Background: Teneligliptin is a 3rd-generation dipeptidyl peptidase-4 (DPP-4) inhibitor. There is a limited evidence regarding the effect of teneligliptin. Therefore, this study is to assess the efficacy and safety of teneligliptin in type 2 diabetes mellitus (T2DM) patients with inadequately glycemic controlled. Methods: A search of PubMed, Medline, Embase, and The Cochrane Library during 2000.01-2018.03 was performed for randomized controlled trials of teneligliptin compared to placebo in patients with T2DM with monotherapy or add-on treatment. Results: Ten trials with 2119 patients were analyzed. Teneligliptin produced absolute reductions in glycated hemoglobin A1c (HbA1c) levels (weighted mean difference (WMD) 0.82%, 95% confidence interval (CI) [-0.91 to -0.72], p < 0.00001) compared with placebo. However, after 36-42 weeks of follow-up (open-label), HbA1c level rise higher than duration (double-blind) in teneligliptin group. Teneligliptin led to greater decrease of fasting plasma glucose (FPG) level (vs. placebo, WMD -18.32%, 95% CI [-21.05 to -15.60], p < 0.00001). Teneligliptin also significantly decreased the 2 h post-prandial plasma glucose (2 h PPG) (WMD -46.94%, 95% CI [-51.58 to -42.30], p < 0.00001) and area under the glucose plasma concentration-time curve from 0 to 2 h (AUC0-2h) for PPG (WMD -71.50%, 95% CI [-78.09 to -64.91], p < 0.00001) compared with placebo. Patients treated with teneligliptin achieved increased homeostasis model assessment of β cell function (HOMA-β) with 9.31 (WMD, 95% CI [7.78-10.85], p < 0.00001). However, there was no significant difference between teneligliptin and placebo in overall adverse effects (0.96 risk ratio (RR), 95% CI [0.87, 1.06], p = 0.06). The risks of hypoglycemia were not significantly different between teneligliptin and placebo (1.16 RR, 95% CI [0.59, 2.26], p = 0.66). Conclusions: Teneligliptin improved blood glucose levels and β-cells function with low risk of hypoglycemia in patients with T2DM. Common adverse effects of teneligliptin including hypoglycemia were identified and reviewed. Risks of cardiovascular events are less certain, and more data for long-term effects are needed.

Aim: Combined use of herbal medicines in patients underwent dual antiplatelet therapy (DAPT) might cause bleeding or thrombosis because herbal medicines with anti-platelet activities may exhibit interactions with DAPT. In this study, we tried to use a feedback system control (FSC) optimization technique to optimize dose strategy and clarify possible interactions in combined use of DAPT and herbal medicines. Methods: Herbal medicines with reported anti-platelet activities were selected by searching related references in Pubmed. Experimental anti-platelet activities of representative compounds originated from these herbal medicines were investigated using in vitro assay, namely ADP-induced aggregation of rat platelet-rich-plasma. FSC scheme hybridized artificial intelligence calculation and bench experiments to iteratively optimize 4-drug combination and 2-drug combination from these drug candidates. Results: Totally 68 herbal medicines were reported to have anti-platelet activities. In the present study, 7 representative compounds from these herbal medicines were selected to study combinatorial drug optimization together with DAPT, i.e., aspirin and ticagrelor. FSC technique first down-selected 9 drug candidates to the most significant 5 drugs. Then, FSC further secured 4 drugs in the optimal combination, including aspirin, ticagrelor, ferulic acid from DangGui, and forskolin from MaoHouQiaoRuiHua. Finally, FSC quantitatively estimated the possible interactions between aspirin:ticagrelor, aspirin:ferulic acid, ticagrelor:forskolin, and ferulic acid:forskolin. The estimation was further verified by experimentally determined Combination Index (CI) values. Conclusion: Results of the present study suggested that FSC optimization technique could be used in optimization of anti-platelet drug combinations and might be helpful in designing personal anti-platelet therapy strategy. Furthermore, FSC analysis could also identify interactions between different drugs which might provide useful information for research of signal cascades in platelet.

