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Damaged acinar cells play a passive role in activating pancreatic stellate cells (PSCs) via recruitment of immune cells that subsequently activate PSCs. However, whether acinar cells directly contribute to PSC activation is unknown. Here, we report that the Hippo pathway, a well-known regulator of proliferation, is essential for suppression of expression of inflammation and fibrosis-associated genes in adult pancreatic acinar cells. Hippo inactivation in acinar cells induced yes-associated protein 1 (YAP1)/transcriptional coactivator with PDZ binding motif (TAZ)-dependent, irreversible fibrosis and inflammation, which was initiated by Hippo-mediated acinar-stromal communications and ameliorated by blocking YAP1/TAZ target connective tissue growth factor (CTGF). Hippo disruption promotes acinar cells to secrete fibroinflammatory factors and induce stromal activation, which precedes acinar proliferation and metaplasia. We found that Hippo disruption did not induce cell-autonomous proliferation but primed acinar cells to exogenous pro-proliferative stimuli, implying a well-orchestrated scenario in which Hippo signaling acts as an intrinsic link to coordinate fibroinflammatory response and proliferation for maintenance of the tissue integrity. Our findings suggest that the fibroinflammatory program in pancreatic acinar cells is suppressed under normal physiological conditions. While transient activation of inflammatory gene expression during tissue injury may contribute to the control of damage and tissue repair, its persistent activation may result in tissue fibrosis and failure of regeneration. [ABSTRACT FROM AUTHOR]

The primary mode of visualization during transcatheter procedures for structrural heart disease is fluoroscopy, which suffers from low contrast and lacks any depth perception, thus limiting the ability of an interventionalist to position a catheter accurately. This paper describes a new image guidance system by utilizing augmented reality to provide a 3D visual environment and quantitative feedback of the catheter’s position within the heart of the patient. The real-time 3D position of the catheter is acquired via two fluoroscopic images taken at different angles, and a patient-specific 3D heart rendering is produced pre-operatively from a CT scan. The spine acts as a fiduciary land marker, allowing the position and orientation of the catheter within the heart to be fully registered. The automated registration method is based on Fourier transformation, and has a high success rate (100%), low registration error (0.42 mm), and clinically acceptable computational cost (1.22 second). The 3D renderings are displayed and updated on the augmented reality device (i.e., Microsoft HoloLens), which can provide pre-set views of various angles of the heart using voice-command. This new image-guidance system with augmented reality provides a better visualization to interventionalists and potentially assists them in understanding of complicated cases. Furthermore, this system coupled with the developed 3D printed models can serve as a training tool for the next generation of cardiac interventionalists. [ABSTRACT FROM AUTHOR]

Complete mitochondrial genomes play important roles in studying genome evolution, phylogenetic relationships, and species identification. Sea cucumbers (Holothuroidea) are ecologically important and diverse members, living from the shallow waters to the hadal trench. In this study, we present the mitochondrial genome sequence of the sea cucumber Benthodytes marianensis collected from the Mariana Trench. To our knowledge, this is the first reported mitochondrial genome from the genus Benthodytes. This complete mitochondrial genome is 17567 bp in length and consists of 13 protein-coding genes, two ribosomal RNA genes and 22 transfer RNA genes (duplication of two tRNAs: trnL and trnS). Most of these genes are coded on the positive strand except for one protein-coding gene (nad6) and five tRNA genes which are coded on the negative strand. Two putative control regions (CRs) have been found in the B. marianensis mitogenome. We compared the order of genes from the 10 available holothurian mitogenomes and found a novel gene arrangement in B. marianensis. Phylogenetic analysis revealed that B. marianensis clustered with Peniagone sp. YYH-2013, forming the deep-sea Elasipodida clade. Positive selection analysis showed that eleven residues (24 S, 45 S, 185 S, 201 G, 211 F and 313 N in nad2; 108 S, 114 S, 322 C, 400 T and 427 S in nad4) were positively selected sites with high posterior probabilities. We predict that nad2 and nad4 may be the important candidate genes for the further investigation of the adaptation of B. marianensis to the deep-sea environment. [ABSTRACT FROM AUTHOR]

Pharmaceutical sludge is considered as a hazardous material with high treatment and disposal costs. In the present study, the catalytic wet oxidation (CWO) of pharmaceutical sludge by CuO-CeO2/γ-Al2O3 as the catalyst was investigated. The catalyst was prepared by traditional wet impregnation. The catalyst was characterized using X-ray Powder Diffraction (XRD) and Scanning Electron Microscopy (SEM). CWO was performed in an experimental batch reactor. Several parameters that could affect the catalytic degradation efficiency, including catalyst dose, temperature, time, oxygen pressure and pH, were investigated. Under optimum conditions, the highest removal rate of volatile suspended solids (VSS) was 87.3% and was achieved at 260°C for 60 min with an oxygen pressure of 1.0 MPa and 10 g/L of catalyst. At the same time, the chemical oxygen demand (COD) removal rate reached as high as 72.6%. This work implies that catalytic wet oxidation is a promising method for the highly efficient degradation of pharmaceutical sludge. [ABSTRACT FROM AUTHOR]

Chinese mitten crabs (Eriocheir japonica sinensis) are catadromous, spending most of their lives in fresh water, but moving to a mixed salt-fresh water environment for reproduction. The characteristics of this life history might imply a rapidly evolutionary transition model for adaptation to marine from freshwater habitats. In this study, transcriptome-wide identification and differential expression on Chinese mitten crab groups were analysed. Results showed: clean reads that were obtained totalled 93,833,096 (47,440,998 in Group EF, the reference, and 46,392,098 in Group ES, the experimental) and 14.08G (7.12G in Group EF 6.96G in Group ES); there were 11,667 unigenes (15.29%) annotated, and they were located to 230 known KEGG pathways in five major categories; in differential expression analysis, most of the top 20 up-regulated pathways were connected to the immune system, disease, and signal transduction, while most of the top 20 down-regulated pathways were related to the metabolism system; meanwhile, 8 representative osmoregulation-related genes (14-3-3 epsilon, Cu2+ transport ATPase, Na+/K+ ATPase, Ca2+ transporting ATPase, V-ATPase subunit A, Putative arsenite-translocating ATPase, and Cation transport ATPase, Na+/K+ symporter) showed up-regulation, and 1 osmoregulation-related gene (V-ATPase subunit H) showed down-regulation. V-ATPase subunit H was very sensitive to the transition of habitats. These results were consistent with the tests of qRT-PCR. The present study has provided a foundation to further understand the molecular mechanism in response to salinity changing in water. [ABSTRACT FROM AUTHOR]

Plant microRNAs (miRNAs) are a class of non-coding RNAs that play important roles in plant development, defense, and symptom development. Here, 547 known miRNAs representing 129 miRNA families, and 282 potential novel miRNAs were identified in Beta macrocarpa using small RNA deep sequencing. A phylogenetic analysis was performed, and 8 Beta lineage-specific miRNAs were identified. Through a differential expression analysis, miRNAs associated with Beet necrotic yellow vein virus (BNYVV) infection were identified and confirmed using a microarray analysis and stem-loop RT-qPCR. In total, 103 known miRNAs representing 38 miRNA families, and 45 potential novel miRNAs were differentially regulated, with at least a two-fold change, in BNYVV-infected plants compared with that of the mock-inoculated control. Targets of these differentially expressed miRNAs were also predicted by degradome sequencing. These differentially expressed miRNAs were involved in hormone biosynthesis and signal transduction pathways, and enhanced axillary bud development and plant defenses. This work is the first to describe miRNAs of the plant genus Beta and may offer a reference for miRNA research in other species in the genus. It provides valuable information on the pathogenicity mechanisms of BNYVV. [ABSTRACT FROM AUTHOR]

Whitebark pine (WBP, Pinus albicaulis Engelm.) is an endangered conifer species due to heavy mortality from white pine blister rust (WPBR, caused by Cronartium ribicola) and mountain pine beetle (Dendroctonus ponderosae). Information about genetic diversity and population structure is of fundamental importance for its conservation and restoration. However, current knowledge on the genetic constitution and genomic variation is still limited for WBP. In this study, an integrated genomics approach was applied to characterize seed collections from WBP breeding programs in western North America. RNA-seq analysis was used for de novo assembly of the WBP needle transcriptome, which contains 97,447 protein-coding transcripts. Within the transcriptome, single nucleotide polymorphisms (SNPs) were discovered, and more than 22,000 of them were non-synonymous SNPs (ns-SNPs). Following the annotation of genes with ns-SNPs, 216 ns-SNPs within candidate genes with putative functions in disease resistance and plant defense were selected to design SNP arrays for high-throughput genotyping. Among these SNP loci, 71 were highly polymorphic, with sufficient variation to identify a unique genotype for each of the 371 individuals originating from British Columbia (Canada), Oregon and Washington (USA). A clear genetic differentiation was evident among seed families. Analyses of genetic spatial patterns revealed varying degrees of diversity and the existence of several genetic subgroups in the WBP breeding populations. Genetic components were associated with geographic variables and phenotypic rating of WPBR disease severity across landscapes, which may facilitate further identification of WBP genotypes and gene alleles contributing to local adaptation and quantitative resistance to WPBR. The WBP genomic resources developed here provide an invaluable tool for further studies and for exploitation and utilization of the genetic diversity preserved within this endangered conifer and other five-needle pines. [ABSTRACT FROM AUTHOR]

