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To investigate the emotional conflict processing during the processing of emotional stimuli in individuals with different levels of social adjustment through developing an event-related potential (ERP) method, the study used positive words (happy), negative words (disgusted), positive faces and negative faces as experimental materials for a face-word Stroop emotional conflict task, which was completed by 34 participants. For the N2 component, there was a significant difference between the high and low social adjustment groups for the congruent condition; the low social adjustment group evoked more negative amplitude under the congruent condition. Under the incongruent condition, there was a marginally significant difference between the high and low social adjustment groups; the low social adjustment group evoked more negative amplitude under the incongruent condition. For the SP component, there were no significant differences for both the high and low social adjustment group between the congruent and incongruent conditions of emotional conflict. However, within the low social adjustment group, the incongruent evoked more positive amplitude. Our findings indicate that the difference in the emotional conflict process between individuals with high and low social adjustment mainly lies in the early processing stages of emotional information. That is, for both congruent and incongruent emotional stimuli, individuals with high social adjustment showed better emotional conflict monitoring, used less cognitive resources, and had a higher degree of automated processing than those with low social adjustment. During the later stages of emotional conflict processing, individuals with low social adjustment showed poorer conflict processing. [ABSTRACT FROM AUTHOR]

Ovarian carcinosarcoma (OCS) accounts for high mortality and lacks effective therapeutic methods. So far, we lack reliable biomarkers capable of predicting the risk of aggressive course of the disease. Programmed death ligand-1 (PD-L1) is expressed in various tumors, and antibodies targeting its receptor programmed cell death 1 (PD-1) are emerging cancer therapeutics. This study was designed to evaluate the expression of PD-L1 and intratumoral CD8+ T lymphocytes by immunohistochemistry from 19 OCS patients who underwent primary surgery at Fudan University Shanghai Cancer Center. The correlations between PD-L1 expression and CD8+ T lymphocytes as well as the patients’ clinicopathologic characteristics were integrated and statistically analyzed. PD-L1-positive expression was observed in 52.6% of intraepithelial tissues and 47.4% of mesenchymal tissues (p = 0.370). Meanwhile, intraepithelial and mesenchymal CD8+ T lymphocytes were positive in 36.8% and 84.2% of OCS, respectively (p = 0.628). A significantly negative correlation was found between mesenchymal CD8+ T lymphocytes and PD-L1 expression (r = -0.630, p = 0.011). Intraepithelial PD-L1-positive expression was associated only with positive ascitic fluid (p = 0.008). Mesenchymal PD-L1-positive patients had a poorer survival than those with negative expression (p = 0.036). Meanwhile, intraepithelial PD-L1-positive patients had a better survival trend than PD-L1-negative patients, though no statistical significance was found (p = 0.061). There was a better postoperative survival noted in mesenchymal CD8-positive patients (p = 0.024), and allthough a better trend of OS was observed in intraepithelial CD8-positive patients, no statistical significance was found (p = 0.382). Positive tumoral CD8+ T lymphocytes and mesenchymal PD-L1-negative expression seem to be associated with better survival in OCS. It is possible that immunotherapy targeting PD-L1 pathway could be used in OCS. [ABSTRACT FROM AUTHOR]

Oxidative stress contributes to the formation of cataracts. The leucine rich repeat containing G protein-coupled receptor 4 (LGR4, also known as GPR48), is important in many developmental processes. Since deletion of Lgr4 has previously been shown to lead to cataract formation in mice, we sought to determine the specific role that Lgr4 plays in the formation of cataracts. Initially, the lens opacities of Lgr4−/− mice at different ages without ocular anterior segment dysgenesis (ASD) were evaluated with slit-lamp biomicroscopy. Lenses from both Lgr4−/− and wild-type mice were subjected to oxidation induced protein denaturation to assess the ability of the lens to withstand oxidation. The expression of antioxidant enzymes was evaluated with real-time quantitative PCR. Phenotypically, Lgr4−/− mice showed earlier onset of lens opacification and higher incidence of cataract formation compared with wild-type mice of similar age. In addition, Lgr4−/− mice demonstrated increased sensitivity to environmental oxidative damage, as evidenced by altered protein expression. Real-time quantitative PCR showed that two prominent antioxidant defense enzymes, catalase (CAT) and superoxidase dismutase-1 (SOD1), were significantly decreased in the lens epithelial cells of Lgr4−/− mice. Our results suggest that the deletion of Lgr4 can lead to premature cataract formation, as well as progressive deterioration with aging. Oxidative stress and altered expression of several antioxidant defense enzymes contribute to the formation of cataracts. [ABSTRACT FROM AUTHOR]

Mortalin is an essential component of the molecular machinery that imports nuclear-encoded proteins into mitochondria, assists in their folding, and protects against damage upon accumulation of dysfunctional, unfolded proteins in aging mitochondria. Mortalin dysfunction associated with Parkinson’s disease (PD) increases the vulnerability of cultured cells to proteolytic stress and leads to changes in mitochondrial function and morphology. To date, Drosophila melanogaster has been successfully used to investigate pathogenesis following the loss of several other PD-associated genes. We generated the first loss-of-Hsc70-5/mortalin-function Drosophila model. The reduction of Mortalin expression recapitulates some of the defects observed in the existing Drosophila PD-models, which include reduced ATP levels, abnormal wing posture, shortened life span, and reduced spontaneous locomotor and climbing ability. Dopaminergic neurons seem to be more sensitive to the loss of mortalin than other neuronal sub-types and non-neuronal tissues. The loss of synaptic mitochondria is an early pathological change that might cause later degenerative events. It precedes both behavioral abnormalities and structural changes at the neuromuscular junction (NMJ) of mortalin-knockdown larvae that exhibit increased mitochondrial fragmentation. Autophagy is concomitantly up-regulated, suggesting that mitochondria are degraded via mitophagy. Ex vivo data from human fibroblasts identifies increased mitophagy as an early pathological change that precedes apoptosis. Given the specificity of the observed defects, we are confident that the loss-of-mortalin model presented in this study will be useful for further dissection of the complex network of pathways that underlie the development of mitochondrial parkinsonism. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) 2 and 4 play critical roles in intestinal inflammation caused by Fusobacterium nucleatum (F. nucleatum) infection, but the role of TLR2/TLR4 in regulation of proinflammatory cytokines remains unknown. In this study, through microarray analysis and qRT-PCR, we showed that TLR2/TLR4 are involved in the F. nucleatum-induced inflammatory signaling pathway in Caco-2 cells, C57BL/6 mice and human clinical specimens. In TLR2-/- and TLR4-/- mice, F. nucleatum infection resulted in increased colonization of the bacteria and production of the proinflammatory cytokines IL-8, IL-1β and TNF-α. In addition, the ratio of Foxp3+ CD4+ T cells in the total CD4+ T cells in TLR2-/- and TLR4-/- mice was less than that in wild-type mice, and the ratio in hybrid mice was more than that in knockout mice, which suggested that TLR2/TLR4 mediated the number of Tregs. Furthermore, it was observed that inflammatory cytokine levels were reduced in TLR2-/- mice after Treg transfer. Thus, these data indicate that TLR2/TLR4 regulate F. nucleatum-induced inflammatory cytokines through Tregs in vivo. [ABSTRACT FROM AUTHOR]

Baicalein, a widely used Chinese herbal medicine, has multiple pharmacological activities. However, the precise mechanisms of the anti-proliferation and anti-metastatic effects of baicalein on gallbladder cancer (GBC) remain poorly understood. Therefore, the aim of this study was to assess the anti-proliferation and anti-metastatic effects of baicalein and the related mechanism(s) on GBC. In the present study, we found that treatment with baicalein induced a significant inhibitory effect on proliferation and promoted apoptosis in GBC-SD and SGC996 cells, two widely used gallbladder cancer cell lines. Additionally, treatment with baicalein inhibited the metastasis of GBC cells. Moreover, we demonstrated for the first time that baicalein inhibited GBC cell growth and metastasis via down-regulation of the expression level of Zinc finger protein X-linked (ZFX). In conclusion, our studies suggest that baicalein may be a potential phytochemical flavonoid for therapeutics of GBC and ZFX may serve as a molecular marker or predictive target for GBC. [ABSTRACT FROM AUTHOR]