Chronic obstructive pulmonary disease (COPD) is a multi-pathogenesis chronic lung disease. The mechanisms underlying COPD have not been adequately illustrated. Many reseachers argue that microRNAs (miRs) could play a crucial role in COPD. The classic animal model of COPD is both time consuming and costly. This study proposes a novel mice COPD model and explores the role of miR-21 in COPD. A total of 50 wide-type (WT) C57BL/6 mice were separated into five euqlly-sized groups-(1) control group (CG), (2) the novel combined method group (NCM, cigarette smoke (CS) exposure for 28 days combined with cigarette smoke extract (CSE) intraperitoneal injection), (3) the short-term CS exposure group (SCSE, CS exposure for 28 days), (4) the CSE intraperitoneal injection group (CSEII, 28 days CSE intraperitoneal injection), and (5) the long-term CS exposure group (LCSE, CS exposure).The body weight gain of mice were recorded and lung function tested once the modeling was done. The pathological changes and the inflammation level by hematoxylin eosin (H&E) staining and immunohistochemical staining (IHS) on the lung tissue sections were also evaluated. The level of miR-21 in the mice lungs of the mice across all groups was detected by RT-qPCR and the effects of miR-21 knock-down in modeled mice were observed. The mice in LCSE and NCM exhibited the most severe inflammation levels and pathological and pathophysiological changes; while the changes for the mice in SCSE and CSEII were less, they remained more severe than the mice in the CG. The level of miR-21 was found to be negatively correlated with lung functions. Moreover, knocking miR-21 down from the modeled mice, ameliorated all those tested COPD-related changes. Our novel modeling method detected virtually the same changes as those detected in the classic method in WT mice, but in less time and cost. Further, it was determined that the level of miR-21 in the lungs could be an indicator of COPD severity and blocking functions of miR-21 could be a potential treatment for early stage COPD.

ResearchGate, a social network site for academics, prominently displays the achievements of people one follows ("With 150 new reads, X was the most read author from their institute"). The goal of this paper was to examine the emotional and motivational effects of these system-generated messages, thereby extending prior research on envy-evoking status updates on Facebook to a professional context. We also extend the research on social comparisons and more broadly, on emotional responses elicited by social media. Specifically, social media research has largely focused on examining emotional reactions to content that is both generated by and is about others. In this research we directly examine updates generated by the system (ResearchGate) while also directly comparing reactions to updates about others' achievements with reactions to updates that are about the self-i.e., one's personal achievements which are also displayed on ResearchGate ("With 150 new reads, you were the most read author from your institute"). Particular attention was paid to the mediating role of envy and pride. The results of our quasi-experimental field study (n = 419) showed that the achievements of others elicited envy, whereas personal achievements elicited pride. People exposed to their personal achievements (vs. the achievement of others) showed a higher motivation to work harder. This effect was mediated by pride, but not envy. The theoretical and practical implications of these findings are discussed.

The potential of bacteriophage as an alternative antibacterial agent has been reconsidered for control of pathogenic bacteria due to the widespread occurrence of multi-drug resistance bacteria. More and more lytic phages have been isolated recently. In the present study, we isolated a lytic phage named vB_EcoS-B2 from waste water. VB_EcoS-B2 has an icosahedral symmetry head and a long tail without a contractile sheath, indicating that it belongs to the family Siphoviridae. The complete genome of vB_EcoS-B2 is composed of a circular double stranded DNA of 44,283 bp in length, with 54.77% GC content. vB_EcoS-B2 is homologous to 14 relative phages (such as Escherichia phage SSL-2009a, Escherichia phage JL1, and Shigella phage EP23), but most of these phages exhibit different gene arrangement. Our results serve to extend our understanding toward phage evolution of family Siphoviridae of coliphages. Sixty-five putative open reading frames were predicted in the complete genome of vB_EcoS-B2. Twenty-one of proteins encoded by vB_EcoS-B2 were determined in phage particles by Mass Spectrometry. Bacteriophage genome and proteome analysis confirmed the lytic nature of vB_EcoS-B2, namely, the absence of toxin-coding genes, islands of pathogenicity, or genes through lysogeny or transduction. Furthermore, vB_EcoS-B2 significantly reduced the growth of E. coli MG1655 and also inhibited the growth of several multi-drug resistant clinical stains of E. coli. Phage vB_EcoS-B2 can kill some of the MRD E. coli entirely, strongly indicating us that it could be one of the components of phage cocktails to treat multi-drug resistant E. coli. This phage could be used to interrupt or reduce the spread of multi-drug resistant E. coli.

