered with by a cell-permeable chemical compound.

Tripartite regulation of Gln3p by TOR, Ure2p, and phosphatases.

Gln3p is a GATA-type transcription factor responsive to different nitrogen nutrients and starvation in yeast Saccharomyces cerevisiae. Recent evidence has linked TOR signaling to Gln3p. Rapamycin causes dephosphorylation and nuclear translocation of Gln3p, thereby activating nitrogen catabolite repressible-sensitive genes. However, a detailed mechanistic understanding of this process is lacking. In this study, we show that Tor1p physically interacts with Gln3p. An intact TOR kinase domain is essential for the phosphorylation of Gln3p, inhibition of Gln3p nuclear entry and repression of Gln3p-dependent transcription. In contrast, at least two distinct protein phosphatases, Pph3p and the Tap42p-dependent phosphatases, are involved in the activation of Gln3p. The yeast pro-prion protein Ure2p binds to both hyper- and hypo-phosphorylated Gln3p. In contrast to the free Gln3p, the Ure2p-bound Gln3p is signifcantly resistant to dephosphorylation. Taken together, these results reveal a tripartite regulatory mechanism by which the phosphorylation of Gln3p is regulated.

TOR signaling regulates microtubule structure and function.

The functional diversity and structural heterogeneity of microtubules are largely determined by microtubule-associated proteins (MAPs) [1] [2]. Bik1p (bilateral karyogamy defect protein) is one of the MAPs required for microtubule assembly, stability and function in cell processes such as karyogamy and nuclear migration and positioning in the yeast Saccharomyces cerevisiae [3]. The macrocyclic immunosuppressive antibiotic rapamycin, complexed with its binding protein FKBP12, binds to and inhibits the target of rapamycin protein (TOR) in yeast [4] [5]. We report here that TOR physically interacts with Bik1p, the yeast homolog of human CLIP-170/Restin [6] [7]. Inhibition of TOR by rapamycin significantly affects microtubule assembly, elongation and stability. This function of TOR is independent of new protein synthesis. Rapamycin also causes defects in spindle orientation, nuclear movement and positioning, karyogamy and chromosomal stability, defects also found in the bikDelta mutant. Our data suggest a role for TOR signaling in regulating microtubule stability and function, possibly through Bik1p.

Cosine transform based preconditioners for total variation deblurring.

In PDE image restoration problems, one has to invert operators which is a sum of a blurring operator and an elliptic operator with highly varying coefficient. We present a preconditioner for such operators, which can be used with the conjugate gradient (CG) method, and compare it with Vogel and Oman's product preconditioner.

Color TV: total variation methods for restoration of vector-valued images.

We propose a new definition of the total variation (TV) norm for vector-valued functions that can be applied to restore color and other vector-valued images. The new TV norm has the desirable properties of 1) not penalizing discontinuities (edges) in the image, 2) being rotationally invariant in the image space, and 3) reducing to the usual TV norm in the scalar case. Some numerical experiments on denoising simple color images in red-green-blue (RGB) color space are presented.