We investigated the genetic diversity of the population of captive forest musk deer (Moschus berezovskii) in Barkam Musk Deer Breeding Centre using twelve microsatellite markers, and then analyzed the change in genetic structure of successive generation groups from the population. The data provide a new understanding for the evaluation and usage of the breeding management system. Microsatellite marker analysis detected 141 alleles with an average of 11.75 alleles for each marker. The average expected heterozygosity (HE) was 0.731. Performing an F-statistical analysis on the data showed that the genetic diversity of population decreased, and the inbreeding coefficient significant increased with the increase of generation, and FIS of the 1st generation is significantly lower than that of the second to fifth generation (p < 0.01). The result suggested that the captive population was facing the pressure of inbreeding (FIS = 0.115) and the subsequent loss of genetic diversity. Therefore, it is necessary to improve the breeding management system of the captive population by preventing close relatives from mating or inducing new individuals from the exotic population.

Thyroid cancer is the most common endocrine malignancy. 131I ablation therapy is an effective treatment for patients with differentiated thyroid cancer (DTC) but frequently causes radiation damage in salivary glands (SGs). Stem cell-based regenerative therapy has been found to reduce radiation sialadenitis. We hypothesize that microtubule motor-regulating protein lissencephaly-1 (LIS1) may be a key stem cell regulator responsible for its efficacy and that upregulating LIS1 would decrease131I-induced radiation sialadenitis. Here, we report that LIS1 was reduced by 131I in submandibular glands (SMGs) of rats, using both proteomic analysis and Western blot approach. Moreover, the levels of LIS1-Sca-1 and LIS1-SOX2 were downregulated by 131I together with the decrease of LIS1. In contrast, phenylephrine pretreatment enhanced LIS1 and improved the co-expressions and co-localizations of LIS1-Sca-1 and LIS1-SOX2 in 131I-irradiated SMGs. Since Sca-1 and SOX2 are the established stem cell biomarkers in salivary gland, our findings demonstrate that LIS1 may be a potential target for regulating stem cell maintenance in irradiated SGs. Importantly, phenylephrine may have the ability to promote endogenous stem cell regeneration in SMGs via upregulating the LIS1/Sca-1 and LIS1/SOX2 signaling pathways, suggesting that phenylephrine application before 131I ablation therapy may provide a practical and effective way to prevent radiation sialadenitis for DTC patients.

BACKGROUND This work aimed to screen key biomarkers related to sepsis progression by bioinformatics analyses. MATERIAL AND METHODS The microarray datasets of blood and neutrophils from patients with sepsis or septic shock were downloaded from Gene Expression Omnibus database. Then, differentially expressed genes (DEGs) from 4 groups (sepsis versus normal blood samples; septic shock versus normal blood samples; sepsis neutrophils versus normal controls and septic shock neutrophils versus controls) were respectively identified followed by functional analyses. Subsequently, protein-protein network was constructed, and key functional sub-modules were extracted. Finally, receiver operating characteristic analysis was conducted to evaluate diagnostic values of key genes. RESULTS There were 2082 DEGs between blood samples of sepsis patients and controls, 2079 DEGs between blood samples of septic shock patients and healthy individuals, 6590 DEGs between neutrophils from sepsis and controls, and 1056 DEGs between neutrophils from septic shock patients and normal controls. Functional analysis showed that numerous DEGs were significantly enriched in ribosome-related pathway, cell cycle, and neutrophil activation involved in immune response. In addition, TRIM25 and MYC acted as hub genes in protein-protein interaction (PPI) analyses of DEGs from microarray datasets of blood samples. Moreover, MYC (AUC=0.912) and TRIM25 (AUC=0.843) had great diagnostic values for discriminating septic shock blood samples and normal controls. RNF4 was a hub gene from PPI analyses based on datasets from neutrophils and RNF4 (AUC=0.909) was capable of distinguishing neutrophil samples from septic shock samples and controls. CONCLUSIONS Our findings identified several key genes and pathways related to sepsis development.