In the storeroom C7 of the Tianjin Museum, one wooden desk and two leather luggages dated back to Qing dynasty (1644-1912 AD) presented viable microbial contamination. The aim of the present study was to investigate microbial communities responsible for the biodeterioration of storeroom objects using a combination of culture-independent and culture-dependent methods as well microscopic techniques. Scanning electron microscopy (SEM) revealed that the microflora on three storeroom objects were characterized by a marked presence of Eurotium halophilicum. Real-time quantitative polymerase chain reaction (qPCR) analysis proved that fungi were the main causative agents behind the biodeterioration in this case. Fungal internal transcribed spacer (ITS) amplicon sequencing documented the presence of two main fungi - Eurotium halophilicum and Aspergillus penicillioides. Molecular identification of fungal strains isolated from the surfaces and the air of the storeroom were most closely related to Chaetomium, Aspergillus, Penicillium, and Fusarium, showing discrepancies in fungal taxa compared to ITS amplicon sequencing. The most isolated bacterial phylum was Firmicutes, mostly Bacillus members. In addition, four biocide products - Preventol® D 7, P 91, 20 N and Euxyl® K 100 were selected to test their capability against fungal strains isolated from the surfaces. According to the susceptibility assay, Preventol® D 7 based on isothiazolinones was the most effective against fungal isolates. Findings from this study provided a knowledge about storeroom fungi, and exemplify a type of preliminary test that may be conducted before planning any biocide treatment, which may be useful to mitigate the fungal deterioration for further conservation of the museum.

Several classes of ligands for Protease-Activated Receptors (PARs) have shown impressive anti-inflammatory and cytoprotective activities, including PAR2 antagonists and the PAR1-targeting parmodulins. In order to support medicinal chemistry studies with hundreds of compounds and to perform detailed mode-of-action studies, it became important to develop a reliable PAR assay that is operational with endothelial cells, which mediate the cytoprotective effects of interest. We report a detailed protocol for an intracellular calcium mobilization assay with adherent endothelial cells in multiwell plates that was used to study a number of known and new PAR1 and PAR2 ligands, including an alkynylated version of the PAR1 antagonist RWJ-58259 that is suitable for the preparation of tagged or conjugate compounds. Using the cell line EA.hy926, it was necessary to perform media exchanges with automated liquid handling equipment in order to obtain optimal and reproducible antagonist concentration-response curves. The assay is also suitable for study of PAR2 ligands; a peptide antagonist reported by Fairlie was synthesized and found to inhibit PAR2 in a manner consistent with reports using epithelial cells. The assay was used to confirm that vorapaxar acts as an irreversible antagonist of PAR1 in endothelium, and parmodulin 2 (ML161) and the related parmodulin RR-90 were found to inhibit PAR1 reversibly, in a manner consistent with negative allosteric modulation.

Vitamin D deficiency has been associated with multiple diseases, but the causal relevance and underlying processes are not fully understood. Elucidating the mechanisms of action of drug treatments in humans is challenging, but application of functional genomic approaches in randomized trials may afford an opportunity to systematically assess molecular responses.

Mobile apps are becoming an increasingly ubiquitous platform for delivery of health behavior interventions among overweight and obese perinatal women. However, only a few methodological guidelines on integrating theory, evidence, and qualitative research for their designs are available.

Patients with orthopedic conditions frequently use the internet to find health information. Patient education that is distributed online may form an easily accessible, time- and cost-effective alternative to education delivered through traditional channels such as one-on-one consultations or booklets. However, no systematic evidence for the comparative effectiveness of Web-based educational interventions exists.