Background: A key challenge in thyroid carcinoma is preoperatively diagnosing malignant thyroid nodules. A novel diagnostic test that measures the expression of a 3-gene signature (DPP4, SCG5 and CA12) has demonstrated promise in thyroid carcinoma assessment. However, more reliable prediction methods combining clinical features with genomic signatures with high accuracy, good stability and low cost are needed. Methodology/Principal Findings: 25 clinical information were recorded in 771 patients. Feature selection and validation were conducted using random forest. Thyroid samples and clinical data were obtained from 142 patients at two different hospitals, and expression of the 3-gene signature was measured using quantitative PCR. The predictive abilities of three models (based on the selected clinical variables, the gene expression profile, and integrated gene expression and clinical information) were compared. Seven clinical characteristics were selected based on a training set (539 patients) and tested in three test sets, yielding predictive accuracies of 82.3% (n = 232), 81.4% (n = 70), and 81.9% (n = 72). The predictive sensitivity, specificity, and accuracy were 72.3%, 80.5% and 76.8% for the model based on the gene expression signature, 66.2%, 81.8% and 74.6% for the model based on the clinical data, and 83.1%, 84.4% and 83.8% for the combined model in a 10-fold cross-validation (n = 142). Conclusions: These findings reveal that the integrated model, which combines clinical data with the 3-gene signature, is superior to models based on gene expression or clinical data alone. The integrated model appears to be a reliable tool for the preoperative diagnosis of thyroid tumors. [ABSTRACT FROM AUTHOR]

Special value of goat milk in human nutrition and well being is associated with medical problems of food allergies which are caused by milk proteins such as β-lactoglobulin (BLG). Here, we employed transcription activator-like effector nuclease (TALEN)-assisted homologous recombination in goat fibroblasts to introduce human α-lactalbumin (hLA) genes into goat BLG locus. TALEN-mediated targeting enabled isolation of colonies with mono- and bi-allelic transgene integration in up to 10.1% and 1.1%, respectively, after selection. Specifically, BLG mRNA levels were gradually decreasing in both mo- and bi-allelic goat mammary epithelial cells (GMECs) while hLA demonstrated expression in GMECs in vitro. Gene-targeted fibroblast cells were efficiently used in somatic cell nuclear transfer, resulting in production of hLA knock-in goats directing down-regulated BLG expression and abundant hLA secretion in animal milk. Our findings provide valuable background for animal milk optimization and expedited development for agriculture and biomedicine. [ABSTRACT FROM AUTHOR]

The white pine blister rust (WPBR) fungus Cronartium ribicola (J.C. Fisch.) is an exotic invasive forest pathogen causing severe stem canker disease of native white pine trees (subgenus Strobus) in North America. The present study reports discovery of five novel mitoviruses in C. ribicola by deep RNA sequencing. The complete genome of each mitovirus was determined by rapid amplification of cDNA ends (RACE) and reverse transcriptase-polymerase chain reaction (RT-PCR). A single open reading frame (ORF) encoding a putative RNA-dependent RNA polymerase (RdRp) was detected in each of the viral genomes using mitochondrial genetic codes. Phylogenetic analysis indicated that the C. ribicola mitoviruses (CrMV1 to CrMV5) are new putative species of the genus Mitovirus. qRT-PCR and RNA-Seq analyses revealed that viral RNAs were significantly increased in fungal mycelia in cankered pine stems compared to expression during two different stages of spore development, suggesting that viral genome replication and transcription benefit from active growth of the host fungus. CrMVs were widespread with relatively high levels of minor allele frequency (MAF) in western North America. As the first report of mitoviruses in the Class Pucciniomycetes, this work allows further investigation of the dynamics of a viral community in the WPBR pathosystem, including potential impacts that may affect pathogenicity and virulence of the host fungus. [ABSTRACT FROM AUTHOR]

A sensitive, effective and optimized method, based on ultra performance liquid chromatography (UPLC) coupled with ESI-triple quadrupole ion MS and ESI-linear ion trap high-resolution MS, has been developed for the simultaneous quantitative and qualitative determination of phenolics, nucleosides and amino acids in the roots of fresh Gastrodia elata. Optimization of the analytical method provided higher separation efficiency and better peak resolution for the targeted compounds. The simultaneous separation protocols were also optimized by routinely using accurate mass measurements, within 5 ppm error, for each molecular ion and the subsequent fragment ions. In total, 31 compounds, including 23 phenolics, two nucleosides, four amino acids, one gastrodin and one other compound were identified or tentatively characterized. Mono-substituted parishin glucoside (9), methoxy mono-substituted parishin (13), methyl parishin (26), p-hydroxybenzyl di-substituted parishin (29), and p-hydroxybenzyl parishin (31) were tentatively identified as new compounds. Principal metabolite content analysis and the composition of eight representative G. elata cultivars of various species indicated that geographic insulation was the main contributor to clustering. [ABSTRACT FROM AUTHOR]

Nedaplatin, a cisplatin analog, was developed to reduce the toxicity of cisplatin, whereas it can be cross-resistant with cisplatin in some circumstances. This study aimed to investigate the role of autophagy in nedaplatin induced cell death in cisplatin-resistant nasopharyngeal carcinoma cells. Here, we showed that HNE1/DDP and CNE2/DDP cells were resistant to nedaplatin-induced cell death with reduced apoptotic activity. Nedaplatin treatment resulted in autophagosome accumulation and increased expression of LC3-II, indicating the induction of autophagy by nedaplatin in HNE1/DDP and CNE2/DDP cells. Inhibition of autophagy by Bafilomycin A1 (Baf A1) and 3-Methyladenine (3-MA) remarkably enhanced the antitumor efficacy of nedaplatin in HNE1/DDP and CNE2/DDP cells, suggesting that the resistance to nedaplatin-induced cell death was caused by enhanced autophagy in nedaplatin-resistant NPC cells. Additionally, Baf A1 enhanced reactive oxygen species (ROS) generation and apoptosis induced by nedaplatin in HNE1/DDP cells. Mechanistically, nedaplatin treatment caused activation of ERK1/2 and suppression of Akt/mTOR signaling pathways. While inhibition of ERK1/2 by MEK1/2 inhibitor, U0126, could reduce the expression of LC3-II in nedaplatin-resistant NPC cells. Furthermore, suppression of ROS could inhibit nedaplatin-induced ERK activation in HNE1/DDP cells, indicating that ROS and ERK were involved in nedaplatin-induced autophagy. Together, these findings suggested that autophagy played a cytoprotective role in nedaplatin-induced cytotoxicity of HNE1/DDP and CNE2/DDP cells. Furthermore, our results highlighted a potential approach to restore the sensitivity of cisplatin-resistant nasopharyngeal cancer cells to nedaplatin in combination with autophagy inhibitors. [ABSTRACT FROM AUTHOR]

Procedural models are widely used in computer graphics for generating realistic, natural-looking textures. However, these mathematical models are not perceptually meaningful, whereas the users, such as artists and designers, would prefer to make descriptions using intuitive and perceptual characteristics like "repetitive," "directional," "structured," and so on. To make up for this gap, we investigated the perceptual dimensions of textures generated by a collection of procedural models. Two psychophysical experiments were conducted: free-grouping and rating. We applied Hierarchical Cluster Analysis (HCA) and Singular Value Decomposition (SVD) to discover the perceptual features used by the observers in grouping similar textures. The results suggested that existing dimensions in literature cannot accommodate random textures. We therefore utilized isometric feature mapping (Isomap) to establish a three-dimensional perceptual texture space which better explains the features used by humans in texture similarity judgment. Finally, we proposed computational models to map perceptual features to the perceptual texture space, which can suggest a procedural model to produce textures according to user-defined perceptual scales. [ABSTRACT FROM AUTHOR]