Internal carotid artery occlusion (ICAO) is a relatively uncommon but important cause of transient ischemic attack and cerebral infarction. The majority of cases of symptomatic ICAO requires surgical treatment. In this study we performed an investigation of the efficacy and safety of hybrid surgery which is a surgical method for symptomatic chronic complete ICAO.

Objective: To identify associated risk factors for the angiographic outcomes after direct and combined bypass surgery in moyamoya disease (MMD). Methods: All direct and combined bypass procedures performed from June 2009 to May 2015 were screened in this prospective cohort study. Patients who acquired presurgical and follow-up catheter angiography were included. Bypass patency and postoperative collateral formation were evaluated. Univariate and multivariate logistic regression analyses were performed to determine the influence factors for bypass patency and postoperative collateral formation. Results: In total, 188 consecutive bypass procedures were included. After an 18-month median follow-up, the anastomosis patency rate was 88.3%. Postoperative collateral formation was associated with the patency of the anastomosis (Gamma = 0.891, p < 0.001). Multivariate logistic regression analysis showed that presence of hemorrhage (OR, 0.298; 95% CI, 0.125-0.709; p = 0.006) was associated with obstructed anastomosis. Among the 188 bypass surgeries, 125 (63.2%) hemispheres had good postoperative collateral formation and 85 (36.8%) had poor postoperative collateral formation. Multivariate logistic regression analysis showed that younger age at operation (OR, 2.396; 95% CI, 1.231-4.664; p = 0.010) was associated with good postoperative collateral formation, while the poor postoperative collateral formation was related to presence of hemorrhage (OR, 0.329; 95% CI, 0.143-0.758; p = 0.009) and dilated anterior choroidal artery (OR, 0.472; 95% CI, 0.240-0.929; p = 0.030). Conclusions: This study has demonstrated that presence of hemorrhage predicts lower patency rates. Younger age at operation was associated with good postoperative collateral formation, while the poor postoperative collateral formation was related to presence of hemorrhage and dilated anterior choroidal artery.

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.

OLA1 is a member of the GTPase protein family; unlike other members, it possess both GTPase and ATPase activities, and can bind and hydrolyze ATP more efficiently than GTP. OLA1 participates in cell proliferation, oxidative response, protein synthesis and tumorigenesis. However, whether OLA1 is also required for oocyte meiosis is still unknown.

Background: Aberrant expression of caveolin-1 (CAV-1) is involved in the pathogenesis of hepatocellular carcinoma (HCC); however, the results have been inconsistent due to the small size of sample in the individual study. Methods: We performed a meta-analysis and evaluated the association of CAV-1 protein overexpression and clinicopathological significance by using Review Manager 5.2. Pooled ORs and HR with corresponding CIs were calculated. Results: Nine studies were included in the meta-analysis with 810 HCC and 172 cirrhosis patients. CAV-1 protein overexpression was correlated with the risk of cirrhosis; OR was 3.25, p=0.01. Furthermore, the rate of CAV-1 protein overexpression was significantly higher in HCC with cirrhosis than HCC without cirrhosis, suggesting that the CAV-1 protein overexpression likely initiated carcinogenesis in liver with cirrhosis and subsequently contributed to the progression of HCC. In addition, CAV-1 protein overexpression was strongly associated with poor differentiated HCC and invasion; ORs were 2.61 and 2.71, respectively. CAV-1 protein overexpression was strongly correlated with poor overall survival in patients with HCC; HR was 0.4, p=0.03. Conclusions: In summary, CAV-1 protein overexpression is at risk for liver cirrhosis and HCC derived from cirrhosis, and CAV-1 is also a promising prognostic predictor in HCC.