Alkaptonuria is often diagnosed clinically with episodes of dark urine, biochemically by the accumulation of peripheral homogentisic acid and molecularly by the presence of mutations in the homogentisate 1,2-dioxygenase gene (HGD). Alkaptonuria is invariably associated with HGD mutations, which consist of single nucleotide variants and small insertions/deletions. Surprisingly, the presence of deletions beyond a few nucleotides among over 150 reported deleterious mutations has not been described, raising the suspicion that this gene might be protected against the detrimental mechanisms of gene rearrangements. The quest for an HGD mutation in a proband with AKU revealed with a SNP array five large regions of homozygosity (5–16 Mb), one of which includes the HGD gene. A homozygous deletion of 649 bp deletion that encompasses the 72 nucleotides of exon 2 and surrounding DNA sequences in flanking introns of the HGD gene was unveiled in a proband with AKU. The nature of this deletion suggests that this in-frame deletion could generate a protein without exon 2. Thus, we modeled the tertiary structure of the mutant protein structure to determine the effect of exon 2 deletion. While the two β-pleated sheets encoded by exon 2 were missing in the mutant structure, other β-pleated sheets are largely unaffected by the deletion. However, nine novel α-helical coils substituted the eight coils present in the native HGD crystal structure. Thus, this deletion results in a deleterious enzyme, which is consistent with the proband’s phenotype. Screening for mutations in the HGD gene, particularly in the Middle East, ought to include this exon 2 deletion in order to determine its frequency and uncover its origin. [ABSTRACT FROM AUTHOR]

Background: Occupational exposure to welding fumes is a serious occupational health problem all over the world. Welders are exposed to many occupational hazards; these hazards might cause some occupational diseases. The aim of the study was to assess the health related quality of life (HRQL) of electric welders in Shanghai China and explore influencing factors to HRQL of welders. Methods: 301 male welders (without pneumoconiosis) and 305 non-dust male workers in Shanghai were enrolled in this study. Short Form-36 (SF-36) health survey questionnaires were applied in this cross-sectional study. Socio-demographic, working and health factors were also collected. Multiple stepwise regress analysis was used to identify significant factors related to the eight dimension scores. Results: Six dimensions including role-physical (RP), bodily pain (BP), general health (GH), validity (VT), social function (SF), and mental health (MH) were significantly worse in welders compared to non-dust workers. Multiple stepwise regress analysis results show that native place, monthly income, quantity of children, drinking, sleep time, welding type, use of personal protective equipment (PPE), great events in life, and some symptoms including dizziness, discomfort of cervical vertebra, low back pain, cough and insomnia may be influencing factors for HRQL of welders. Among these factors, only sleep time and the use of PPE were salutary. Conclusions: Some dimensions of HRQL of these welders have been affected. Enterprises which employ welders should take measures to protect the health of these people and improve their HRQL. [ABSTRACT FROM AUTHOR]

Advances in digital biotelemetry technologies are enabling the collection of bigger and more accurate data on the movements of free-ranging wildlife in space and time. Although many biotelemetry devices record 3D location data with x, y, and z coordinates from tracked animals, the third z coordinate is typically not integrated into studies of animal spatial use. Disregarding the vertical component may seriously limit understanding of animal habitat use and niche separation. We present novel movement-based kernel density estimators and computer visualization tools for generating and exploring 3D home ranges based on location data. We use case studies of three wildlife species – giant panda, dugong, and California condor – to demonstrate the ecological insights and conservation management benefits provided by 3D home range estimation and visualization for terrestrial, aquatic, and avian wildlife research. [ABSTRACT FROM AUTHOR]

RNA surveillance plays an important role in posttranscriptional regulation. Seminal work in this field has largely focused on yeast as a model system, whereas exploration of RNA surveillance in mammals is only recently begun. The increased transcriptional complexity of mammalian systems provides a wider array of targets for RNA surveillance, and, while many questions remain unanswered, emerging data suggest the nuclear RNA surveillance machinery exhibits increased complexity as well. We have used a small interfering RNA in mouse N2A cells to target the homolog of a yeast protein that functions in RNA surveillance (Mtr4p). We used high-throughput sequencing of polyadenylated RNAs (PA-seq) to quantify the effects of the mMtr4 knockdown (KD) on RNA surveillance. We demonstrate that overall abundance of polyadenylated protein coding mRNAs is not affected, but several targets of RNA surveillance predicted from work in yeast accumulate as adenylated RNAs in the mMtr4KD. microRNAs are an added layer of transcriptional complexity not found in yeast. After Drosha cleavage separates the pre-miRNA from the microRNA's primary transcript, the byproducts of that transcript are generally thought to be degraded. We have identified the 5′ leading segments of pri-miRNAs as novel targets of mMtr4 dependent RNA surveillance. [ABSTRACT FROM AUTHOR]

Background: Endothelial dysfunction is the pathophysiological characteristic of pulmonary arterial hypertension (PAH). Some paracrine factors secreted by bone marrow–derived endothelial progenitor cells (BMEPCs) have the potential to strengthen endothelial integrity and function. This study investigated whether BMEPCs have the therapeutic potential to improve monocrotaline (MCT)-induced PAH via producing vasoprotective substances in a paracrine fashion. Methods and Results: Bone marrow-derived mononuclear cells were cultured for 7 days to yield BMEPCs. 24 hours or 3 weeks after exposure to BMEPCs in vitro or in vivo, the vascular reactivity, cyclooxygenase-2 (COX-2) expression, prostacyclin (PGI2) and cAMP release in isolated pulmonary arteries were examined respectively. Treatment with BMEPCs could improve the relaxation of pulmonary arteries in MCT-induced PAH and BMEPCs were grafted into the pulmonary bed. The COX-2/prostacyclin synthase (PGIS) and its progenies PGI2/cAMP were found to be significantly increased in BMEPCs treated pulmonary arteries, and this action was reversed by a selective COX-2 inhibitor, NS398. Moreover, the same effect was also observed in conditioned medium obtained from BMEPCs culture. Conclusions: Implantation of BMEPCs effectively ameliorates MCT-induced PAH. Factors secreted in a paracrine fashion from BMEPCs promote vasoprotection by increasing the release of PGI2 and level of cAMP. [ABSTRACT FROM AUTHOR]

Objective: To describe the epidemiology of holoprosencephaly (HPE) in China with special reference to prevalence and associated anomalies. Methods: Data were abstracted from the Chinese Birth Defects Monitoring Network for the period 2007–2014. Birth prevalence of HPE were assessed by birth year, fetal/infant sex, maternal age, and maternal residential area. Poisson regressions were used to calculate the crude and adjusted prevalence ratios (PR) and their 95% confidence intervals, and linear chi-square test was used to explore time trend for the prevalence of HPE. Results: A total of 1222 HPE cases were identified in 13,284,142 births, yielding an overall prevalence of 0.92 per 10,000 births. The annual prevalence of HPE presented an upward trend (P<0.001), from 0.54 per 10,000 births in 2007 to 1.21 per 10,000 births in 2014. Higher prevalence was found in older maternal-age groups (30–34 years, adjusted PR: 1.19, 95% CI: 1.02–1.40; ≥35 years, adjusted PR: 1.53, 95% CI: 1.26–1.86) in comparison with the maternal-age group of 25 to 29 years. Higher prevalence was also found in infants born to mothers resided in urban areas (adjusted PR: 1.23, 95% CI: 1.08–1.39) and female infants (adjusted PR: 1.30, 95% CI: 1.15–1.47). Conclusions: HPE is an important perinatal health issue because of its poor prognosis. This is the first study depicting a picture of epidemiological characteristics of HPE in China, which can provide useful references for future studies. [ABSTRACT FROM AUTHOR]