TNFAIP3 is a ubiquitin-editing enzyme that negatively regulates multiple NF-κB signaling pathways and dysregulation of TNFAIP3 is related to systemic lupus erythematosus (SLE). Although there exists evidence indicating that microRNAs (miRNAs) modulate the expression of TNFAIP3, whether and how miRNAs regulate TNFAIP3 and contribute to lupus nephritis (LN) is still not well understood. In this study, we screened eleven selected miRNAs that potentially regulated TNFAIP3 expression by dual luciferase assay and found that Let-7 miRNAs repressed TNFAIP3 expression by targeting the 3′UTR of TNFAIP3 mRNA. Overexpression of Let-7 miRNAs led to increased phosphorylation and sustained degradation of IκBα and enhanced phosphorylation of p65 following TNFα stimulation and promoted SeV-induced production of cytokines in HEK293T cells. In addition, the expression of Let-7 miRNAs was significantly up-regulated, and TNFAIP3 level was remarkably down-regulated in samples from LN patients compared control samples. Our findings have uncovered Let-7-TNFAIP3-NF-κB pathway that is involved in LN and thus provided a potential target for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Purpose: Programmed Death-1 (PD-1) and its ligand, PD-L1, are regulators of immune/ inflammatory mechanisms. We explored the potential involvement of PD-1/PD-L1 pathway in the inflammatory response and tissue damage in cardiac injury models. Experimental Design: Ischemic-reperfused and cryoinjured hearts were processed for flow cytometry and immunohistochemical studies for determination of cardiac PD-1 and PD-L1 in the context of assessment of the growth arrest- and DNA damage-inducible protein 153 (GADD153) which regulates both inflammation and cell death. Further, we explored the potential ability of injured cardiac cells to influence proliferation of T lymphocytes. Results: The isolated ischemic-reperfused hearts displayed marked increases in expression of PD-1 and PD-L1 in cardiomyocytes; however, immunofluorescent studies indicate that PD-1 and PD-L1 are not primarily co-expressed on the same cardiomyocytes. Upregulation of PD-1/PD-L1 was associated with a) marked increases in GADD153 and interleukin (IL)-17 but a mild increase in IL-10 and b) disruption of mitochondrial membrane potential (ψm) as well as apoptotic and necrotic cell death. Importantly, while isotype matching treatment did not affect the aforementioned changes, treatment with the PD-L1 blocking antibody reversed those effects in association with marked cardioprotection. Further, ischemic-reperfused cardiac cells reduced proliferation of T lymphocytes, an effect partially reversed by PD-L1 antibody. Subsequent studies using the cryoinjury model of myocardial infarction revealed significant increases in PD-1, PD-L1, GADD153 and IL-17 positive cells in association with significant apoptosis/necrosis. Conclusions: The data suggest that upregulation of PD-1/PD-L1 pathway in cardiac injury models mediates tissue damage likely through a paracrine mechanism. Importantly, inhibition of T cell proliferation by ischemic-reperfused cardiac cells is consistent with the negative immunoregulatory role of PD-1/PD-L1 pathway, likely reflecting an endogenous cardiac mechanism to curtail the deleterious impact of infiltrating immune cells to the damaged myocardium. The balance of these countervailing effects determines the extent of cardiac injury. [ABSTRACT FROM AUTHOR]

Cryopreservation is a key technology in biology and clinical practice. This paper presents a digital microfluidic device that automates sample preparation for mammalian embryo vitrification. Individual micro droplets manipulated on the microfluidic device were used as micro-vessels to transport a single mouse embryo through a complete vitrification procedure. Advantages of this approach, compared to manual operation and channel-based microfluidic vitrification, include automated operation, cryoprotectant concentration gradient generation, and feasibility of loading and retrieval of embryos. [ABSTRACT FROM AUTHOR]

KIF20A (Kinesin-like family member 20A), also called mitotic kinesin-like proteins 2 (MKLP2), is a mammalian mitotic kinesin-like motor protein of the Kinesin superfamily proteins (KIFs), which was originally involved in Golgi apparatus dynamics and thought to essential for cell cycle regulation during successful cytokinesis. In the present study, we investigated whether KIF20A has roles on porcine oocyte meiotic maturation and subsequent early embryo development. By immunofluorescence staining, KIF20A was found to exhibit a dynamic localization pattern during meiosis. KIF20A was restricted to centromeres after germinal vesicle breakdown (GVBD), transferred to the midbody at telophase I (TI), and again associated with centromeres at metaphase II (MII). Inhibition of endogenous KIF20A via a specific inhibitor, Paprotrain, resulted in failure of polar body extrusion. Further cell cycle analysis showed that the percentage of oocytes that arrested at early metaphase I (MI) stage increased after KIF20A activity inhibition; however, the proportion of oocytes at anaphase/telophase I (ATI) and MII stages decreased significantly. Our results also showed that KIF20A inhibition did not affect spindle morphology. In addition, KIF20A was localized at the nucleus of early embryos, and KIF20A inhibition resulted in failure of early parthenogenetic embryo development. These results demonstrated that KIF20A is critical for porcine oocyte meiotic maturation and subsequent early embryo development. [ABSTRACT FROM AUTHOR]

Background: Cysteine-rich 61/connective tissue growth factor/nephroblastoma overexpressed (CCN) 3 has been recently reported to play a role in regulating inflammation of vascular endothelial cells. However, the role of CCN3 in atherosclerosis, which is characterized by vascular inflammation, remains unclear. Hypothesis and Objectives: Overexpression of CCN3 may relieve the inflammation response in and inhibit the progress of atherosclerosis. We aimed to explore the potential roles of CCN3 in inflammation in atherosclerosis. Strategy and Main Results: In in vitro studies using cultured human aortic endothelial cells and human umbilical vein endothelial cells, CCN3 mRNA and protein expression significantly decreased in response to tumor necrosis factor-α and interleukin-1β treatments (p<0.05), when analyzed by quantitative real-time polymerase chain reaction and Western blot. Using a mouse model of atherosclerosis, the mRNA and protein levels of CCN3 decreased by 72.2% (p = 0.041) and 86.4% (p = 0.036), respectively, compared with levels in wild-type control mice, respectively. Overexpression of CCN3 by adenovirus-mediated gene overexpression decreased low-density lipoprotein cholesterol by 48.9% (p = 0.017), total cholesterol by 58.9% (p = 0.031), and triglycerides by 56.8% (p = 0.022), and it increased high-density lipoprotein cholesterol level by 2.16-fold (p = 0.039), compared with control groups. Additionally, a reduced plaque area and increased fibrous cap were observed (p<0.05). Furthermore, CCN3 overexpression decreased cell adhesion molecule-1 mRNA expression by 84.7% (p = 0.007) and intercellular adhesion molecule-1 mRNA expression by 61.2% (p = 0.044). Inflammatory factors, including matrix metalloproteinases, cyclooxygenase 2, and tissue factor also significantly (p<0.05) decreased with CCN3 overexpression in the atherosclerotic mouse model. Additionally, CCN1 and CCN2, which have been reported to be highly expressed in aortic atherosclerotic plaques, were significantly downregulated (p<0.05) by CCN3 overexpression. Conclusion: CCN3 overexpression is associated with control of inflammatory processes and reversion of dyslipidemia in the process of atherosclerosis, which implies that CCN3 may be a promising target in the treatment of atherosclerosis. [ABSTRACT FROM AUTHOR]

Background: No specific antiviral agent against hand foot and mouth disease (HFMD) is available for clinical practice today. Objective: To evaluate the efficacy and safety of Jinzhen oral solution in treating uncomplicated HFMD. Methods: In this randomized, double-blind, placebo-controlled trial, 399 children aged 1 to 7 years with laboratory confirmed HFMD were randomized to receive Jinzhen oral liquid or placebo 3 times daily for 7 days with a 3-day follow-up. The primary outcomes were time to the first disappearance of oral ulcers and vesicles on hand or foot and time to the first normalization of temperature (fever clearance). Results: There were 199 children enrolling into the Jinzhen group including 79 with fever and 200 into the placebo group including 93 with fever. Jinzhen reduced the time to the first disappearance of oral ulcers and vesicles on hand or foot to 4.9 days (95% CI, 4.6 to 5.2 days), compared with 5.7 days (95% CI, 5.4 to 6.0 days) in the placebo group (P = 0.0036). The median time of fever clearance was shorter in the 79 children who received Jinzhen (43.41 hrs, 95% CI, 37.05 to 49.76) than that in the 93 children who received placebo (54.92 hrs, 95% CI, 48.16 to 61.68) (P = 0.0161). Moreover, Jinzhen reduced the risk of symptoms by 28.5% compared with placebo (HR, 0.7150, 95% CI, 0.5719 to 0.8940, P = 0.0032). More importantly, treatment failure rate was significantly lower in the Jinzhen group (8.04%) compared with that in the placebo group (15.00%) (P = 0.0434). The incidence of serious adverse events did not differ significantly between the two groups (9 in Jinzhen group vs. 18 in placebo, P = 0.075). Conclusions: Children with HFMD may benefit from Jinzhen oral liquid treatment as compared with placebo. Trial Registration: Chinese Clinical Trial Registry (http://www.chictr.org/en/) ChiCTR-TRC-10000937 [ABSTRACT FROM AUTHOR]

