Karyotypic diversification is more prominent in Equus species than in other mammals. Here, using next generation sequencing technology, we generated and de novo assembled quality genomes sequences for a male wild horse (Przewalski's horse) and a male domestic horse (Mongolian horse), with about 93-fold and 91-fold coverage, respectively. Portion of Y chromosome from wild horse assemblies (3 M bp) and Mongolian horse (2 M bp) were also sequenced and de novo assembled. We confirmed a Robertsonian translocation event through the wild horse's chromosomes 23 and 24, which contained sequences that were highly homologous with those on the domestic horse's chromosome 5. The four main types of rearrangement, insertion of unknown origin, inserted duplication, inversion, and relocation, are not evenly distributed on all the chromosomes, and some chromosomes, such as the X chromosome, contain more rearrangements than others, and the number of inversions is far less than the number of insertions and relocations in the horse genome. Furthermore, we discovered the percentages of LINE_L1 and LTR_ERV1 are significantly increased in rearrangement regions. The analysis results of the two representative Equus species genomes improved our knowledge of Equus chromosome rearrangement and karyotype evolution.

5-Hydroxymethylcytosine (5hmC) is present in T-even phage and mammalian DNA as well as some nucleoside antibiotics, including mildiomycin and bacimethrin, during whose synthesis 5hmC is produced by the hydrolysis of 5-hydroxymethyl cytidine 5'-monophosphate (hmCMP) by an N-glycosidase MilB. Recently, the MilB-CMP complex structure revealed its substrate specificity for CMP over dCMP. However, hmCMP instead of CMP is the preferred substrate for MilB as supported by that its KM for CMP is ∼27-fold higher than that for hmCMP. Here, we determined the crystal structures of MilB and its catalytically inactive E103A mutant in complex with hmCMP. In the structure of the complex, Phe22 and Arg23 are positioned in a cage-like active site resembling the binding pocket for the flipped 5-methylcytosine (5mC) in eukaryotic 5mC-binding proteins. Van der Waals interaction between the benzene ring of Phe22 and the pyrimidine ring of hmCMP stabilizes its binding. Remarkably, upon hmCMP binding, the guanidinium group of Arg23 was bent ∼65° toward hmCMP to recognize its 5-hydroxymethyl group, inducing semi-closure of the cage-like pocket. Mutagenesis studies of Arg23 and bioinformatics analysis demonstrate that the positively charged Arg/Lys at this site is critical for the specific recognition of the 5-hydroxymethyl group of hmCMP.

Bunostomum trigonocephalum and Bunostomum phlebotomum are blood-feeding hookworms of sheep and cattle, causing considerable economic losses to the live stock industries. Studying genetic variability within and among hookworm populations is critical to addressing epidemiological and ecological questions. Mitochondrial (mt) DNA is known to provide useful markers for investigations of population genetics of hookworms, but mt genome sequence data are scant. In the present study, the complete mitochondrial DNA (mtDNA) sequences of the sheep and goat hookworm B. trigonocephalum were determined for the first time, and the mt genome of B. phlebotomum from yak in China was also sequenced for comparative analyses of their gene contents and genome organizations. The lengths of mt DNA sequences of B. trigonocephalum sheep isolate, B. trigonocephalum goat isolate and B. phlebotomum China yak isolate were 13,764bp, 13,771bp and 13,803bp in size, respectively. The identity of the mt genomes was 99.7% between B. trigonocephalum sheep isolate and B. trigonocephalum goat isolate. The identity of B. phlebotomum China yak isolate mt genomes was 85.3% with B. trigonocephalum sheep isolate, and 85.2% with B. trigonocephalum goat isolate. All the mt genes of the two hookworms were transcribed in the same direction and gene arrangements were consistent with those of the GA3 type, including 12 protein-coding genes, 2 rRNA genes and 22 tRNA genes, but lacking ATP synthetase subunit 8 gene. The mt genomes of B. trigonocephalum and B. phlebotomum were similar to prefer bases A and T, the contents of A+T are 76.5% (sheep isolate), 76.4% (goat isolate) and 76.9% (China yak isolate), respectively. Phylogenetic relationships reconstructed using concatenated amino acid sequences of 12 protein-coding genes with three methods (maximum likelihood, Bayesian inference and neighbor joining) revealed that the B. trigonocephalum and B. phlebotomum represent distinct but closely-related species. These data provide novel and useful genetic markers for studying the systematics, and population genetics of the two ruminant hookworms.

Cervical cancer is the second most common female carcinoma. Current therapies are often unsatisfactory, especially for advanced stage patients. The aim of this study was to explore the effects of tatariside G (TG) on apoptosis in human cervical cancer HeLa cells and the possible mechanism of action involved. An MTT assay was employed to evaluate cell viability. Hoechst 33258 staining and flow cytometry (FCM) assays were used to detect cell apoptosis. The protein expression of phosphorylated JNK, P38, ERK and Akt and cleaved caspase-3 and caspase-9 was evaluated by western blot analysis. Additionally, the mRNA expression of caspase-3 and caspase-9 was measured by fluorescent quantitative reverse transcription-PCR (FQ-RT-PCR). TG notably inhibited cell viability, enhanced the percentage of apoptotic cells, facilitated the phosphorylation of p38 MAPK and JNK proteins and caspase-3 and caspase-9 cracking, downregulated the phosphorylation level of Akt, and increased the loss of MMP and the mRNA expression of caspase-3 and caspase-9. TG-induced apoptosis is associated with activation of the mitochondrial death pathway. TG may be an effective candidate for chemotherapy against cervical cancer.