In preterm infants (i.e. the gestational age less than 37 weeks), postnatal growth remains a concern. This study used multicenter longitudinal data from China’s Under 5 Child Nutrition and Health Surveillance System to investigate the postnatal growth in the weight and length of preterm infants. Gender-stratified differences in weight and length were assessed between preterm and term infants. 1221 preterm infants and 1221 matched term infants were included. The rates of growth in weight and length in preterm infants was greater than those in term infants, especially from the first to sixth month. The rates were higher in males compared to females in the first 3 months. The differences of weight and length between preterm and term infants decreased with increasing age, however, these measurements did not reach the level of their term peers until 12 months before adjusting for gestational age. The median values of weight and length were even larger in preterm infants in the first month after adjusting for gestational age. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a common and highly lethal form of cancer. Although the etiologic role of Fusobacterium nucleatum (F. nucleatum) in the development of CRC has been elucidated, the specific tumor molecules involved in the progression of CRC induced by F. nucleatum have not been identified. This study investigated several miRNAs and genes involved in the progression of F. nucleatum-induced CRC by Affymetrix miRNA microarray technology and GeneChip Human Transcriptome Array 2.0. The results suggest that miR-4474 and miR-4717 are up-regulated in CRC tissues in response to F. nucleatum infection, compared with the control group (paracancerous tissues), while other genes associated with signaling pathways in cancer, including CREB-binding protein (CREBBP), STAT1, PRKACB, CAMK2B, JUN, TP53 and EWSR1, were dysregulated. Bioinformatic analysis identified CREBBP as the primary aberrantly expressed gene in F. nucleatum-induced CRC. Consistent with the microarray analysis results, real-time RT-PCR analysis demonstrated that the expression of miR-4474/4717 was upregulated while that of CREBBP mRNA was downregulated in CRC patients infected with F. nucleatum. Additionally, CREBBP was identified as a novel target of miR-4474/4717. The results of this study suggest that miR-4474 and miR-4717 are involved in the progression of F. nucleatum-induced CRC by posttranscriptionally regulating the target gene CREBBP. [ABSTRACT FROM AUTHOR]

Bacterial pathogens are highly adaptable organisms, a quality that enables them to overcome changing hostile environments. For example, Vibrio cholerae, the causative agent of cholera, is able to colonize host small intestines and combat host-produced reactive oxygen species (ROS) during infection. To dissect the molecular mechanisms utilized by V. cholerae to overcome ROS in vivo, we performed a whole-genome transposon sequencing analysis (Tn-seq) by comparing gene requirements for colonization using adult mice with and without the treatment of the antioxidant, N-acetyl cysteine. We found that mutants of the methyl-directed mismatch repair (MMR) system, such as MutS, displayed significant colonization advantages in untreated, ROS-rich mice, but not in NAC-treated mice. Further analyses suggest that the accumulation of both catalase-overproducing mutants and rugose colony variants in NAC- mice was the leading cause of mutS mutant enrichment caused by oxidative stress during infection. We also found that rugose variants could revert back to smooth colonies upon aerobic, in vitro culture. Additionally, the mutation rate of wildtype colonized in NAC- mice was significantly higher than that in NAC+ mice. Taken together, these findings support a paradigm in which V. cholerae employs a temporal adaptive strategy to battle ROS during infection, resulting in enriched phenotypes. Moreover, ΔmutS passage and complementation can be used to model hypermuation in diverse pathogens to identify novel stress resistance mechanisms. [ABSTRACT FROM AUTHOR]

Anthocyanins are the polyphenolic phytochemicals which have been shown to scavenge free radicals. In this study, we investigated the effects of anthocyanins extracted from red-fleshed apples (Malus sieversii) on reducing oxidative damage by Rosup in porcine granulosa cells (GCs) by measuring intracellular reactive oxygen species (ROS), content of glutathione (GSH), activities of superoxide dismutase (SOD1), catalase (CAT) and glutathione peroxidase (GPX1) and the gene expression of SOD1, CAT, GPX1. Apoptosis was determined with TdT-mediated dUTP-biotin nick end labeling (TUNEL) and apoptosis-related proteins were quantified with Western blotting. The results indicate that Rosup increases oxidative stress by inducing reactive oxygen species production in porcine GCs and the oxidative stress could be reduced by anthocyanins. The gene expression of SOD1, CAT, GPX1 and the activities of these enzymes were increased when GCs were treated with anthocyanins and Rosup for 6 hours. Anthocyanins inhibit Rosup-induced apoptosis by increasing expression of antiapoptotic protein Bcl-2 and suppressing the expression of pro-apoptotic protein Bax. Collectively, anthocyanins from red-fleshed apples reduce oxidative stress and inhibit apoptosis in porcine GCs in vitro. This approach indicates that antioxidants might be developed from red-fleshed apples. [ABSTRACT FROM AUTHOR]

Some frame components, such as SYNC (frame synchronization) and RTS/CTS (Ready to Send/Clear to Send), are not taken into consideration when the traditional setting strategies conduct the optimization of SMAC (Sensor MAC) contention window size. This paper proposes mathematical models that allow the analysis of data packets forwarding delay within one SMAC virtual cluster. Simulation results in OMNeT++ show good agreements with the proposed mathematical models, validating the models’ correctness. The curve analyses of the models confirm the existence of delay-optimization-oriented contention window size that is closely related to the number of simultaneously contending nodes. Afterwards, it is shown that SYNC, RTS/CTS and EIFS (Extended InterFrame Space) have impacts on the optimal contention window size and expected delivery delay to various degrees, as well as throughput and energy efficiency. One ideal setting strategy of delay-optimization-oriented SMAC contention window size requires the combination of the network scale, SYNC, RTS/CTS and EIFS. Additionally, it is demonstrated that the proposed setting strategy makes contributions to the improvement in the existing SMAC extensions when they are integrated with each other, in terms of the end-to-end delay, throughput and energy consumption. [ABSTRACT FROM AUTHOR]

Germination is a key event in the angiosperm life cycle. N-glycosylation of proteins is one of the most common post-translational modifications, and has been recognized to be an important regulator of the proteome of the germinating embryo. Here, we report the first N-linked glycosites mapping of rice embryos during germination by using a hydrophilic interaction chromatography (HILIC) glycopeptides enrichment strategy associated with high accuracy mass spectrometry identification. A total of 242 glycosites from 191 unique proteins was discovered. Inspection of the motifs and sequence structures involved suggested that all the glycosites were concentrated within [NxS/T] motif, while 82.3% of them were in a coil structure. N-glycosylation preferentially occurred on proteins with glycoside hydrolase activities, which were significantly enriched in the starch and sucrose metabolism pathway, suggesting that N-glycosylation is involved in embryo germination by regulating carbohydrate metabolism. Notably, protein-protein interaction analysis revealed a network with several Brassinosteroids signaling proteins, including XIAO and other BR-responsive proteins, implying that glycosylation-mediated Brassinosteroids signaling may be a key mechanism regulating rice embryo germination. In summary, this study expanded our knowledge of protein glycosylation in rice, and provided novel insight into the PTM regulation in rice seed germination. [ABSTRACT FROM AUTHOR]

Ion channels and transporters have increasingly recognized roles in cancer progression through the regulation of cell proliferation, migration, and death. Glioblastoma stem-like cells (GSCs) are a source of tumor formation and recurrence in glioblastoma multiforme, a highly aggressive brain cancer, suggesting that ion channel expression may be perturbed in this population. However, little is known about the expression and functional relevance of ion channels that may contribute to GSC malignancy. Using RNA sequencing, we assessed the enrichment of ion channels in GSC isolates and non-tumor neural cell types. We identified a unique set of GSC-enriched ion channels using differential expression analysis that is also associated with distinct gene mutation signatures. In support of potential clinical relevance, expression of selected GSC-enriched ion channels evaluated in human glioblastoma databases of The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project correlated with patient survival times. Finally, genetic knockdown as well as pharmacological inhibition of individual or classes of GSC-enriched ion channels constrained growth of GSCs compared to normal neural stem cells. This first-in-kind global examination characterizes ion channels enriched in GSCs and explores their potential clinical relevance to glioblastoma molecular subtypes, gene mutations, survival outcomes, regional tumor expression, and experimental responses to loss-of-function. Together, the data support the potential biological and therapeutic impact of ion channels on GSC malignancy and provide strong rationale for further examination of their mechanistic and therapeutic importance. [ABSTRACT FROM AUTHOR]