Fear behaviors and fear memories in rodents have been traditionally assessed by the amount of freezing upon the presentation of conditioned cues or unconditioned stimuli. However, many experiences, such as encountering earthquakes or accidental fall from tree branches, may produce long-lasting fear memories but are behaviorally difficult to measure using freezing parameters. Here, we have examined changes in heartbeat interval dynamics as physiological readout for assessing fearful reactions as mice were subjected to sudden air puff, free-fall drop inside a small elevator, and a laboratory-version earthquake. We showed that these fearful events rapidly increased heart rate (HR) with simultaneous reduction of heart rate variability (HRV). Cardiac changes can be further analyzed in details by measuring three distinct phases: namely, the rapid rising phase in HR, the maximum plateau phase during which HRV is greatly decreased, and the recovery phase during which HR gradually recovers to baseline values. We showed that durations of the maximum plateau phase and HR recovery speed were quite sensitive to habituation over repeated trials. Moreover, we have developed the fear resistance index based on specific cardiac response features. We demonstrated that the fear resistance index remained largely consistent across distinct fearful events in a given animal, thereby enabling us to compare and rank individual mouse’s fear responsiveness among the group. Therefore, the fear resistance index described here can represent a useful parameter for measuring personality traits or individual differences in stress-susceptibility in both wild-type mice and post-traumatic stress disorder (PTSD) models. [ABSTRACT FROM AUTHOR]

Objective: To compare the accuracy of ultrasonography (US) with the current clinical standard of endoscopy for a diagnosis of nasopharyngeal carcinoma (NPC). Methods: A total of 150 patients suspected of having NPC underwent US and endoscopy. A diagnosis was obtained from an endoscopic biopsy collected from each suspected tumor and was compared with a biopsy obtained from a normal nasopharynx. The diagnostic accuracy of US and endoscopy for NPC was evaluated using receiver operating curve (ROC) analysis performed by MedCalc Software. Results: The sensitivity, specificity, and accuracy of US versus endoscopy for this cohort were 90.1%, 84.8%, and 87.3% for US, and 88.7%, 97.5%, and 93.3% for endoscopy, respectively. Both US and endoscopy exhibited good diagnostic accuracy for NPC with area under the curve (AUC) values of 0.929 and 0.938, respectively. However, this difference was not significant (Z = 0.36, P = 0.72). Conclusion: US is a useful tool for the detection of tumors in endoscopically suspicious nasopharynx tissues, and also for the detection of subclinical tumors in endoscopically normal nasopharynx tissues. [ABSTRACT FROM AUTHOR]

A rare subset of IL-10-producing B cells, named regulatory B cells (Bregs), suppresses adaptive immune responses and inflammation in mice. In this study, we examined the role of IL-10-producing B cells in HIV-1 infection. Compared to uninfected controls, IL-10-producing B cell frequencies were elevated in both blood and sigmoid colon during the early and chronic phase of untreated HIV-1 infection. Ex vivo IL-10-producing B cell frequency in early HIV-1 infection directly correlated with viral load. IL-10-producing B cells from HIV-1 infected individuals were enriched in CD19+TIM-1+ B cells and were enriched for specificity to trimeric HIV-1 envelope protein. Anti-retroviral therapy was associated with reduced IL-10-producing B cell frequencies. Treatment of B cells from healthy donors with microbial metabolites and Toll-like receptor (TLR) agonists could induce an IL-10 producing phenotype, suggesting that the elevated bacterial translocation characteristic of HIV-1 infection may promote IL-10-producing B cell development. Similar to regulatory B cells found in mice, IL-10-producing B cells from HIV-1-infected individuals suppressed HIV-1-specific T cell responses in vitro, and this suppression is IL-10-dependent. Also, ex vivo IL-10-producing B cell frequency inversely correlated with contemporaneous ex vivo HIV-1-specific T cell responses. Our findings show that IL-10-producing B cells are induced early in HIV-1 infection, can be HIV-1 specific, and are able to inhibit effective anti-HIV-1 T cell responses. HIV-1 may dysregulate B cells toward Bregs as an immune evasion strategy. [ABSTRACT FROM AUTHOR]

This study investigated the effects of dietary glutamine (Gln) on T-helper (Th) and T regulatory (Treg) cell homeostasis and colonic inflammatory mediator expression in mice with dextran sulfate sodium (DSS)-induced colitis. Mice were randomly assigned to 4 groups with 2 normal control (C and G) and 2 DSS-treated groups (DC and DG). The C and DC groups were fed a common semipurified diet, while the G and DG groups received an identical diet except that part of the casein was replaced by Gln, which provided 25% of the total amino acid nitrogen. Mice were fed the diets for 10 days. On day 6, mice in the normal control groups were given distilled water, while those in the DSS groups were given distilled water containing 1.5% DSS for 5 d. At the end of the experiment, the mice were sacrificed for further examination. Results showed that DC group had higher plasma haptoglobin, colonic weight, immunoglobulin G, inflammatory cytokine and nuclear factor (NF)-κB protein levels. Gln administration lowered inflammatory mediators and NF-κB/IκBα ratio in colitis. Compared with the DC group, the percentages of interleukin-17F and interferon-γ in blood and transcription factors, T-bet and RAR-related orphan receptor-γt, gene expressions in mesenteric lymph nodes were lower, whereas blood Foxp3 was higher in the DG group. Also, DG group had lower colon injury score. These results suggest that Gln administration suppressed Th1/Th17 and Th-associated cytokine expressions and upregulated the expression of Tregs, which may modulate the balance of Th/Treg and reduce inflammatory reactions in DSS-induced colitis. [ABSTRACT FROM AUTHOR]

Objective: CYP4A11 oxidizes endogenous arachidonic acid to 20-hydroxyeicosatetraenoic acid, a renal vasoconstrictor and natriuretic in humans. Previous studies demonstrated an association between a functional variant (T8590C) of CYP4A11 and essential hypertension, though with conflicting results. To elucidate this relationship, a case-control study and meta-analysis were performed to assess the possible association of essential hypertension with CYP4A11 genetic variations. Methods: Associations between the T8590C polymorphism and essential hypertension were examined in 328 unrelated cases and 297 age-matched controls in Han Chinese individuals. High-resolution melting was used to identify the CYP4A11 variant. To further investigate the association, we conducted a meta-analysis including eight studies published previously in July 2012. Results: The frequency of the CYP4A11 T8590C polymorphism showed no significant difference between cases and controls (all P>0.05). However, the meta-analysis showed that the CYP4A11 T8590C polymorphism may increase the risk of essential hypertension in an additive model (OR: 1.15, 95% CI: 1.02–1.29, P = 0.02), a dominant model (OR: 1.06, 95% CI: 1.01–1.32, P = 0.03), a recessive model (OR: 1.52, 95% CI: 1.15–2.02, P = 0.003) and a homozygote contrast (OR: 1.38, 95% CI: 1.07–1.78, P = 0.01). Also, a significant relationship was observed among Caucasians in the additive model, the homozygote contrast, the recessive model and the dominant model (all P<0.05). However, no association was observed in an Asian population (all P>0.05). Conclusions: This meta-analysis suggests there is a significant association between the CYP4A11 T8590C variant and essential hypertension, especially in Caucasians. The case-control study did not find a significant association among the Han Chinese population, but the controls were poorly matched and meaningful conclusions cannot therefore be made. Further large-scale studies are needed to clarify whether the CYP4A11 T8590C polymorphism is associated with hypertension risk in Asians or has a gender-specific effect. [ABSTRACT FROM AUTHOR]

Background: Growing evidence indicates that advanced glycation end-product receptor (RAGE) might play a contributory role in the pathogenesis of coronary artery disease (CAD). To shed some light from a genetic perspective, we sought to investigate the interactive association of RAGE gene four common polymorphisms (rs1800625 or T-429C, rs1800624 or T-374A, rs2070600 or Gly82Ser, and rs184003 or G1704A) with the risk of developing CAD in a large northeastern Han Chinese population. Methodology/Principal Findings: This was a hospital-based case-control study incorporating 1142 patients diagnosed with CAD and 1106 age- and gender-matched controls. All individuals were angiographically confirmed. Risk estimates were expressed as odds ratio (OR) and 95% confidence interval (CI). Overall there were significant differences in the genotype and allele distributions of rs1800625 and rs184003, even after the Bonferroni correction. Logistic regression analyses indicated that rs1800625 and rs184003 were associated with significant risk of CAD under both additive (OR = 1.20 and 1.23; 95% CI: 1.06–1.37 and 1.06–1.42; P = 0.006 and 0.008) and recessive (OR = 1.75 and 2.39; 95% CI: 1.28–2.40 and 1.47–3.87; P<0.001 and <0.001) models after adjusting for confounders. In haplotype analyses, haplotypes C-T-G-G and T-A-G-T (alleles in order of rs1800625, rs1800624, rs2070600 and rs184003), overrepresented in patients, were associated with 52% (95% CI: 1.19–1.87; P = 0.0052) and 63% (95% CI: 1.14–2.34; P = 0.0075) significant increases in adjusted risk for CAD. Further interactive analyses identified an overall best multifactor dimensionality reduction (MDR) model including rs1800625 and rs184003. This model had a maximal testing accuracy of 0.6856 and a cross-validation consistency of 10 out of 10 (P = 0.0016). The validity of this model was substantiated by classical Logistic regression analysis. Conclusions: Our findings provided strong evidence for the potentially contributory roles of RAGE multiple genetic polymorphisms, especially in the context of locus-to-locus interaction, in the pathogenesis of CAD among northeastern Han Chinese. [ABSTRACT FROM AUTHOR]