Neurotensin receptor 1 (NTSR1) is a G-protein-coupled receptor (GPCR) that engages multiple subtypes of G protein, and is involved in the regulation of blood pressure, body temperature, weight and the response to pain. Here we present structures of human NTSR1 in complex with the agonist JMV449 and the heterotrimeric Gi1 protein, at a resolution of 3 Å. We identify two conformations: a canonical-state complex that is similar to recently reported GPCR-Gi/o complexes (in which the nucleotide-binding pocket adopts more flexible conformations that may facilitate nucleotide exchange), and a non-canonical state in which the G protein is rotated by about 45 degrees relative to the receptor and exhibits a more rigid nucleotide-binding pocket. In the non-canonical state, NTSR1 exhibits features of both active and inactive conformations, which suggests that the structure may represent an intermediate form along the activation pathway of G proteins. This structural information, complemented by molecular dynamics simulations and functional studies, provides insights into the complex process of G-protein activation.

Successful ST-segment elevation myocardial infarction (STEMI) management is time-sensitive and is based on prompt reperfusion mainly to reduce patient mortality. It has evolved from a single hospital care to an integrated regional network approach over the last decades. This prospective study, named the China STEMI Care Project (CSCAP), aims to show how implementation of different types of integrated regional STEMI care networks can improve the reperfusion treatment rate, shorten the total duration of myocardial ischaemia and lead to mortality reduction step by step.

Results of previous studies on the association of the CpG island methylator phenotype (CIMP) with colorectal cancer (CRC) prognosis were inconsistent and mostly based on different CIMP definitions. The current study aimed to comprehensively investigate the associations between DNA methylation on genes previously used to define CIMP status with CRC survival.

Epstein-Barr virus (EBV), the first human tumor virus to have been discovered, sustains an asymptomatic lifelong infection in ∼95% of the world's population. Reportedly, EBV infection induces the expression of specific cellular microRNAs (miRNAs), such as miR-155, miR-146a, miR-21, which can contribute to the persistence of latently infected cells. In this study, we investigated whether C-X-C chemokine receptor type 4 (CXCR4) is a cellular target of human miR-146a. We also investigated the role of miR-146a and CXCR4 in EBV-associated cells. The results indicate that miR-146a is more abundantly expressed in EBV-positive than in EBV-negative cells. MiR-146a down-regulated CXCR4 expression in a dose- and time-dependent manner. Phenotypic experiments detected miR-146a mimics that could suppress cell proliferation and cell migration and promote cell apoptosis by targeting CXCR4. In addition, miR-146a mimics suppressed cell survival by decreasing the population of G0/G1 phase cells. Latent membrane protein (LMP)1, an importance oncoprotein, can stimulate miR-146a and inhibit the CXCR4 expression. Our findings indicate that LMP1-miR-146a-CXCR4 axis functions as a regulator in the EBV-associated cells.

Adventitious roots (ARs) are important for some plants that depend on clonal propagation. In this study, we demonstrate that a salt-responsive gene module is involved in the negative regulation of AR development in poplar. In this module, the expression of bZIP53 is induced by salt stress and it encodes a transcription factor with transactivation activity. Overexpression or induced expression of bZIP53 in poplar lines resulted in inhibition of AR growth, while heterologous overexpression of bZIP53 in Arabidopsis resulted in a similar phenotype. Results from RNA-seq and RT-qPCR assays predicted IAA4-1 and IAA4-2 to be downstream genes that were regulated by bZIP53. Further investigation of protein-DNA interactions using yeast one-hybrid, electrophoretic mobility shift, dual luciferase reporter, and GUS co-expression assays also showed that IAA4-1/2 were the genes that were directly regulated by bZIP53. Induced-expression IAA4-1/2 transgenic poplar lines also showed inhibited AR growth. In addition, both poplar bZIP53 and IAA4-1/2 showed a response to salt stress. On the basis of these results, we conclude that the bZIP53-IAA4 module is involved in the negative regulation of AR development in poplar.

The urgent problem in the treatment of breast cancer is the recurrence induced by breast cancer stem cells (CSCs). Understanding the role and molecular mechanism of specific molecules in breast cancer stem cells can provide a theoretical basis for better treatment. TRIP6 is an adapter protein which belongs to the zyxin family of LIM proteins and is important in regulating the functions of CSCs. The present study aims to investigate the effects and mechanism of TRIP6 in breast cancer.