Biliary atresia (BA) is a multifactorial pathogenic disease with possible genetic components. As a member of membrane skeletal proteins in the liver and bile ducts, a haplotype composed by five single nucleotide polymorphisms (SNPs) on adducin 3 (ADD3) has been identified as associated with BA. However, limited study was designed to further elaborate the mutual relationship amongst those replicated SNPs to disease. We selected three susceptibility SNPs in ADD3 and conducted a replication study using 510 BA cases and 1473 controls to evaluate the individual function of the SNPs and further stratified the potential roles with disease and its subclinical features. Two SNPs in ADD3 were replicated as associated with BA (1.60E-04 ≤ P≤1.70E-04, 1.33 ≤ odds ratio (OR) ≤ 1.58 for rs17095355, 2.10E-04 ≤ P≤5.30E-04, 1.26 ≤ OR ≤ 1.57 for rs2501577). Though we failed to replicate the individual association of rs10509906 to disease, the intragenic epistatic effect between rs10509906 and rs2501577 was suggested as exhibiting susceptibility to BA, further cross-validated by multifactor dimensionality reduction (MDR) (P=0.068, OR = 1.37), which may explain extra hidden heritability of ADD3 to BA. Furthermore, through subclinical stratification, we also observed the association of risk to disease mainly came from the female patients.

Preoperative serum albumin has been considered to be closely correlated with the prognosis of various cancers, including urothelial carcinoma (UC). However, to date, this conclusion remains controversial. The aim of this meta-analysis is to investigate the prognostic significance of preoperative serum albumin in UC. A literature search was performed in PubMed, Web of Science, Embase, and Cochrane Library up to 4 July 2017. Herein, a total of 15506 patients from 23 studies were enrolled in our meta-analysis. Decreased preoperative serum albumin level predicted poor overall survival (OS) (HR = 1.88, 95% CI: 1.44-2.45, P<0.0001), cancer-specific survival (CSS) (HR = 2.03, 95% CI: 1.42-2.90, P=0.0001), recurrence-free survival (HR = 1.85, 95% CI: 1.15-2.97, P=0.01), 30-day complications (30dCs) after surgery (odds ratio (OR) = 1.93, 95% CI: 1.16-3.20, P=0.01), and 90-day mortality after surgery (OR = 4.24, 95% CI: 2.20-8.16, P<0.001). The subgroup analyses indicated that low preoperative serum albumin level is still positively associated with a worse prognosis of UC based on ethnicity, cut-off value, tumor type, analyses type, and sample size. Our meta-analysis indicated that reduced preoperative serum albumin level was a predictor of poor prognosis of UC.

The morbidity and mortality resulting from acute gastroenteritis and associated chronic sequelae represent a substantial burden on health care systems worldwide. Few studies have investigated changes in the gut microbiome following an episode of acute gastroenteritis. By using nondirected 16S rRNA gene amplicon sequencing, the fecal microbiota of 475 patients with acute gastroenteritis was examined. Patient age was correlated with the overall microbial composition, with a decrease in the abundance of Faecalibacterium being observed in older patients. We observed the emergence of a potential Escherichia-Shigella-dominated enterotype in a subset of patients, and this enterotype was predicted to be more proinflammatory than the other common enterotypes, with the latter being dominated by Bacteroides or Faecalibacterium The increased abundance of Escherichia-Shigella did not appear to be associated with infection with an agent of a similar sequence similarity. Stool color and consistency were associated with the diversity and composition of the microbiome, with deviations from the norm (not brown and solid) showing increases in the abundances of bacteria such as Escherichia-Shigella and Veillonella Analysis of enriched outliers within the data identified a range of genera previously associated with gastrointestinal diseases, including Treponema, Proteus, Capnocytophaga, Arcobacter, Campylobacter, Haemophilus, Aeromonas, and Pseudomonas Our data represent the first in-depth analysis of gut microbiota in acute gastroenteritis. Phenotypic changes in stool color and consistency were associated with specific changes in the microbiota. Enriched bacterial taxa were detected in cases where no causative agent was identified by using routine diagnostic tests, suggesting that in the future, microbiome analyses may be utilized to improve diagnostics.