Background: Plasma fibrin d-dimer has been taken as a marker for thrombus. The aim of this study was to evaluate the relationship between d-dimer (DD) levels and left atrial spontaneous echo contrast (SEC)/left atrial thrombus (LAT). Methods: We identified clinical studies by systematic search of MEDLINE and EMBASE databases up to Feb 2016. All observational studies that considered DD as a study factor and trans-esophageal echocardiography (TEE) identified SEC/LAT as an outcome were included. Two reviewers independently selected the studies and extracted the data. Results: Of the 21 included studies, 16 studies (2652 patients) have compared the mean DD differences between patients with and without an evidence of the presence of SEC/LAT, 9 studies (1667 patients) have estimated the diagnostic value of DD in the presence of LAT, and 11 studies (1856 patients) have available information to calculate a ratio of the presence of LAT among individuals in the top and the bottom third of DD levels. The pooled standardized mean difference (SMD) of DD between patients with and without left atrial SEC and/or LAT was 1.29 [95%CI: 0.51, 2.08], with SMDs of 0.42 [95% CI: 0.08, 0.77] and 2.34 [95% CI: 1.01, 3.68] in SEC/LAT and LAT subgroups, respectively. The combined risk ratio of the presence of LAT among individuals between the top of the distribution of DD levels and that in the bottom third was 3.84 [95% CI: 2.35, 6.28], associating with a mean difference of 0.78 ug/ml (1.10 vs 0.32 ug/ml). The pooled sensitivity, specificity and positive likelihood ratio of DD for LAT were 0.75 [95% CI: 0.65, 0.83], 0.81 [95% CI: 0.59, 0.93] and 4.0 [95% CI: 1.7, 9.9], respectively. Conclusions: High plasma fibrin DD was associated with left atrial SEC/LAT, particularly among patients with LAT. DD levels have moderate sensitivity and specificity for diagnosing LAT. [ABSTRACT FROM AUTHOR]

Vibrio cholerae is the causative agent of cholera, a dehydrating diarrheal disease. This Gram-negative pathogen is able to modulate its gene expression in order to combat stresses encountered in both aquatic and host environments, including stress posed by reactive oxygen species (ROS). In order to further the understanding of V. cholerae’s transcriptional response to ROS, we performed an RNA sequencing analysis to determine the transcriptional profile of V. cholerae when exposed to hydrogen hydroperoxide. Of 135 differentially expressed genes, VC0139 was amongst the genes with the largest induction. VC0139 encodes a protein homologous to the DPS (DNA-binding protein from starved cells) protein family, which are widely conserved and are implicated in ROS resistance in other bacteria. Using a promoter reporter assay, we show that during exponential growth, dps is induced by H2O2 in a manner dependent on the ROS-sensing transcriptional regulator, OxyR. Upon entry into stationary phase, the major stationary phase regulator RpoS is required to transcribe dps. Deletion of dps impaired V. cholerae resistance to both inorganic and organic hydroperoxides. Furthermore, we show that Dps is involved in resistance to multiple environmental stresses. Finally, we found that Dps is important for V. cholerae adult mouse colonization, but becomes dispensable in the presence of antioxidants. Taken together, our results suggest that Dps plays vital roles in both V. cholerae stress resistance and pathogenesis. [ABSTRACT FROM AUTHOR]

Genetic architecture of branch traits has large influences on the morphological structure, photosynthetic capacity, planting density, and yield of Upland cotton (Gossypium hirsutum L.). This research aims to reveal the genetic effects of six branch traits, including bottom fruit branch node number (BFBNN), bottom fruit branch length (BFBL), middle fruit branch node number (MFBNN), middle fruit branch length (MFBL), upper fruit branch node number (UFBNN), and upper fruit branch length (UFBL). Association mapping was conducted for these traits of 39 lines and their 178 F1 hybrids in three environments. There were 20 highly significant Quantitative Trait SSRs (QTSs) detected by mixed linear model approach analyzing a full genetic model with genetic effects of additive, dominance, epistasis and their environment interaction. The phenotypic variation explained by genetic effects ranged from 32.64 ~ 91.61%, suggesting these branch traits largely influenced by genetic factors. [ABSTRACT FROM AUTHOR]

The metastasis of gastric cancer, one of the most common tumors, has a molecular mechanism that is still largely unclear. Here we investigated the role of possible tumor-suppressor miR-1296-5p in the cell migration and invasion of ERBB2-positive gastric cancer. It found that miR-1296-5p was significantly down-regulated in gastric cancer tissues. Moreover, it was down-regulated in lymph node metastatic gastric cancer tissues compared with non-metastatic gastric cancer tissues. The luciferase activity of ERBB2 3'-untranslated region-based reporters constructed in SNU-216 and NUGC-4 gastric cancer cells suggested that ERBB2 was the target gene of miR-1296-5p. Overexpressed miR-1296-5p reduced its target protein level and Rac1 activation, and inhibited the migration and invasion of SNU-216 and NUGC-4 gastric cancer cells. MiR-1296-5p was down-regulated in ERBB2-positive gastric cancer tissues compared with ERBB2-negative gastric cancer tissues. In ERBB2-positive gastric cancers, the miR-1296-5p expression was suppressed in a majority of metastatic lymph node tissues compared to non-metastatic gastric cancer samples. The migration and invasion of gastric cancer cells was inhibited by miR-1296-5p overexpression or herceptin treatment, and rescued by the overexpression of constitutively active Rac1-Q61L or ERBB2. Taken together, our findings first suggest that miR-1296-5p might be involved in the regulation on the migration and invasion of human gastric cancer cells at least in part via targeting ERBB2/Rac1 signaling pathway. [ABSTRACT FROM AUTHOR]

Objective: The accuracy of a population-based sex ratio at birth (SRB) in China has long been questioned. To depict a more accurate profile, the present study used data from a national surveillance system for health facility births to explore the characteristics of SRB in China. Methods: Data from China’s National Maternal Near Miss Surveillance System between 2012 and 2015 were used. We restricted the analysis to live births of ≥28 completed gestational weeks or ≥1000 g birth weight. The strength of association between obstetric characteristics and SRB was examined using logistic regression, taking into account the sampling strategy and clustering of births within health facilities. Results: There were 2,785,513 boys and 2,549,269 girls born alive between 2012 and 2015 in 441 health facilities. The SRB was 111.04 in 2012, 110.16 in 2013, 108.79 in 2014, and 109.53 in 2015. The SRB was high in the eastern region, especially in rural areas. The SRBs increased with mother’s age and decreased with mother’s education. The SRB in women who were pregnant for the first time was 104.30. The SRB in primipara was normal (104.35), but it was extremely high in non-primipara, especially for women with three or more parities (141.76); only 5.26% of live births fell within this group. The SRBs increased significantly by the number of parities, especially in the rural areas of the central region. After adjustment for sociodemographic factors, women with three or more parities were 1.39 (95% CI 1.34, 1.43) times more likely to give birth to a boy compared with primiparae who were pregnant for the first time. Conclusion: Our analysis suggests that the SRB was lower than what was reported officially but higher than normal. The government should keep strengthening supervision to prevent sex-selection, especially in the wake of the two-child policy implemented in 2015. [ABSTRACT FROM AUTHOR]

Fusobacterium nucleatum (F. nucleatum) plays a critical role in gastrointestinal inflammation. However, the exact mechanism by which F. nucleatum contributes to inflammation is unclear. In the present study, it was revealed that F. nucleatum could induce the production of proinflammatory cytokines (IL-8, IL-1β and TNF-α) and reactive oxygen species (ROS) in Caco-2 colorectal) adenocarcinoma cells. Furthermore, ROS scavengers (NAC or Tiron) could decrease the production of proinflammatory cytokines during F. nucleatum infection. In addition, we observed that autophagy is impaired in Caco-2 cells after F. nucleatum infection. The production of proinflammatory cytokines and ROS induced by F. nucleatum was enhanced with either autophagy pharmacologic inhibitors (3-methyladenine, bafilomycin A1) or RNA interference in essential autophagy genes (ATG5 or ATG12) in Caco-2 cells. Taken together, these results indicate that F. nucleatum-induced impairment of autophagic flux enhances the expression of proinflammatory cytokines via ROS in Caco-2 Cells. [ABSTRACT FROM AUTHOR]