With the escalating costs in drug development, discovering new uses of approved drugs, i.e., drug repurposing, has attracted increasing interest. Spermidine and spermine are important polyamines for most cells and their biosynthesis are strictly regulated by the polyamine metabolic network. In cancerous cells and tumor environments, the concentrations of polyamines are much higher than in normal cells. During the synthesis of spermidine and spermine, an amino-propyl group is provided by decarboxylated S-adenosylmethionine, and the latter is generated from S-adenosylmethionine by AdoMetDC (AdoMet decarboxylase). Therefore, as a rate-limiting enzyme in the biosynthesis of spermidine and spermine, AdoMetDC has been an attractive drug target in cancer studies. In the last decades, many AdoMetDC inhibitors have been discovered, and several AdoMetDC inhibitors are under clinical trials, but unfortunately, none of them have been approved yet. To overcome the high costs in time and money for discovering de novo inhibitors, we set out to repurpose clinic drugs as AdoMetDC inhibitors. We used steric-clashes alleviating receptors (SCAR), a computer-aided drug discovery strategy developed by us recently for in silico screening. By combining computational screening and experimental validation, we successfully identified two approved drugs that have inhibitory potency on AdoMetDC's enzymatic activity. SCAR was previously shown to be suitable for the discovery of both covalent and non-covalent inhibitors, and this work further demonstrated the value of the SCAR strategy in drug repurposing.

G-protein-coupled receptors (GPCRs) are pivotal drug targets for many diseases. Coagulation Factor II Thrombin Receptor (F2R) is an important member of GPCR family that is highly expressed in osteoclasts. However, the role of F2r in osteoclasts is still unclear. Here, to examine the functions of F2r on osteoclast formation, differentiation, activation, survival, and acidification, we employed loss-of-function and gain-of-function approaches to study F2r using F2r-targeted short hairpin RNA (sh-F2r) lentivirus and overexpression plasmid pLX304-F2r lentivirus respectively, in mouse bone marrow cells (MBMs) induced osteoclasts. We used three shRNAs targeting F2r which had the ability to efficiently and consistently knock down the expression of F2r at different levels. Notably, F2r knockdown trigged a significant increase in osteoclast activity, number, and size, as well as promoted bone resorption and F-actin ring formation with increased osteoclast marker gene expression. Moreover, F2r overexpression blocked osteoclast formation, maturation, and acidification, indicating that F2r negatively regulates osteoclast formation and function. Furthermore, we investigated the mechanism(s) underlying the role of F2r in osteoclasts. We detected RANKL-induced signaling pathways related protein changes F2r knockdown cells and found significantly increased pAkt levels in sh-F2r infected cells, as well as significantly enhanced phosphorylation of p65 and IKBα in early stages of RANKL stimulation. These data demonstrated that F2r responds to RANKL stimulation to attenuate osteoclastogenesis through inhibiting the both F2r-Akt and F2r-NFκB signaling pathways, which lead a reduction in the expression of osteoclast genes. Our study suggests that targeting F2r may be a novel therapeutic approach for bone diseases, such as osteoporosis.

We conducted a cross-sectional study investigating community-dwelling older population to determine association between immunoscenescence marker, inflammatory cytokines and frailty. Frailty status was classified with 33-item modified frailty index and latent class analysis was applied to explore the latent classes (subtypes) of frailty. In multivariable analysis, higher Tfh2 cells were associated with a higher risk of frailty [1.13(1.03-1.25)] in females, but a lower risk of cognitive and functional frail [0.92(0.86-0.99)] and physiological frail [0.92(0.87-0.98)]. Additionally, a greater risk of multi-frail and physiological frail correlated with low Tfh1 [0.77(0.60-0.99); 0.87(0.79-0.96)] and Tfh17 cells [0.79(0.65-0.96); 0.86(0.78-0.94)], respectively. Higher B cells were associated with decreased frailty/pre-frailty both in females [0.89(0.81-0.98)] and males [0.82(0.71-0.96)], but did not correlate with frailty subtypes. Regarding inflammatory markers, participants in the TGF-β 2nd quartile showed a decreased risk of pre-frailty/frailty in females [0.39(0.17-0.89)] and psychological frail [0.37(0.16-0.88)], compared with those in the top tertile. Moreover, we found participants in the 2nd tertile for IL-12 levels showed a decreased risk of physiological frail [0.40 (0.17-0.97)]. Our study highlights the importance of Tfh cell subsets and inflammatory markers in frailty in a sex-specific manner, particularly in terms of frailty subtype.