Background: Conflicting results have been reported on the association of the Pro12Ala polymorphism of the PPARγ2 gene with the risk of type 2 diabetes or obesity. Methods and Findings: A total of 3146 subjects with 1145 cases of type 2 diabetes and 2001 healthy controls were included in the study. Genomic DNA was obtained from blood samples and the screening for the gene polymorphisms was done using an allelic discrimination assay-by-design TaqMan method. Overall, the Ala allele frequency was 5.6% in control subjects and 3.9% in diabetes subjects (P = 0.023). We found a statistically significant association of carriers of the Ala allele with greater homoeostasis model assessment of beta cell function index in all subjects (P = 0.046). After controlling for confounders, carriers of the Ala allele had a decreased risk of diabetes compared with noncarriers [odds ratio (OR) 0.64, 95% confidence interval (CI) 0.49–0.83; P = 0.001]. A beneficial effect of the Ala allele was also observed for obesity (OR 0.64, 95% CI 0.42–0.96; P = 0.030). Conclusion: Our results suggested that the presence of the Ala allele may contribute to improved insulin secretory capacity and may confer protection from type 2 diabetes and obesity in the Chinese population. [ABSTRACT FROM AUTHOR]

The present study was conducted to determine whether recombinant human β-defensin-3 (rHBD3) in the milk of transgenic goats has an anti-bacterial activity against Escherichia coli (E. coli), Staphylococcus aureus (S. aureus) and Streptococcus agalactiae (S. agalactiae) that could cause mastitis. A HBD3 mammary-specific expression vector was transfected by electroporation into goat fetal fibroblasts which were used to produce fourteen healthy transgenic goats by somatic cell nuclear transfer. The expression level of rHBD3 in the milk of the six transgenic goats ranged from 98 to 121 µg/ml at 15 days of lactation, and was maintained at 90–111 µg/ml during the following 2 months. Milk samples from transgenic goats showed an obvious inhibitory activity against E. coli, S. aureus and S. agalactiae in vitro. The minimal inhibitory concentrations of rHBD3 in milk against E. coli, S. aureus and S. agalactiae were 9.5–10.5, 21.8–23.0 and 17.3–18.5 µg/mL, respectively, which was similar to those of the HBD3 standard (P>0.05). The in vivo anti-bacterial activities of rHBD3 in milk were examined by intramammary infusion of viable bacterial inoculums. We observed that 9/10 and 8/10 glands of non-transgenic goats infused with S. aureus and E. coli became infected. The mean numbers of viable bacteria went up to 2.9×103 and 95.4×103 CFU/ml at 48 h after infusion, respectively; the mean somatic cell counts (SCC) in infected glands reached up to 260.4×105 and 622.2×105 cells/ml, which were significantly higher than the SCC in uninfected goat glands. In contrast, no bacteria was presented in glands of transgenic goats and PBS-infused controls, and the SSC did not significantly change throughout the period. Moreover, the compositions and protein profiles of milk from transgenic and non-transgenic goats were identical. The present study demonstrated that HBD3 were an effective anti-bacterial protein to enhance the mastitis resistance of dairy animals. [ABSTRACT FROM AUTHOR]

Heart physiology is a highly useful indicator for measuring not only physical states, but also emotional changes in animals. Yet changes of heart rate variability during fear conditioning have not been systematically studied in mice. Here, we investigated changes in heart rate and heart rate variability in both short-term and long-term contextual and cued fear conditioning. We found that while fear conditioning could increase heart rate, the most significant change was the reduction in heart rate variability which could be further divided into two distinct stages: a highly rhythmic phase (stage-I) and a more variable phase (stage-II). We showed that the time duration of the stage-I rhythmic phase were sensitive enough to reflect the transition from short-term to long-term fear memories. Moreover, it could also detect fear extinction effect during the repeated tone recall. These results suggest that heart rate variability is a valuable physiological indicator for sensitively measuring the consolidation and expression of fear memories in mice. [ABSTRACT FROM AUTHOR]

Human embryonic stem cell (hESC)-derived skeletal muscle progenitors (SMP)—defined as PAX7-expressing cells with myogenic potential—can provide an abundant source of donor material for muscle stem cell therapy. As in vitro myogenesis is decoupled from in vivo timing and 3D-embryo structure, it is important to characterize what stage or type of muscle is modeled in culture. Here, gene expression profiling is analyzed in hESCs over a 50 day skeletal myogenesis protocol and compared to datasets of other hESC-derived skeletal muscle and adult murine satellite cells. Furthermore, day 2 cultures differentiated with high or lower concentrations of CHIR99021, a GSK3A/GSK3B inhibitor, were contrasted. Expression profiling of the 50 day time course identified successively expressed gene subsets involved in mesoderm/paraxial mesoderm induction, somitogenesis, and skeletal muscle commitment/formation which could be regulated by a putative cascade of transcription factors. Initiating differentiation with higher CHIR99021 concentrations significantly increased expression of MSGN1 and TGFB-superfamily genes, notably NODAL, resulting in enhanced paraxial mesoderm and reduced ectoderm/neuronal gene expression. Comparison to adult satellite cells revealed that genes expressed in 50-day cultures correlated better with those expressed by quiescent or early activated satellite cells, which have the greatest therapeutic potential. Day 50 cultures were similar to other hESC-derived skeletal muscle and both expressed known and novel SMP surface proteins. Overall, a putative cascade of transcription factors has been identified which regulates four stages of myogenesis. Subsets of these factors were upregulated by high CHIR99021 or their binding sites were significantly over-represented during SMP activation, ranging from quiescent to late-activated stages. This analysis serves as a resource to further study the progression of in vitro skeletal myogenesis and could be mined to identify novel markers of pluripotent-derived SMPs or regulatory transcription/growth factors. Finally, 50-day hESC-derived SMPs appear similar to quiescent/early activated satellite cells, suggesting they possess therapeutic potential. [ABSTRACT FROM AUTHOR]

Several microRNAs (miRNAs) have been suggested as novel biomarkers for diagnosing gastric cancer (GC) at an early stage, but the single-marker strategy may ignore the co-regulatory relationships and lead to low diagnostic specificity. Thus, multi-target modular diagnostic biomarkers are urgently needed. In this study, a Zsummary and NetSVM-based method was used to identify GC-related hub miRNAs and activated modules from clinical miRNA co-expression networks. The NetSVM-based sub-network consisting of the top 20 hub miRNAs reached a high sensitivity and specificity of 0.94 and 0.82. The Zsummary algorithm identified an activated module (miR-486, miR-451, miR-185, and miR-600) which might serve as diagnostic biomarker of GC. Three members of this module were previously suggested as biomarkers of GC and its 24 target genes were significantly enriched in pathways directly related to cancer. The weighted diagnostic ROC AUC of this module was 0.838, and an optimized module unit (miR-451 and miR-185) obtained a higher value of 0.904, both of which were higher than that of individual miRNAs. These hub miRNAs and module have the potential to become robust biomarkers for early diagnosis of GC with further validations. Moreover, such modular analysis may offer valuable insights into multi-target approaches to cancer diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Self-Organizing Map (SOM) algorithm as an unsupervised learning method has been applied in anomaly detection due to its capabilities of self-organizing and automatic anomaly prediction. However, because of the algorithm is initialized in random, it takes a long time to train a detection model. Besides, the Cloud platforms with large scale virtual machines are prone to performance anomalies due to their high dynamic and resource sharing characters, which makes the algorithm present a low accuracy and a low scalability. To address these problems, an Improved Incremental Self-Organizing Map (IISOM) model is proposed for anomaly detection of virtual machines. In this model, a heuristic-based initialization algorithm and a Weighted Euclidean Distance (WED) algorithm are introduced into SOM to speed up the training process and improve model quality. Meanwhile, a neighborhood-based searching algorithm is presented to accelerate the detection time by taking into account the large scale and high dynamic features of virtual machines on cloud platform. To demonstrate the effectiveness, experiments on a common benchmark KDD Cup dataset and a real dataset have been performed. Results suggest that IISOM has advantages in accuracy and convergence velocity of anomaly detection for virtual machines on cloud platform. [ABSTRACT FROM AUTHOR]