Background: Diabetes is a major global public health problem driven by a high prevalence of metabolic risk factors. Objective: To describe the differences of metabolic risk factors of type 2 diabetes, as well as glycemic control and complicated diabetic complications between rural and urban Uygur residents in Xinjiang Uygur Autonomous Region of China. Methods: This comparative cross-sectional study, conducted among 2879 urban and 918 rural participants in Xinjiang, China, assessed the metabolic risk factors of diabetes and related complications differences between urban and rural settlements. Results: Compared to rural areas, urban participants had higher education level and more average income, little physical activity, less triglycerides and higher HDL-c (p < 0.05 respectively). Differences in metabolic risk factors by urban/rural residence included overweight or obesity, triglycerides (≥1.71mmol/l), HDL-c (< 1.04 mmol/l), alcohol intake, and physical inactivity (p < 0.01 respectively). There was significant difference regarding the prevalence of HbA1c >8% (48.1% versus 54.5%, p = 0.019) between rural and urban diabetic participants. No significant difference in the prevalence of type 2 diabetic complications between urban and rural participants (74.9% versus 72.2%; p = 0.263) was detected. Compared to rural participants, the most prevalent modifiable risk factors associated with diabetic complications in urban participants were obesity (BMI ≥ 28 Kg/m2), HDL-c (< 1.04 mmol/l), physical inactivity and irregular eating habits (p = 0.035, p = 0.001, p < 0.001, and p = 0.013, respectively). Conclusions: Urban settlers were significantly more likely to have metabolic risk factors highlighting the need for public health efforts to improve health outcomes for these vulnerable populations. Diabetes related complications risk factors were prevalent amongst rural and urban diabetes settlers. [ABSTRACT FROM AUTHOR]

We present a gridded 8 km-resolution data product of the estimated composition of tree taxa at the time of Euro-American settlement of the northeastern United States and the statistical methodology used to produce the product from trees recorded by land surveyors. Composition is defined as the proportion of stems larger than approximately 20 cm diameter at breast height for 22 tree taxa, generally at the genus level. The data come from settlement-era public survey records that are transcribed and then aggregated spatially, giving count data. The domain is divided into two regions, eastern (Maine to Ohio) and midwestern (Indiana to Minnesota). Public Land Survey point data in the midwestern region (ca. 0.8-km resolution) are aggregated to a regular 8 km grid, while data in the eastern region, from Town Proprietor Surveys, are aggregated at the township level in irregularly-shaped local administrative units. The product is based on a Bayesian statistical model fit to the count data that estimates composition on the 8 km grid across the entire domain. The statistical model is designed to handle data from both the regular grid and the irregularly-shaped townships and allows us to estimate composition at locations with no data and to smooth over noise caused by limited counts in locations with data. Critically, the model also allows us to quantify uncertainty in our composition estimates, making the product suitable for applications employing data assimilation. We expect this data product to be useful for understanding the state of vegetation in the northeastern United States prior to large-scale Euro-American settlement. In addition to specific regional questions, the data product can also serve as a baseline against which to investigate how forests and ecosystems change after intensive settlement. The data product is being made available at the NIS data portal as version 1.0. [ABSTRACT FROM AUTHOR]

Here we used predictive gene expression signatures within a multi-species framework to identify the genes that underlie cardiac cell fate decisions in differentiating embryonic stem cells. We show that the overlapping orthologous mouse and human genes are the most accurate candidate cardiogenic genes as these genes identified the most conserved developmental pathways that characterize the cardiac lineage. An RNAi-based screen of the candidate genes in Drosophila uncovered numerous novel cardiogenic genes. shRNA knockdown combined with transcriptome profiling of the newly-identified transcription factors zinc finger protein 503 and zinc finger E-box binding homeobox 2 and the well-known cardiac regulatory factor NK2 homeobox 5 revealed that zinc finger E-box binding homeobox 2 activates terminal differentiation genes required for cardiomyocyte structure and function whereas zinc finger protein 503 and NK2 homeobox 5 are required for specification of the cardiac lineage. We further demonstrated that an essential role of NK2 homeobox 5 and zinc finger protein 503 in specification of the cardiac lineage is the repression of gene expression programs characteristic of alternative cell fates. Collectively, these results show that orthologous gene expression signatures can be used to identify conserved cardiogenic pathways. [ABSTRACT FROM AUTHOR]

High concentrations of arsenic, which can be occasionally found in drinking water, have been recognized as a global health problem. Exposure to arsenic can disrupt spatial memory; however, the underlying mechanism remains unclear. In the present study, we tested whether exercise could interfere with the effect of arsenic exposure on the long-term memory (LTM) of object recognition in mice. Arsenic (0, 1, 3, and 10 mg/ kg, i.g.) was administered daily for 12 weeks. We found that arsenic at dosages of 1, 3, and 10 mg/kg decreased body weight and increased the arsenic content in the brain. The object recognition LTM (tested 24 h after training) was disrupted by 3 mg/ kg and 10 mg/ kg, but not 1 mg/ kg arsenic exposure. Swimming exercise also prevented LTM impairment induced by 3 mg/ kg, but not with 10 mg/ kg, of arsenic exposure. The expression of brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP-response element binding protein (pCREB) in the CA1 and dentate gyrus areas (DG) of the dorsal hippocampus were decreased by 3 mg/ kg and 10 mg/ kg, but not by 1 mg/ kg, of arsenic exposure. The decrease in BDNF and pCREB in the CA1 and DG induced by 3 mg/ kg, but not 10 mg/ kg, of arsenic exposure were prevented by swimming exercise. Arsenic exposure did not affect the total CREB expression in the CA1 or DG. Taken together, these results indicated that swimming exercise prevented the impairment of object recognition LTM induced by arsenic exposure, which may be mediated by BDNF and CREB in the dorsal hippocampus. [ABSTRACT FROM AUTHOR]

Toxin–antitoxin (TA) systems are small genetic elements that typically encode a stable toxin and its labile antitoxin. These cognate pairs are abundant in prokaryotes and have been shown to regulate various cellular functions. Vibrio cholerae, a human pathogen that is the causative agent of cholera, harbors at least thirteen TA loci. While functional HigBA, ParDE have been shown to stabilize plasmids and Phd/Doc to mediate cell death in V. cholerae, the function of seven RelBE-family TA systems is not understood. In this study we investigated the function of the RelBE TA systems in V. cholerae physiology and found that six of the seven relBE loci encoded functional toxins in E. coli. Deletion analyses of each relBE locus indicate that RelBE systems are involved in biofilm formation and reactive oxygen species (ROS) resistance. Interestingly, all seven relBE loci are induced under the standard virulence induction conditions and two of the relBE mutants displayed a colonization defect, which was not due to an effect on virulence gene expression. Although further studies are needed to characterize the mechanism of action, our study reveals that RelBE systems are important for V. cholerae physiology. [ABSTRACT FROM AUTHOR]

Objectives: We investigated the mortality rate of pneumonia (PMR) among children under 5 and its time trend from 1996 to 2013 to determine the priorities for ending preventable deaths from pneumonia in children under 5, and share China’s successful experience in reducing PMR with other developing countries. Methods: We used data from China’s Under 5 Child Mortality Surveillance System (U5CMSS) to calculate the PMR and the proportion of pneumonia deaths to total deaths of children under 5. The data were grouped by urban and rural areas with Cochran-Mantel-Haensel (CMH) test and Chi-square test to examine the differences of PMR and proportion. The time trend was tested by Cochran-Armitage trend test. Results: The overall PMR of children under 5 was reduced by 85.5% (from 1053.2 to 153.2 per 100,000 live births) from 1996 to 2013, with the urban and rural areas reduced by 69.1% (from 188.4 to 58.2 per 100,000 live births) and 84.7% (from 1252.8 to 191.9 per 100,000 live births), respectively. The overall proportion of pneumonia deaths to total deaths was also declined from 23.4% in 1996 to 12.8% in 2013, with the rural areas decreased from 24.4% to 13.2% and the urban areas decreased from 11.1% to 9.7%. The PMRs in neonates (0-27 days), post-neonates (1-11 months), and childhood (12-59 months) were reduced by 80.7%, 77.4%, and 80.1%, respectively in rural areas, and 71.7%, 69.6%, and 39.0%, respectively in urban areas. During 1996-2013, the PMR in children under 5 years was 4.9 fold higher in rural areas relative to that in urban areas, with relative risk (RR) of 3.6 and 6.4 in neonates and 1- to 59-month-old children, respectively. Conclusions: PMR in children under 5 significantly declined in China from 1996 to 2013, especially in rural areas. However, huge disparities still existed between rural and urban areas. Infants had the highest PMR, which indicated that interventions aiming at prevention and control of infant pneumonia should be the priority for further reducing PMR in China. [ABSTRACT FROM AUTHOR]