Amino acid metabolism plays important roles in innate immune cells, including macrophages. Recently, we reported that a lysosomal adaptor protein, Lamtor1, which serves as the scaffold for amino acid-activated mechanistic target of rapamycin complex 1 (mTORC1), is critical for the polarization of M2 macrophages. However, little is known about how Lamtor1 affects the inflammatory responses that are triggered by the stimuli for TLRs. In this article, we show that Lamtor1 controls innate immune responses by regulating the phosphorylation and nuclear translocation of transcription factor EB (TFEB), which has been known as the master regulator for lysosome and autophagosome biogenesis. Furthermore, we show that nuclear translocation of TFEB occurs in alveolar macrophages of myeloid-specific Lamtor1 conditional knockout mice and that these mice are hypersensitive to intratracheal administration of LPS and bleomycin. Our observation clarified that the amino acid-sensing pathway consisting of Lamtor1, mTORC1, and TFEB is involved in the regulation of innate immune responses.

Neurotransmitter switching in the adult mammalian brain occurs following photoperiod-induced stress, but the mechanism of regulation is unknown. Here, we demonstrate that elevated activity of dopaminergic neurons in the paraventricular nucleus of the hypothalamus (PaVN) in the adult rat is required for the loss of dopamine expression after long-day photoperiod exposure. The transmitter switch occurs exclusively in PaVN dopaminergic neurons that coexpress vesicular glutamate transporter 2 (VGLUT2), is accompanied by a loss of dopamine type 2 receptors (D2Rs) on corticotrophin-releasing factor (CRF) neurons, and can lead to increased release of CRF. Suppressing activity of all PaVN glutamatergic neurons decreases the number of inhibitory PaVN dopaminergic neurons, indicating homeostatic regulation of transmitter expression in the PaVN.

Mass extinctions documented by the fossil record provide critical benchmarks for assessing changes through time in biodiversity and ecology. Efforts to compare biotic crises of the past and present, however, encounter difficulty because taxonomic and ecological changes are decoupled, and although various metrics exist for describing taxonomic turnover, no methods have yet been proposed to quantify the ecological impacts of extinction events. To address this issue, we apply a network-based approach to exploring the evolution of marine animal communities over the Phanerozoic Eon. Network analysis of fossil co-occurrence data enables us to identify nonrandom associations of interrelated paleocommunities. These associations, or evolutionary paleocommunities, dominated total diversity during successive intervals of relative community stasis. Community turnover occurred largely during mass extinctions and radiations, when ecological reorganization resulted in the decline of one association and the rise of another. Altogether, we identify five evolutionary paleocommunities at the generic and familial levels in addition to three ordinal associations that correspond to Sepkoski's Cambrian, Paleozoic, and Modern evolutionary faunas. In this context, we quantify magnitudes of ecological change by measuring shifts in the representation of evolutionary paleocommunities over geologic time. Our work shows that the Great Ordovician Biodiversification Event had the largest effect on ecology, followed in descending order by the Permian-Triassic, Cretaceous-Paleogene, Devonian, and Triassic-Jurassic mass extinctions. Despite its taxonomic severity, the Ordovician extinction did not strongly affect co-occurrences of taxa, affirming its limited ecological impact. Network paleoecology offers promising approaches to exploring ecological consequences of extinctions and radiations.

Mutations in cardiac myosin-binding protein C (cMyBP-C) are a major cause of familial hypertrophic cardiomyopathy. Although cMyBP-C has been considered to regulate the cardiac function via cross-bridge arrangement at the C-zone of the myosin-containing A-band, the mechanism by which cMyBP-C functions remains unclear. We identified formin Fhod3, an actin organizer essential for the formation and maintenance of cardiac sarcomeres, as a cMyBP-C-binding protein. The cardiac-specific N-terminal Ig-like domain of cMyBP-C directly interacts with the cardiac-specific N-terminal region of Fhod3. The interaction seems to direct the localization of Fhod3 to the C-zone, since a noncardiac Fhod3 variant lacking the cMyBP-C-binding region failed to localize to the C-zone. Conversely, the cardiac variant of Fhod3 failed to localize to the C-zone in the cMyBP-C-null mice, which display a phenotype of hypertrophic cardiomyopathy. The cardiomyopathic phenotype of cMyBP-C-null mice was further exacerbated by Fhod3 overexpression with a defect of sarcomere integrity, whereas that was partially ameliorated by a reduction in the Fhod3 protein levels, suggesting that Fhod3 has a deleterious effect on cardiac function under cMyBP-C-null conditions where Fhod3 is aberrantly mislocalized. Together, these findings suggest the possibility that Fhod3 contributes to the pathogenesis of cMyBP-C-related cardiomyopathy and that Fhod3 is critically involved in cMyBP-C-mediated regulation of cardiac function via direct interaction.