Compressive sensing (CS) theory asserts that we can reconstruct signals and images with only a small number of samples or measurements. Recent works exploiting the nonlocal similarity have led to better results in various CS studies. To better exploit the nonlocal similarity, in this paper, we propose a non-convex smoothed rank function based model for CS image reconstruction. We also propose an efficient alternating minimization method to solve the proposed model, which reduces a difficult and coupled problem to two tractable subproblems. Experimental results have shown that the proposed method performs better than several existing state-of-the-art CS methods for image reconstruction. [ABSTRACT FROM AUTHOR]

Background:O6-methylguanine-DNA methyltransferase is one of the few proteins to directly remove alkylating agents in the human DNA direct reversal repair pathway. A large number of case-control studies have been conducted to explore the association between MGMT Leu84Phe polymorphism and cancer risk. However, the results were not consistent. Methods:We carried out a meta-analysis of 44 case-control studies to clarify the association between the Leu84Phe polymorphism and cancer risk. Results:Overall, significant association of the T allele with cancer susceptibility was verified with meta-analysis under a recessive genetic model (P<0.001, OR=1.30, 95%CI 1.24-1.50) and TT versus CC comparison (P=0.001, OR=1.29, 95% CI 1.12-1.50). In subgroup analysis, a significant increased risk was found for lung cancer (TT versus CC, P=0.027, OR=1.67, 95% CI 1.06-2.63; recessive genetic model, P=0.32, OR=1.64, 95% CI 1.04-2.58), whereas risk of colorectal cancer was significantly low under a dominant genetic model (P=0.019, OR=0.84, 95% CI 0.72-0.97). Additionally, a significant association between TT genetic model and total cancer risk was found in the Caucasian population (TT versus CC, P=0.014, OR=1.29, 95% CI 1.05-1.59; recessive genetic model, P=0.009, OR=1.31, 95% CI 1.07-1.61), but not in the Asian population. An increased risk for lung cancer was also verified in the Caucasian population (TT versus CC, P=0.035, OR=1.62, 95% CI 1.04-2.53; recessive genetic model, P=0.048, OR=1.57, 95% CI 1.01-2.45). Conclusions:These results suggest that MGMT Leu84Phe polymorphism might contribute to the susceptibility of certain cancers. [ABSTRACT FROM AUTHOR]

The filamentous fungus Colletotrichum fructicola is found in all five continents and is capable of causing severe diseases in a number of economically important plants such as avocado, fig, cocoa, pear, and tea-oil trees. However, almost nothing is known about its patterns of genetic variation and epidemiology on any of its host plant species. Here we analyzed 167 isolates of C. fructicola obtained from the leaves of tea-oil tree Camellia oleifera at 15 plantations in seven Chinese provinces. Multilocus sequence typing was conducted for all isolates based on DNA sequences at fragments of four genes: the internal transcribed spacers of the nuclear ribosomal RNA gene cluster (539 bp), calmodulin (633 bp), glutamine synthetase (711 bp), and glyceraldehyde-3-phosphate dehydrogenase (190 bp), yielding 3.52%, 0.63%, 8.44%, and 7.89% of single nucleotide polymorphic sites and resulting in 15, 5, 12 and 11 alleles respectively at the four gene fragments in the total sample. The combined allelic information from all four loci identified 53 multilocus genotypes with the most frequent represented by 21 isolates distributed in eight tea-oil plantations in three provinces, consistent with long-distance clonal dispersal. However, despite evidence for clonal dispersal, statistically significant genetic differentiation among geographic populations was detected. In addition, while no evidence of recombination was found within any of the four gene fragments, signatures of recombination were found among the four gene fragments in most geographic populations, consistent with sexual mating of this species in nature. Our study provides the first insights into the population genetics and epidemiology of the important plant fungal pathogen C. fructicola. [ABSTRACT FROM AUTHOR]

Schisandra chinensis extracts (SEs) have traditionally been used as an oriental medicine for the treatment of various human diseases, however, their further application in the biocontrol of plant disease remains poorly understood. This study was conducted to develop eco-friendly botanical pesticides from extracts of S. chinensis and assess whether they could play a key role in plant disease defense. Concentrated active fractions (SE-I, SE-II, and SE-III) were obtained from S. chinensis via specific extraction and separation. Then, lignan-like substances, such as Schisanhenol B, were detected via High-Performance Liquid Chromatography-ElectroSpray Ionization-Mass Spectrometry (HPLC-ESI-MS) analyses of the active fractions. Moreover, the results from biological tests on colony growth inhibition and spore germination indicated that SE-I, SE-II, and SE-III could inhibit hyphal growth and spore generation of three important plant pathogenic fungi (Monilinia fructicola, Fusarium oxysporum, and Botryosphaeria dothidea). The study of the mechanisms of resistant fungi revealed that the oxidation resistance system, including reactive oxygen species (ROS), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD), was activated. The expression of genes related to defense, such as pathogenesis-related protein (PR4), α-farnesene synthase (AFS), polyphenol oxidase (PPO), and phenylalanine ammonia lyase (PAL) were shown to be up-regulated after treatment with SEs, which suggested an increase in apple immunity and that fruits were induced to effectively defend against the infection of pathogenic fungi (B. dothidea). This study revealed that SEs and their lignans represent promising resources for the development of safe, effective, and multi-targeted agents against pathogenic fungi. [ABSTRACT FROM AUTHOR]

Machine learning-based approaches play an important role in examining functional magnetic resonance imaging (fMRI) data in a multivariate manner and extracting features predictive of group membership. This study was performed to assess the potential for measuring brain intrinsic activity to identify minimal hepatic encephalopathy (MHE) in cirrhotic patients, using the support vector machine (SVM) method. Resting-state fMRI data were acquired in 16 cirrhotic patients with MHE and 19 cirrhotic patients without MHE. The regional homogeneity (ReHo) method was used to investigate the local synchrony of intrinsic brain activity. Psychometric Hepatic Encephalopathy Score (PHES) was used to define MHE condition. SVM-classifier was then applied using leave-one-out cross-validation, to determine the discriminative ReHo-map for MHE. The discrimination map highlights a set of regions, including the prefrontal cortex, anterior cingulate cortex, anterior insular cortex, inferior parietal lobule, precentral and postcentral gyri, superior and medial temporal cortices, and middle and inferior occipital gyri. The optimized discriminative model showed total accuracy of 82.9% and sensitivity of 81.3%. Our results suggested that a combination of the SVM approach and brain intrinsic activity measurement could be helpful for detection of MHE in cirrhotic patients. [ABSTRACT FROM AUTHOR]

Skeletal muscle growth and development are highly orchestrated processes involving significant changes in gene expressions. Differences in the location-specific and breed-specific genes and pathways involved have important implications for meat productions and meat quality. Here, RNA-Seq was performed to identify differences in the muscle deposition between two muscle locations and two duck breeds for functional genomics studies. To achieve those goals, skeletal muscle samples were collected from the leg muscle (LM) and the pectoral muscle (PM) of two genetically different duck breeds, Heiwu duck (H) and Peking duck (P), at embryonic 15 days. Functional genomics studies were performed in two experiments: Experiment 1 directly compared the location-specific genes between PM and LM, and Experiment 2 compared the two breeds (H and P) at the same developmental stage (embryonic 15 days). Almost 13 million clean reads were generated using Illumina technology (Novogene, Beijing, China) on each library, and more than 70% of the reads mapped to the Peking duck (Anas platyrhynchos) genome. A total of 168 genes were differentially expressed between the two locations analyzed in Experiment 1, whereas only 8 genes were differentially expressed when comparing the same location between two breeds in Experiment 2. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes pathways (KEGG) were used to functionally annotate DEGs (differentially expression genes). The DEGs identified in Experiment 1 were mainly involved in focal adhesion, the PI3K-Akt signaling pathway and ECM-receptor interaction pathways (corrected P-value<0.05). In Experiment 2, the DEGs were associated with only the ribosome signaling pathway (corrected P-value<0.05). In addition, quantitative real-time PCR was used to confirm 15 of the differentially expressed genes originally detected by RNA-Seq. A comparative transcript analysis of the leg and pectoral muscles of two duck breeds not only improves our understanding of the location-specific and breed-specific genes and pathways but also provides some candidate molecular targets for increasing muscle products and meat quality by genetic control. [ABSTRACT FROM AUTHOR]