Callose synthesis is critical for the formation of the pollen wall pattern. CalS5 is thought to be the major synthethase for the callose wall. In the Arabidopsis anther, ARF17 regulates the expression of CalS5 and is the target of miR160. Plants expressing miR160-resistant ARF17 (35S:5mARF17 lines) with increased ARF17 mRNA levels display male sterility. Here we report a zinc finger family gene, AtTTP, which is involved in miR160 maturation and callose synthesis in Arabidopsis. AtTTP is expressed in microsporocytes, tetrads and tapetal cells in the anther. Over-expression lines of AtTTP (AtTTP-OE line) exhibited reduced male fertility. CalS5 expression was tremendously reduced and the tetrad callose wall became much thinner in the AtTTP-OE line. Northern blotting hybridization and quantitative RT-PCR analysis revealed that miR160 was decreased, while the expression of ARF17 was increased in the AtTTP-OE line. Based on these results, we propose that AtTTP associates with miR160 in order to regulate the ARF17 expression needed for callose synthesis and pollen wall formation. [ABSTRACT FROM AUTHOR]

Gene co-expression networks comprise one type of valuable biological networks. Many methods and tools have been published to construct gene co-expression networks; however, most of these tools and methods are inconvenient and time consuming for large datasets. We have developed a user-friendly, accelerated and optimized tool for constructing gene co-expression networks that can fully harness the parallel nature of GPU (Graphic Processing Unit) architectures. Genetic entropies were exploited to filter out genes with no or small expression changes in the raw data preprocessing step. Pearson correlation coefficients were then calculated. After that, we normalized these coefficients and employed the False Discovery Rate to control the multiple tests. At last, modules identification was conducted to construct the co-expression networks. All of these calculations were implemented on a GPU. We also compressed the coefficient matrix to save space. We compared the performance of the GPU implementation with those of multi-core CPU implementations with 16 CPU threads, single-thread C/C++ implementation and single-thread R implementation. Our results show that GPU implementation largely outperforms single-thread C/C++ implementation and single-thread R implementation, and GPU implementation outperforms multi-core CPU implementation when the number of genes increases. With the test dataset containing 16,000 genes and 590 individuals, we can achieve greater than 63 times the speed using a GPU implementation compared with a single-thread R implementation when 50 percent of genes were filtered out and about 80 times the speed when no genes were filtered out. [ABSTRACT FROM AUTHOR]

Chronic Obstructive Pulmonary Disease (COPD) is a complex disease. Genetic, epigenetic, and environmental factors are known to contribute to COPD risk and disease progression. Therefore we developed a systematic approach to identify key regulators of COPD that integrates genome-wide DNA methylation, gene expression, and phenotype data in lung tissue from COPD and control samples. Our integrative analysis identified 126 key regulators of COPD. We identified EPAS1 as the only key regulator whose downstream genes significantly overlapped with multiple genes sets associated with COPD disease severity. EPAS1 is distinct in comparison with other key regulators in terms of methylation profile and downstream target genes. Genes predicted to be regulated by EPAS1 were enriched for biological processes including signaling, cell communications, and system development. We confirmed that EPAS1 protein levels are lower in human COPD lung tissue compared to non-disease controls and that Epas1 gene expression is reduced in mice chronically exposed to cigarette smoke. As EPAS1 downstream genes were significantly enriched for hypoxia responsive genes in endothelial cells, we tested EPAS1 function in human endothelial cells. EPAS1 knockdown by siRNA in endothelial cells impacted genes that significantly overlapped with EPAS1 downstream genes in lung tissue including hypoxia responsive genes, and genes associated with emphysema severity. Our first integrative analysis of genome-wide DNA methylation and gene expression profiles illustrates that not only does DNA methylation play a ‘causal’ role in the molecular pathophysiology of COPD, but it can be leveraged to directly identify novel key mediators of this pathophysiology. [ABSTRACT FROM AUTHOR]

PML/RARA is the oncoprotein driving acute promyelocytic leukemia (APL). It suppresses genes expression by recruitment of a number of transcriptional repressors, resulting in differentiation block and malignant transformation of hematopoietic cells. Here, we found that mice primary hematopoietic progenitor cells (HPCs), transduced by DNA-binding-defective PML/RARA mutants, were deficient in colony formation. Further experiments showed that DNA-binding-defective PML/RARA mutants could not repress the transcription of retinoic acid regulated genes. Intriguingly, there were no significant differences of the micro-speckled intracellular distribution between the mutants and wild-type PML/RARA. Some retinoic acid target genes regulated by PML/RARA are involved in not only differentiation block but also hematopoietic cell self-renewal. Altogether, our data demonstrate that direct DNA-binding is essential for PML/RARA to immortalize hematopoietic cells, while disruption of PML-nuclear body does not seem to be a prerequisite for hematopoietic cell transformation. [ABSTRACT FROM AUTHOR]

Objective: To develop a reference of population-based gestational age-specific birth weight percentiles for contemporary Chinese. Methods: Birth weight data was collected by the China National Population-based Birth Defects Surveillance System. A total of 1,105,214 live singleton births aged ≥28 weeks of gestation without birth defects during 2006–2010 were included. The lambda-mu-sigma method was utilized to generate percentiles and curves. Results: Gestational age-specific birth weight percentiles for male and female infants were constructed separately. Significant differences were observed between the current reference and other references developed for Chinese or non-Chinese infants. Conclusion: There have been moderate increases in birth weight percentiles for Chinese infants of both sexes and most gestational ages since 1980s, suggesting the importance of utilizing an updated national reference for both clinical and research purposes. [ABSTRACT FROM AUTHOR]

Errors in sample annotation or labeling often occur in large-scale genetic or genomic studies and are difficult to avoid completely during data generation and management. For integrative genomic studies, it is critical to identify and correct these errors. Different types of genetic and genomic data are inter-connected by cis-regulations. On that basis, we developed a computational approach, Multi-Omics Data Matcher (MODMatcher), to identify and correct sample labeling errors in multiple types of molecular data, which can be used in further integrative analysis. Our results indicate that inspection of sample annotation and labeling error is an indispensable data quality assurance step. Applied to a large lung genomic study, MODMatcher increased statistically significant genetic associations and genomic correlations by more than two-fold. In a simulation study, MODMatcher provided more robust results by using three types of omics data than two types of omics data. We further demonstrate that MODMatcher can be broadly applied to large genomic data sets containing multiple types of omics data, such as The Cancer Genome Atlas (TCGA) data sets. [ABSTRACT FROM AUTHOR]

The molecular mechanism that regulates epicardial development has yet to be understood. In this study, we explored the function of CDX1, a Caudal-related family member, in epicardial epithelial-to-mesenchymal transition (EMT) and in the migration and the differentiation of epicardium-derived progenitors into vascular smooth muscle cells. We detected a transient expression of CDX1 in murine embryonic hearts at 11.5 days post coitum (dpc). Using a doxycycline-inducible CDX1 mouse model, primary epicardium, and ex vivo heart culture, we further demonstrated that ectopic expression of CDX1 promoted epicardial EMT. In addition, a low-dose CDX1 induction led to enhanced migration and differentiation of epicardium-derived cells into α-SMA+ vascular smooth muscles. In contrast, either continued high-level induction of CDX1 or CDX1 deficiency attenuated the ability of epicardium-derived cells to migrate and to mature into smooth muscles induced by TGF-β1. Further RNA-seq analyses showed that CDX1 induction altered the transcript levels of genes involved in neuronal development, angiogenesis, and cell adhesions required for EMT. Our data have revealed a previously undefined role of CDX1 during epicardial development, and suggest that transient expression of CDX1 promotes epicardial EMT, whereas subsequent down-regulation of CDX1 after 11.5 dpc in mice is necessary for further subepicardial invasion of EPDCs and contribution to coronary vascular endothelium or smooth muscle cells. [ABSTRACT FROM AUTHOR]

The majority of the heritability of coronary artery disease (CAD) remains unexplained, despite recent successes of genome-wide association studies (GWAS) in identifying novel susceptibility loci. Integrating functional genomic data from a variety of sources with a large-scale meta-analysis of CAD GWAS may facilitate the identification of novel biological processes and genes involved in CAD, as well as clarify the causal relationships of established processes. Towards this end, we integrated 14 GWAS from the CARDIoGRAM Consortium and two additional GWAS from the Ottawa Heart Institute (25,491 cases and 66,819 controls) with 1) genetics of gene expression studies of CAD-relevant tissues in humans, 2) metabolic and signaling pathways from public databases, and 3) data-driven, tissue-specific gene networks from a multitude of human and mouse experiments. We not only detected CAD-associated gene networks of lipid metabolism, coagulation, immunity, and additional networks with no clear functional annotation, but also revealed key driver genes for each CAD network based on the topology of the gene regulatory networks. In particular, we found a gene network involved in antigen processing to be strongly associated with CAD. The key driver genes of this network included glyoxalase I (GLO1) and peptidylprolyl isomerase I (PPIL1), which we verified as regulatory by siRNA experiments in human aortic endothelial cells. Our results suggest genetic influences on a diverse set of both known and novel biological processes that contribute to CAD risk. The key driver genes for these networks highlight potential novel targets for further mechanistic studies and therapeutic interventions. [ABSTRACT FROM AUTHOR]