Identification and characterization of lncRNAs in cancer with a view to their application in improving diagnosis and therapy remains a major challenge that requires new and innovative approaches. We have developed an integrative framework termed "CLING", aimed to prioritize candidate cancer-related lncRNAs based on their associations with known cancer lncRNAs. CLING focuses on joint optimization and prioritization of all candidates for each cancer type by integrating lncRNA topological properties and multiple lncRNA-centric networks. Validation analyses revealed that CLING is more effective than prioritization based on a single lncRNA network. Reliable AUC (Area Under Curve) scores were obtained across 10 cancer types, ranging from 0.85 to 0.94. Several novel lncRNAs predicted in the top 10 candidates for various cancer types have been confirmed by recent biological experiments. Furthermore, using a case study on liver hepatocellular carcinoma as an example, CLING facilitated the successful identification of novel cancer lncRNAs overlooked by differential expression analyses (DEA). This time- and cost-effective computational model may provide a valuable complement to experimental studies and assist in future investigations on lncRNA involvement in the pathogenesis of cancers. We have developed a web-based server for users to rapidly implement CLING and visualize data, which is freely accessible at http://bio-bigdata.hrbmu.edu.cn/cling/. CLING has been successfully applied to predict a few potential lncRNAs from thousands of candidates for many cancer types.

Trophoblasts as the particular cells of the placenta play an important role in implantation and formation of the maternal-fetal interface. RND3 (also known as RhoE) is a unique member of the Rnd subfamily of small GTP-binding proteins. However, its function in cytotrophoblasts (CTBs) at the maternal-fetal interface is poorly understood. In the present study, we found that RND3 expression was significantly increased in trophoblasts from the villous tissues of patients with recurrent miscarriage (RM). RND3 inhibited proliferation and migration and promoted apoptosis in HTR-8/SVneo cells. Using dual-luciferase reporter and chromatin immunoprecipitation assays, we found that forkhead box D3 (FOXD3) is a key transcription factor that binds to the RND3 core promoter region and regulates RND3 expression. Here, the level of FOXD3 was upregulated in the first-trimester CTBs of patients with RM, which in turn mediated RND3 function, including inhibition of cell proliferation and migration and promotion of apoptosis. Further, we found that RND3 regulates trophoblast migration and proliferation via the RhoA-ROCK1 signaling pathway and inhibits apoptosis via ERK1/2 signaling. Taken together, our findings suggest that RND3 and FOXD3 may be involved in pathogenesis of RM and may serve as potential therapeutic targets.

Colorectal cancer (CRC) is highly heterogeneous leading to variable prognosis and treatment responses. Therefore, it is necessary to explore novel personalized and reproducible prognostic signatures to aid clinical decision-making. The present study combined large-scale gene expression profiles and clinical data of 1828 patients with CRC from multi-centre studies and identified a personalized gene prognostic signature consisting of 46 unique genes (called function-derived personalized gene signature [FunPGS]) from an integrated statistics and function-derived perspective. In the meta-training and multiple independent validation cohorts, the FunPGS effectively discriminated patients with CRC with significantly different prognosis at the individual level and remained as an independent factor upon adjusting for clinical covariates in multivariate analysis. Furthermore, the FunPGS demonstrated superior performance for risk stratification with respect to other recently reported signatures and clinical factors. The complementary value of the molecular signature and clinical factors was further explored, and it was observed that the composite signature called IMCPS greatly improved the predictive performance of survival estimation relative to molecular signatures or clinical factors alone. With further prospective validation in clinical trials, the FunPGS may become a promising and powerful personalized prognostic tool for stratifying patients with CRC in order to achieve an optimal systemic therapy.