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an important enzyme in energy metabolism with diverse cellular regulatory roles in vertebrates, but few reports have investigated the importance of plant GAPDH isoforms outside of their role in glycolysis. While animals possess one GAPDH isoform, plants possess multiple isoforms. In this study, cell biological and genetic approaches were used to investigate the role of GAPDHs during plant immune responses. Individual Arabidopsis GAPDH knockouts (KO lines) exhibited enhanced disease resistance phenotypes upon inoculation with the bacterial plant pathogen Pseudomonas syringae pv. tomato. KO lines exhibited accelerated programmed cell death and increased electrolyte leakage in response to effector triggered immunity. Furthermore, KO lines displayed increased basal ROS accumulation as visualized using the fluorescent probe H2DCFDA. The gapa1-2 and gapc1 KOs exhibited constitutive autophagy phenotypes in the absence of nutrient starvation. Due to the high sequence conservation between vertebrate and plant cytosolic GAPDH, our experiments focused on cytosolic GAPC1 cellular dynamics using a complemented GAPC1-GFP line. Confocal imaging coupled with an endocytic membrane marker (FM4-64) and endosomal trafficking inhibitors (BFA, Wortmannin) demonstrated cytosolic GAPC1 is localized to the plasma membrane and the endomembrane system, in addition to the cytosol and nucleus. After perception of bacterial flagellin, GAPC1 dynamically responded with a significant increase in size of fluorescent puncta and enhanced nuclear accumulation. Taken together, these results indicate that plant GAPDHs can affect multiple aspects of plant immunity in diverse sub-cellular compartments. [ABSTRACT FROM AUTHOR]

The total variation (TV) regularization method is an effective method for image deblurring in preserving edges. However, the TV based solutions usually have some staircase effects. In order to alleviate the staircase effects, we propose a new model for restoring blurred images under impulse noise. The model consists of an ℓ1-fidelity term and a TV with overlapping group sparsity (OGS) regularization term. Moreover, we impose a box constraint to the proposed model for getting more accurate solutions. The solving algorithm for our model is under the framework of the alternating direction method of multipliers (ADMM). We use an inner loop which is nested inside the majorization minimization (MM) iteration for the subproblem of the proposed method. Compared with other TV-based methods, numerical results illustrate that the proposed method can significantly improve the restoration quality, both in terms of peak signal-to-noise ratio (PSNR) and relative error (ReE). [ABSTRACT FROM AUTHOR]

Mild traumatic brain injury (mTBI) is a significant public health care burden in the United States. However, we lack a detailed understanding of the pathophysiology following mTBI and its relation to symptoms and recovery. With advanced magnetic resonance imaging (MRI), we can investigate brain perfusion and oxygenation in regions known to be implicated in symptoms, including cortical gray matter and subcortical structures. In this study, we assessed 14 mTBI patients and 18 controls with susceptibility weighted imaging and mapping (SWIM) for blood oxygenation quantification. In addition to SWIM, 7 patients and 12 controls had cerebral perfusion measured with arterial spin labeling (ASL). We found increases in regional cerebral blood flow (CBF) in the left striatum, and in frontal and occipital lobes in patients as compared to controls (p = 0.01, 0.03, 0.03 respectively). We also found decreases in venous susceptibility, indicating increases in venous oxygenation, in the left thalamostriate vein and right basal vein of Rosenthal (p = 0.04 in both). mTBI patients had significantly lower delayed recall scores on the standardized assessment of concussion, but neither susceptibility nor CBF measures were found to correlate with symptoms as assessed by neuropsychological testing. The increased CBF combined with increased venous oxygenation suggests an increase in cerebral blood flow that exceeds the oxygen demand of the tissue, in contrast to the regional hypoxia seen in more severe TBI. This may represent a neuroprotective response following mTBI, which warrants further investigation. [ABSTRACT FROM AUTHOR]

Purpose: The inhibition of serum glucocorticoid-regulated kinase-1 (SGK-1) has been found to decrease growth of colon and prostate cancer cells. The purpose of this study is to evaluate the therapeutic effect of SGK-1 inhibition in head and neck squamous cell carcinoma (SCC). Experimental Design: Human head and neck tumors (HTB41/43) were established in athymic mice. Growth rates between mice treated with vehicle (PBS) injection (group 1, n = 5), SGK-1 Inhibitor GSK 650394 (group 2, n = 6), systemic cisplatin (group 3, n = 6), and a combination of SGK-1 Inhibitor and cisplatin (group 4, n = 6) were compared using repeated measures one-way ANOVA with Newman-Keuls Multiple Comparison Test. Tumor cells were subsequently submitted to further analyses. Results: At the end of the experiment mean tumor sizes were 122.33+/−105.86, 76.73+/−36.09, 94.52+/−75.92, and 25.76+/−14.89 mm2 (mean +/− SD) for groups 1 to 4. Groups 2 and 3 showed decreased tumor growth compared to controls (p<0.001). Group 4 displayed even greater growth suppression (p<0.0001). Importantly, group 4 fared better than group 3 (p<0.001). CD44 expression was reduced in group 2 (p<0.05), and to an even greater extent in groups 3 and 4 (p<0.0025). A trend towards reduction of HER 2 expression was noted in group 4. Conclusions: SGK-1 inhibition suppresses tumor growth, and in combination with systemic cisplatin exceeds the effect of cisplatin alone. Decreased expression of CD44 and HER 2 implies depletion of tumor stem cells, and less tumorigenicity. SGK-1 inhibition represents a potential modality of local control for palliation in advanced cases. [ABSTRACT FROM AUTHOR]

Protein carbonylation is one of the most pervasive oxidative stress-induced post-translational modifications (PTMs), which plays a significant role in the etiology and progression of several human diseases. It has been regarded as a biomarker of oxidative stress due to its relatively early formation and stability compared with other oxidative PTMs. Only a subset of proteins is prone to carbonylation and most carbonyl groups are formed from lysine (K), arginine (R), threonine (T) and proline (P) residues. Recent advancements in analysis of the PTM by mass spectrometry provided new insights into the mechanisms of protein carbonylation, such as protein susceptibility and exact modification sites. However, the experimental approaches to identifying carbonylation sites are costly, time-consuming and capable of processing a limited number of proteins, and there is no bioinformatics method or tool devoted to predicting carbonylation sites of human proteins so far. In the paper, a computational method is proposed to identify carbonylation sites of human proteins. The method extracted four kinds of features and combined the minimum Redundancy Maximum Relevance (mRMR) feature selection criterion with weighted support vector machine (WSVM) to achieve total accuracies of 85.72%, 85.95%, 83.92% and 85.72% for K, R, T and P carbonylation site predictions respectively using 10-fold cross-validation. The final optimal feature sets were analysed, the position-specific composition and hydrophobicity environment of flanking residues of modification sites were discussed. In addition, a software tool named CarSPred has been developed to facilitate the application of the method. Datasets and the software involved in the paper are available at . [ABSTRACT FROM AUTHOR]

Kir channels display voltage-dependent block by cytosolic cations such as Mg2+ and polyamines that causes inward rectification. In fact, cations can regulate K channel activity from both the extracellular and intracellular sides. Previous studies have provided insight into the up-regulation of Kir channel activity by extracellular K+ concentration. In contrast, extracellular Mg2+ has been found to reduce the amplitude of the single-channel current at milimolar concentrations. However, little is known about the molecular mechanism of Kir channel blockade by external Mg2+ and the relationship between the Mg2+ blockade and activity potentiation by permeant K+ ions. In this study, we applied an interactive approach between theory and experiment. Electrophysiological recordings on Kir2.2 and its mutants were performed by heterologous expression in Xenopus laevis oocytes. Our results confirmed that extracellular Mg2+ could reduce heterologously expressed WT Kir2.2 currents in a voltage dependent manner. The kinetics of inhibition and recovery of Mg2+ exhibit a 3∼4s time constant. Molecular dynamics simulation results revealed a Mg2+ binding site located at the extracellular mouth of Kir2.2 that showed voltage-dependent Mg2+ binding. The mutants, G119D, Q126E and H128D, increased the number of permeant K+ ions and reduced the voltage-dependent blockade of Kir2.2 by extracellular Mg2+. [ABSTRACT FROM AUTHOR]

A number of case-control studies have been conducted to clarify the association between ApoE polymorphisms and myocardial infarction (MI); however, the results are inconsistent. This meta-analysis was performed to clarify this issue using all the available evidence. Searching in PubMed retrieved all eligible articles. A total of 33 studies were included in this meta-analysis, including 18752 MI cases and 18963 controls. The pooled analysis based on all included studies showed that the MI patients had a decreased frequency of the ε2 allele (OR = 0.78, 95% CI = 0.70–0.87) and an increased frequency of the ε4 allele (OR = 1.15, 95% CI = 1.10–1.20); The results also showed a decreased susceptibility of MI in the ε2ε3 vs. ε3ε3 analysis (OR = 0.79, 95% CI = 0.68–0.90) and in the ε2 vs. ε3 analysis (OR = 0.78, 95% CI = 0.69–0.89), an increased susceptibility of MI in the ε3ε4 vs. ε3ε3 analysis (OR = 1.26, 95% CI = 1.12–1.41), in the ε4 vs. ε3 analysis (OR = 1.22, 95% CI = 1.12–1.32) and in the ε4ε4 vs. ε3ε3 analysis (OR = 1.59, 95% CI = 1.15–2.19). However, there were no significant associations among polymorphisms and MI for the following genetic models: frequency of the ε3 allele (OR = 0.99, 95% CI = 0.96–1.02); ε2ε2 vs. ε3ε3 analysis (OR = 0.73, 95% CI = 0.40–1.32); or ε2ε4 vs. ε3ε3 analysis (OR = 1.10, 95% CI = 0.99–1.21). Our results suggested that the ε4 allele of ApoE is a risk factor for the development of MI and the ε2 allele of ApoE is a protective factor in the development of MI. [ABSTRACT FROM AUTHOR]