Improving yield is a major objective for cotton breeding schemes, and lint yield and its three component traits (boll number, boll weight and lint percentage) are complex traits controlled by multiple genes and various environments. Association mapping was performed to detect markers associated with these four traits using 651 simple sequence repeats (SSRs). A mixed linear model including epistasis and environmental interaction was used to screen the loci associated with these four yield traits by 323 accessions of Gossypium hirsutum L. evaluated in nine different environments. 251 significant loci were detected to be associated with lint yield and its three components, including 69 loci with individual effects and all involved in epistasis interactions. These significant loci explain ∼ 62.05% of the phenotypic variance (ranging from 49.06% ∼ 72.29% for these four traits). It was indicated by high contribution of environmental interaction to the phenotypic variance for lint yield and boll numbers, that genetic effects of SSR loci were susceptible to environment factors. Shared loci were also observed among these four traits, which may be used for simultaneous improvement in cotton breeding for yield traits. Furthermore, consistent and elite loci were screened with −Log10 (P-value) >8.0 based on predicted effects of loci detected in different environments. There was one locus and 6 pairs of epistasis for lint yield, 4 loci and 10 epistasis for boll number, 15 loci and 2 epistasis for boll weight, and 2 loci and 5 epistasis for lint percentage, respectively. These results provided insights into the genetic basis of lint yield and its components and may be useful for marker-assisted breeding to improve cotton production. [ABSTRACT FROM AUTHOR]

Background: Genome-wide association studies (GWAS) have identified many loci associated with breast cancer risk. These studies have primarily been conducted in populations of European descent. Objective: To determine whether previously reported susceptibility loci in other ethnic groups are also risk factors for breast cancer in a Chinese population. Method: We genotyped 21 previously reported single nucleotide polymorphisms (SNPs) within a female Chinese cohort of 1203 breast cancer cases and 2525 healthy controls using the Sequenom iPlex platform. Fourteen SNPs passed the quality control test. These SNPs were subjected to statistical analysis for the entire cohort and were further analyzed for estrogen receptor (ER) status. The associations of the SNPs with disease susceptibility were assessed using logistic regression, adjusting for age. The Bonferroni correction was used to conservatively account for multiple testing, and the threshold for statistical significance was P<3.57×10−3 (0.05/14). Result: Although none of the SNPs showed an overall association with breast cancer, an analysis of the ER status of the breast cancer patients revealed that the SIAH2 locus (rs6788895; P = 5.73×10−4, odds ratio [OR] = 0.81) is associated with ER-positive breast cancer. Conclusion: A common variant in the SIAH2 locus is associated with ER-positive breast cancer in the Chinese Han population. The replication of published GWAS results in other ethnic groups provides important information regarding the genetic etiology of breast cancer. [ABSTRACT FROM AUTHOR]

RNA polyadenylation (pA) is one of the major steps in regulation of gene expression at the posttranscriptional level. In this report, a genome landscape of pA sites of viral transcripts in B lymphocytes with Kaposi sarcoma-associated herpesvirus (KSHV) infection was constructed using a modified PA-seq strategy. We identified 67 unique pA sites, of which 55 could be assigned for expression of annotated ∼90 KSHV genes. Among the assigned pA sites, twenty are for expression of individual single genes and the rest for multiple genes (average 2.7 genes per pA site) in cluster-gene loci of the genome. A few novel viral pA sites that could not be assigned to any known KSHV genes are often positioned in the antisense strand to ORF8, ORF21, ORF34, K8 and ORF50, and their associated antisense mRNAs to ORF21, ORF34 and K8 could be verified by 3′RACE. The usage of each mapped pA site correlates to its peak size, the larger (broad and wide) peak size, the more usage and thus, the higher expression of the pA site-associated gene(s). Similar to mammalian transcripts, KSHV RNA polyadenylation employs two major poly(A) signals, AAUAAA and AUUAAA, and is regulated by conservation of cis-elements flanking the mapped pA sites. Moreover, we found two or more alternative pA sites downstream of ORF54, K2 (vIL6), K9 (vIRF1), K10.5 (vIRF3), K11 (vIRF2), K12 (Kaposin A), T1.5, and PAN genes and experimentally validated the alternative polyadenylation for the expression of KSHV ORF54, K11, and T1.5 transcripts. Together, our data provide not only a comprehensive pA site landscape for understanding KSHV genome structure and gene expression, but also the first evidence of alternative polyadenylation as another layer of posttranscriptional regulation in viral gene expression. [ABSTRACT FROM AUTHOR]

Objectives: To perform a meta-analysis assessing the ability of shear wave elastography (SWE) to identify malignant breast masses. Methods: PubMed, the Cochrane Library, and the ISI Web of Knowledge were searched for studies evaluating the accuracy of SWE for identifying malignant breast masses. The diagnostic accuracy of SWE was evaluated according to sensitivity, specificity, and hierarchical summary receiver operating characteristic (HSROC) curves. An analysis was also performed according to the SWE mode used: supersonic shear imaging (SSI) and the acoustic radiation force impulse (ARFI) technique. The clinical utility of SWE for identifying malignant breast masses was evaluated using analysis of Fagan plot. Results: A total of 9 studies, including 1888 women and 2000 breast masses, were analyzed. Summary sensitivities and specificities were 0.91 (95% confidence interval [CI], 0.88–0.94) and 0.82 (95% CI, 0.75–0.87) by SSI and 0.89 (95% CI, 0.81–0.94) and 0.91 (95% CI, 0.84–0.95) by ARFI, respectively. The HSROCs for SSI and ARFI were 0.92 (95% CI, 0.90–0.94) and 0.96 (95% CI, 0.93–0.97), respectively. SSI and ARFI were both very informative, with probabilities of 83% and 91%, respectively, for correctly differentiating between benign and malignant breast masses following a “positive” measurement (over the threshold value) and probabilities of disease as low as 10% and 11%, respectively, following a “negative” measurement (below the threshold value) when the pre-test probability was 50%. Conclusions: SWE could be used as a good identification tool for the classification of breast masses. [ABSTRACT FROM AUTHOR]

Background: Androgenetic alopecia (AGA) is a well-characterized type of progressive hair loss commonly seen in men, with different prevalences in different ethnic populations. It is generally considered to be a polygenic heritable trait. Several susceptibility genes/loci, such as AR/EDA2R, HDAC9 and 20p11, have been identified as being involved in its development in European populations. In this study, we aim to validate whether these loci are also associated with AGA in the Chinese Han population. Methods: We genotyped 16 previously reported single nucleotide polymorphisms (SNPs) with 445 AGA cases and 546 healthy controls using the Sequenom iPlex platform. The trend test was used to evaluate the association between these loci and AGA in the Chinese Han population. Conservatively accounting for multiple testing by the Bonferroni correction, the threshold for statistical significance was P ≤3.13×10−3. Results: We identified that 5 SNPs at 20p11 were significantly associated with AGA in the Chinese Han population (1.84×10−11≤P≤2.10×10−6). Conclusions: This study validated, for the first time, that 20p11 also confers risk for AGA in the Chinese Han population and implicated the potential common genetic factors for AGA shared by both Chinese and European populations. [ABSTRACT FROM AUTHOR]