Faithful inheritance of genetic information through sexual reproduction relies on the formation of crossovers between homologous chromosomes during meiosis, which, in turn, relies on the formation and repair of numerous double-strand breaks (DSBs). As DSBs pose a potential threat to the genome, mechanisms that ensure timely and error-free DSB repair are crucial for successful meiosis. Here, we identify NBS-1, the Caenorhabditis elegans ortholog of the NBS1 (mutated in Nijmegen Breakage Syndrome) subunit of the conserved MRE11-RAD50-NBS1/Xrs2 (MRN) complex, as a key mediator of DSB repair via homologous recombination (HR) during meiosis. Loss of nbs-1 leads to severely reduced loading of recombinase RAD-51, ssDNA binding protein RPA, and pro-crossover factor COSA-1 during meiotic prophase progression; aggregated and fragmented chromosomes at the end of meiotic prophase; and 100% progeny lethality. These phenotypes reflect a role for NBS-1 in processing of meiotic DSBs for HR that is shared with its interacting partners MRE-11-RAD-50 and COM-1 (ortholog of Com1/Sae2/CtIP). Unexpectedly, in contrast to MRE-11 and RAD-50, NBS-1 is not required for meiotic DSB formation. Meiotic defects of the nbs-1 mutant are partially suppressed by abrogation of the nonhomologous end-joining (NHEJ) pathway, indicating a role for NBS-1 in antagonizing NHEJ during meiosis. Our data further reveal that NBS-1 and COM-1 play distinct roles in promoting HR and antagonizing NHEJ. We propose a model in which different components of the MRN-C complex work together to couple meiotic DSB formation with efficient and timely engagement of HR, thereby ensuring crossover formation and restoration of genome integrity before the meiotic divisions.

Upregulation of B-cell CLL/lymphoma (BCL)2 expression following lithium treatment is seemingly well established and has been related to the neuroprotective property of the drug. However, while demonstrated by some (but not all) studies based on low-throughput techniques (e.g. qPCR) this effect is not reflected in high-throughput studies, such as microarrays and RNAseq. This manuscript presents a systematic review of currently available reports of lithium's effect on BCL2 expression. To our surprise, we found that the majority of the literature does not support the effect of lithium on BCL2 transcript or protein levels. Moreover, among the positive reports, several used therapeutically irrelevant lithium doses while others lack statistical power. We also noticed that numerous low-throughput studies normalized the signal using genes/proteins affected by lithium, imposing possible bias. Using wet bench experiments and reanalysis of publicly available microarray data, here we show that the reference gene chosen for normalization critically impacts the outcome of qPCR analyses of lithium's effect on BCL2 expression. Our findings suggest that experimental results might be severely affected by the choice of normalizing genes, and emphasize the need to re-evaluate stability of these genes in the context of the specific experimental conditions.

Viral infections associate with disease risk and select families of viruses encode miRNAs that control an efficient viral cycle. The association of viral miRNA expression with disease in a large human population has not been previously explored. We sequenced plasma RNA from 40 participants of the Framingham Heart Study (FHS, Offspring Cohort, Visit 8) and identified 3 viral miRNAs from 3 different human Herpesviridae. These miRNAs were mostly related to viral latency and have not been previously detected in human plasma. Viral miRNA expression was then screened in the plasma of 2763 participants of the remaining cohort utilizing high-throughput RT-qPCR. All 3 viral miRNAs associated with combinations of inflammatory or prothrombotic circulating biomarkers (sTNFRII, IL-6, sICAM1, OPG, P-selectin) but did not associate with hypertension, coronary heart disease or cancer. Using a large observational population, we demonstrate that the presence of select viral miRNAs in the human circulation associate with inflammatory biomarkers and possibly immune response, but fail to associate with overt disease. This study greatly extends smaller singular observations of viral miRNAs in the human circulation and suggests that select viral miRNAs, such as those for latency, may not impact disease manifestation.