Background: Calcium oxalate monohydrate (COM) is the major crystalline component in kidney stones and its adhesion to renal tubular cells leads to tubular injury. However, COM-induced toxic effects in renal tubular cells remain ambiguous. MicroRNAs (miRNAs) play an important role in gene regulation at the posttranscriptional levels. Objective: The present study aimed to assess the potential changes in microRNAs of proximal renal tubular cells in response to the adhesion of calcium oxalate monohydrate (COM) crystals. Methodology: Lactate dehydrogenase (LDH) activity and DAPI staining were used to measure the toxic effects of HK-2 cells exposed to COM crystals. MicroRNA microarray and mRNA microarray were applied to evaluate the expression of HK-2 cells exposed to COM crystals. Quantitative real-time PCR (qRT-PCR) technology was used to validate the microarray results. Target prediction, Gene Ontology (GO) analysis and pathway analysis were applied to predict the potential roles of microRNAs in biological processes. Principal Findings: Our study showed that COM crystals significantly altered the global expression profile of miRNAs in vitro. After 24 h treatment with a dose (1 mmol/L), 25 miRNAs were differentially expressed with a more than 1.5-fold change, of these miRNAs, 16 were up-regulated and 9 were down-regulated. A majority of these differentially expressed miRNAs were associated with cell death, mitochondrion and metabolic process. Target prediction and GO analysis suggested that these differentially expressed miRNAs potentially targeted many genes which were related to apoptosis, regulation of metabolic process, intracellular signaling cascade, insulin signaling pathway and type 2 diabetes. Conclusion: Our study provides new insights into the role of miRNAs in the pathogenesis associated with nephrolithiasis. [ABSTRACT FROM AUTHOR]

The spirochete periplasmic flagellum has many unique attributes. One unusual characteristic is the flagellar hook. This structure serves as a universal joint coupling rotation of the membrane-bound motor to the flagellar filament. The hook is comprised of about 120 FlgE monomers, and in most bacteria these structures readily dissociate to monomers (∼ 50 kDa) when treated with heat and detergent. However, in spirochetes the FlgE monomers form a large mass of over 250 kDa [referred to as a high molecular weight complex (HMWC)] that is stable to these and other denaturing conditions. In this communication, we examined specific aspects with respect to the formation and structure of this complex. We found that the Lyme disease spirochete Borrelia burgdorferi synthesized the HMWC throughout the in vitro growth cycle, and also in vivo when implanted in dialysis membrane chambers in rats. The HMWC was stable to formic acid, which supports the concept that the stability of the HMWC is dependent on covalent cross-linking of individual FlgE subunits. Mass spectrometry analysis of the HMWC from both wild type periplasmic flagella and polyhooks from a newly constructed ΔfliK mutant indicated that other proteins besides FlgE were not covalently joined to the complex, and that FlgE was the sole component of the complex. In addition, mass spectrometry analysis also indicated that the HMWC was composed of a polymer of the FlgE protein with both the N- and C-terminal regions remaining intact. These initial studies set the stage for a detailed characterization of the HMWC. Covalent cross-linking of FlgE with the accompanying formation of the HMWC we propose strengthens the hook structure for optimal spirochete motility. [ABSTRACT FROM AUTHOR]

Ischemia-Reperfusion (IR) injury of limb remains a significant clinical problem causing secondary complications and restricting clinical recovery, despite rapid restoration of blood flow and successful surgery. In an attempt to further improve post ischemic tissue repair, we investigated the effect of a local administration of bone marrow derived stem cells (BMDSCs) in the presence or absence of immune-regulatory enzyme, IDO, in a murine model. A whole limb warm ischemia-reperfusion model was developed using IDO sufficient (WT) and deficient (KO) mice with C57/BL6 background. Twenty-four hours after injury, 5×105 cells (5×105 cells/200 µL of PBS solution) BMDSCs (Sca1 + cells) were injected intramuscularly while the control group received just the vehicle buffer (PBS). Forty-eight to seventy-two hours after limb BMDSC injection, recovery status including the ratio of intrinsic paw function between affected and normal paws, general mobility, and inflammatory responses were measured using video micrometery, flow cytometry, and immunohistochemistry techniques. Additionally, MRI/MRA studies were performed to further study the inflammatory response between groups and to confirm reconstitution of blood flow after ischemia. For the first time, our data, showed that IDO may potentially represent a partial role in triggering the beneficial effects of BMDSCs in faster recovery and protection against structural changes and cellular damage in a hind limb IR injury setting (P = 0.00058). [ABSTRACT FROM AUTHOR]

This article provides a fully Bayesian approach for modeling of single-dose and complete pharmacokinetic data in a population pharmacokinetic (PK) model. To overcome the impact of outliers and the difficulty of computation, a generalized linear model is chosen with the hypothesis that the errors follow a multivariate Student t distribution which is a heavy-tailed distribution. The aim of this study is to investigate and implement the performance of the multivariate t distribution to analyze population pharmacokinetic data. Bayesian predictive inferences and the Metropolis-Hastings algorithm schemes are used to process the intractable posterior integration. The precision and accuracy of the proposed model are illustrated by the simulating data and a real example of theophylline data. [ABSTRACT FROM AUTHOR]

Background: Both microRNAs and human papillomavirus (HPV) infection play an important role in the development and progression of oral squamous cell carcinoma (OSCC). In addition, microRNAs affect all facets of the immune/inflammation responses to infection, which may control HPV clearance. We thus hypothesized that microRNA polymorphisms modify the association between HPV16 seropositivity and OSCC risk. Methods: Four single-nucleotide polymorphisms in microRNAs were genotyped and HPV16 serology was determined in 325 cases and 335 matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using univariate and multivariable logistic regression models. Results: Overall, each polymorphism had no significant main effect on OSCC risk. Compared with the risk among individuals with both miR146 rs2910164 GG genotype and HPV16 seronegativity, risk of OSCC was increased among those with CG or CC genotype and HPV16 seronegativity (OR, 1.2; 95% CI, 0.9–1.8), GG genotype and HPV16 seropositivity (OR, 3.0; 95% CI, 1.8–5.0), and CG or CC genotype and HPV16 seropositivity (OR, 4.7; 95% CI, 2.3–9.4). Similar results were found for miR149 rs2292832, miR196 rs11614913, and miR499 rs3746444. Analyses stratified by tumor sites and smoking status showed that each polymorphism significantly increased the risk of HPV16-associated squamous cell carcinoma of the oropharynx (SCCOP), and such effect modification was particularly prominent in never smokers. Conclusions: Our results indicate that microRNA polymorphisms modify the risk of OSCC associated with HPV16 seropositivity, particularly in patients with SCCOP and never smokers. Larger studies are needed to verify our findings. [ABSTRACT FROM AUTHOR]

Crimean-Congo hemorrhagic fever (CCHF) is the most medically important tick-borne viral disease of humans and tuberculosis is the leading cause of death worldwide by a bacterial pathogen. These two diseases overlap geographically, however, concurrent infection of CCHF virus (CCHFV) with mycobacterial infection has not been assessed nor has the ability of virus to persist and cause long-term sequela in a primate model. In this study, we compared the disease progression of two diverse strains of CCHFV in the recently described cynomolgus macaque model. All animals demonstrated signs of clinical illness, viremia, significant changes in clinical chemistry and hematology values, and serum cytokine profiles consistent with CCHF in humans. The European and Asian CCHFV strains caused very similar disease profiles in monkeys, which demonstrates that medical countermeasures can be evaluated in this animal model against multiple CCHFV strains. We identified evidence of CCHFV persistence in the testes of three male monkeys that survived infection. Furthermore, the histopathology unexpectedly revealed that six additional animals had evidence of a latent mycobacterial infection with granulomatous lesions. Interestingly, CCHFV persisted within the granulomas of two animals. This study is the first to demonstrate the persistence of CCHFV in the testes and within the granulomas of non-human primates with concurrent latent tuberculosis. Our results have important public health implications in overlapping endemic regions for these emerging pathogens. [ABSTRACT FROM AUTHOR]