Plant disease resistance genes are a key component of defending plants from a range of pathogens. The majority of these resistance genes belong to the super-family that harbors a Nucleotide-binding site (NBS). A number of studies have focused on NBS-encoding genes in disease resistant breeding programs for diverse plants. However, little information has been reported with an emphasis on systematic analysis and comparison of NBS-encoding genes in cotton. To fill this gap of knowledge, in this study, we identified and investigated the NBS-encoding resistance genes in cotton using the whole genome sequence information of Gossypium raimondii. Totally, 355 NBS-encoding resistance genes were identified. Analyses of the conserved motifs and structural diversity showed that the most two distinct features for these genes are the high proportion of non-regular NBS genes and the high diversity of N-termini domains. Analyses of the physical locations and duplications of NBS-encoding genes showed that gene duplication of disease resistance genes could play an important role in cotton by leading to an increase in the functional diversity of the cotton NBS-encoding genes. Analyses of phylogenetic comparisons indicated that, in cotton, the NBS-encoding genes with TIR domain not only have their own evolution pattern different from those of genes without TIR domain, but also have their own species-specific pattern that differs from those of TIR genes in other plants. Analyses of the correlation between disease resistance QTL and NBS-encoding resistance genes showed that there could be more than half of the disease resistance QTL associated to the NBS-encoding genes in cotton, which agrees with previous studies establishing that more than half of plant resistance genes are NBS-encoding genes. [ABSTRACT FROM AUTHOR]

Mutualisms are common in nature, though these symbioses can be quite permeable to cheaters in situations where one individual parasitizes the other by discontinuing cooperation yet still exploits the benefits of the partnership. In the Rhizobium-legume system, there are two separate contexts, namely nodulation and nitrogen fixation processes, by which resident Rhizobium individuals can benefit by cheating. Here, we constructed reversible and irreversible mutations in key nodulation and nitrogen-fixation pathways of Rhizobium etli and compared their interaction with plant hosts Phaseolus vulgaris to that of wild type. We show that R. etli reversible mutants deficient in nodulation factor production are capable of intra-specific cheating, wherein mutants exploit other Rhizobium individuals capable of producing these factors. Similarly, we show that R. etli mutants are also capable of cheating inter-specifically, colonizing the host legume yet contributing nothing to the partnership in terms of nitrogen fixation. Our findings indicate that cheating is possible in both of these frameworks, seemingly without damaging the stability of the mutualism itself. These results may potentially help explain observations suggesting that legume plants are commonly infected by multiple bacterial lineages during the nodulation process. [ABSTRACT FROM AUTHOR]

Delphinidin-3-glucoside (Dp) is a member of a family of bioactive compounds known as anthocyanins that occur naturally in pigmented plants and are known to ameliorate oxidative stress. Previous studies have showed that Dp decreased oxidative stress in vascular endothelial cells, however, the underlying mechanisms remain largely unknown. In the present study, we showed that pretreatment with Dp significantly suppressed oxidized low-density lipoprotein (oxLDL)-induced cell proliferation inhibition and apoptosis in primary human umbilical vein endothelial cells (HUVECs). Also, Dp pretreatment attenuated oxLDL-induced mitochondrial dysfunction via decreased reactive oxygen species (ROS) and superoxide anion generation, thereby repressing mitochondrial membrane potential and closing mitochondrial permeability transition pore. Furthermore, in vitro and in vivo data showed that Dp was transported into endothelial cells in a temperature, concentration, and time-dependent manner via the sodium-dependent glucose transporter (SGLT1). Suppression of SGLT1 by its substrate glucose, its inhibitor phlorizin or SGLT1 siRNA blocked Dp transportation. Repression of SGLT1 significantly inhibited Dp function of ameliorating mitochondrial dysfunction induced by pro-apoptotic factors (Apoptosis-inducing factor, Cytochrome c, Caspase-3 and Bax/Bcl-2 ratio). Taken together, our data indicate that Dp protects VECs via the SGLT1-ROS-mitochodria pathway. This new insight may help to elucidate the molecular mechanisms underlying the vascular protection afforded by Dp, and anthocyanins in general, in the context of prevention of endothelial dysfunction and atherosclerosis. [ABSTRACT FROM AUTHOR]

High-voltage spindles (HVSs) have been reported to appear spontaneously and widely in the cortical–basal ganglia networks of rats. Our previous study showed that dopamine depletion can significantly increase the power and coherence of HVSs in the globus pallidus (GP) and motor cortex of freely moving rats. However, it is unclear whether dopamine regulates HVS activity by acting on dopamine D1-like receptors or D2-like receptors. We employed local-field potential and electrocorticogram methods to simultaneously record the oscillatory activities in the GP and primary motor cortex (M1) in freely moving rats following systemic administration of dopamine receptor antagonists or saline. The results showed that the dopamine D2-like receptor antagonists, raclopride and haloperidol, significantly increased the number and duration of HVSs, and the relative power associated with HVS activity in the GP and M1 cortex. Coherence values for HVS activity between the GP and M1 cortex area were also significantly increased by dopamine D2-like receptor antagonists. On the contrary, the selective dopamine D1-like receptor antagonist, SCH23390, had no significant effect on the number, duration, or relative power of HVSs, or HVS-related coherence between M1 and GP. In conclusion, dopamine D2-like receptors, but not D1-like receptors, were involved in HVS regulation. This supports the important role of dopamine D2-like receptors in the regulation of HVSs. An siRNA knock-down experiment on the striatum confirmed our conclusion. [ABSTRACT FROM AUTHOR]

Although genome-wide association studies (GWAS) have identified a significant number of single-nucleotide polymorphisms (SNPs) associated with many complex human traits, the susceptibility loci identified so far can explain only a small fraction of the genetic risk. Among other possible explanations, the lack of a comprehensive examination of gene–gene interaction (G×G) is often considered a source of the missing heritability. Previously, we reported a model-free Generalized Multifactor Dimensionality Reduction (GMDR) approach for detecting G×G in both dichotomous and quantitative phenotypes. However, the computational burden and less efficient implementation of the original programs make them impossible to use for GWAS. In this study, we developed a graphics processing unit (GPU)-based GMDR program (named GWAS-GPU), which is able not only to analyze GWAS data but also to run much faster than the earlier version of the GMDR program. As a demonstration of the program, we used the GMDR-GPU software to analyze a publicly available GWAS dataset on type 2 diabetes (T2D) from the Wellcome Trust Case Control Consortium. Through an exhaustive search of pair-wise interactions and a selected search of three- to five-way interactions conditioned on significant pair-wise results, we identified 24 core SNPs in six genes (FTO: rs9939973, rs9940128, rs9922047, rs1121980, rs9939609, rs9930506; TSPAN8: rs1495377; TCF7L2: rs4074720, rs7901695, rs4506565, rs4132670, rs10787472, rs11196205, rs10885409, rs11196208; L3MBTL3: rs10485400, rs4897366; CELF4: rs2852373, rs608489; RUNX1: rs445984, rs1040328, rs990074, rs2223046, rs2834970) that appear to be important for T2D. Of these core SNPs, 11 in FTO, TSPAN8, and TCF7L2 have been reported to be associated with T2D, obesity, or both, providing an independent replication of previously reported SNPs. Importantly, we identified three new susceptibility genes; i.e., L3MBTL3, CELF4, and RUNX1, for T2D, a finding that warrants further investigation with independent samples. [ABSTRACT FROM AUTHOR]

Uptake through the Dopamine Transporter (DAT) is the primary mechanism of terminating dopamine signaling within the brain, thus playing an essential role in neuronal homeostasis. Deregulation of DAT function has been linked to several neurological and psychiatric disorders including ADHD, schizophrenia, Parkinson’s disease, and drug addiction. Over the last 15 years, several studies have revealed a plethora of mechanisms influencing the activity and cellular distribution of DAT; suggesting that fine-tuning of dopamine homeostasis occurs via an elaborate interplay of multiple pathways. Here, we show for the first time that the βγ subunits of G proteins regulate DAT activity. In heterologous cells and brain tissue, a physical association between Gβγ subunits and DAT was demonstrated by co-immunoprecipitation. Furthermore, in vitro pull-down assays using purified proteins established that this association occurs via a direct interaction between the intracellular carboxy-terminus of DAT and Gβγ. Functional assays performed in the presence of the non-hydrolyzable GTP analog GTP-γ-S, Gβγ subunit overexpression, or the Gβγ activator mSIRK all resulted in rapid inhibition of DAT activity in heterologous systems. Gβγ activation by mSIRK also inhibited dopamine uptake in brain synaptosomes and dopamine clearance from mouse striatum as measured by high-speed chronoamperometry in vivo. Gβγ subunits are intracellular signaling molecules that regulate a multitude of physiological processes through interactions with enzymes and ion channels. Our findings add neurotransmitter transporters to the growing list of molecules regulated by G-proteins and suggest a novel role for Gβγ signaling in the control of dopamine homeostasis. [ABSTRACT FROM AUTHOR]