Objective. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) reduces inflammation and has been identified as an anti-inflammatory prostaglandin in numerous animal models. In this study, we investigated both effects of 15d-PGJ2 and its protection mechanism in concanavalin A- (ConA-) induced autoimmune hepatitis in mice. Materials and Methods. In vivo, Balb/C mice were injected with ConA (25 mg/kg) to induce acute autoimmune hepatitis, and 15d-PGJ2 (10 μg or 25 μg) was administered 1 h before the ConA injection. The histological grade, proinflammatory cytokine levels, and NF-κB and PPARγ activity were determined 6, 12, and 24 h after the ConA injection. In vitro, LO2 cells and RAW264.7 cells were pretreated with 15d-PGJ2 (2 μM) 1 h before the stimulation with ConA (30 μg/mL). The NF-κB and PPARγ activity were determined 30 min after the ConA administration. Results. Pretreatment with 15d-PGJ2 reduced the pathological effects of ConA-induced autoimmune hepatitis and significantly reduced the levels of cytokines after injection. 15d-PGJ2 activated PPARγ, blocked the degradation of IκBα, and inhibited the translocation of NF-κB into the nucleus. Conclusion. These results indicate that 15d-PGJ2 protects against ConA-induced autoimmune hepatitis by reducing proinflammatory cytokines. This reduction in inflammation may correlate with the activation of PPARγ and the reduction in NF-κB activity.

Gray leaf spot (GLS) caused by Cercospora zeae-maydis (Czm) or Cercospora zeina (Cz) is a devastating maize disease and results in substantial yield reductions worldwide. GLS resistance is a quantitatively inherited trait. The development and cultivation of GLS-resistant maize hybrids are the most cost-effective and efficient ways to control this disease.

Hepatic ischemia/reperfusion (I/R) injury is an important clinical problem, and its consequences can seriously threaten human health. Apoptosis and autophagy have been shown to contribute to cell death in hepatic I/R injury. Hydrogen sulfide (H2S) is the third most common endogenously produced gaseous signaling molecule and is known to exert a protective effect against hepatic I/R injury. In this study, the purpose is to explore both the effect and mechanism of H2S on hepatic I/R injury.

To evaluate the benefits and harms of aspirin for the primary prevention of CVD and determine whether the effects vary by sex and diabetes status.

Hydrogen sulfide (H2S) is known to exert anti-inflammatory properties. Apoptosis and autophagy play important roles in concanavalin A (Con A)-induced acute hepatitis. The purpose of this study was to explore both the effect and mechanism of H2S on Con A-induced acute hepatitis.

miRNAs have extensive functions in differentiation, metabolism, programmed cell death, and tumor metastasis by post-transcriptional regulation. Vasculogenic mimicry is an important pathway in tumor metastasis. Many factors can regulate vasculogenic mimicry, including miRNAs. In previous studies, miR-124 was found to repress proliferation and metastasis in different types of cancers, but whether it functions in cervical cancer remained unknown. Here, we demonstrate that miR-124 can repress vasculogenic mimicry, migration and invasion in HeLa and C33A cells in vitro. Furthermore, we reveal that the effect of miR-124 on vasculogenic mimicry, migration and invasion results from its interaction with AmotL1. MiR-124 regulates AmotL1 negatively by targeting its 3'untranslated region (3'UTR). We found that miR-124 can repress the EMT process. Together, these results improve our understanding of the function of miR-124 in tumor metastasis and will help to provide new potential target sites for cervical cancer treatment.

Trithorax group protein MLL5 is an important epigenetic modifier that controls cell cycle progression, chromatin architecture maintenance, and hematopoiesis. However, whether MLL5 has a role in innate antiviral immunity is largely unknown. Here we show that MLL5 suppresses the RIG-I-mediated anti-viral immune response. Mll5-deficient mice infected with vesicular stomatitis virus show enhanced anti-viral innate immunity, reduced morbidity, and viral load. Mechanistically, a fraction of MLL5 located in the cytoplasm interacts with both RIG-I and its E3 ubiquitin ligase STUB1, which promotes K48-linked polyubiquitination and proteasomal degradation of RIG-I. MLL5 deficiency attenuates the RIG-I and STUB1 association, reducing K48-linked polyubiquitination and accumulation of RIG-I protein in cells. Upon virus infection, nuclear MLL5 protein translocates from the nucleus to the cytoplasm inducing STUB1-mediated degradation of RIG-I. Our study uncovers a previously unrecognized role for MLL5 in antiviral innate immune responses and suggests a new target for controlling viral infection.

The bromodomain and extra-terminal proteins (BET) have emerged as promising therapeutic targets for the treatment of castration-resistant prostate cancer (CRPC). We report the design, synthesis and evaluation of a new series of benzoxazinone-containing 3,5-dimethylisoxazole derivatives as selective BET inhibitors. One of the new compounds, (R)-12 (Y02234), binds to BRD4(1) with a Kd value of 110 nM and blocks bromodomain and acetyl lysine interactions with an IC50 value of 100 nM. It also exhibits selectivity for BET over non-BET bromodomain proteins and demonstrates reasonable anti-proliferation and colony formation inhibition effect in prostate cancer cell lines such as 22Rv1 and C4-2B. The BRD4 inhibitor (R)-12 also significantly suppresses the expression of ERG, Myc and AR target gene PSA at the mRNA level in prostate cancer cells. Treatment with (R)-12 significantly suppresses the tumor growth of prostate cancer (TGI = 70%) in a 22Rv1-derived xenograft model. These data suggest that compound (R)-12 is a promising lead compound for the development of a new class of therapeutics for the treatment of CRPC.

Long non-coding RNAs (lncRNAs) constitute an important layer of chromatin regulation that contributes to various biological processes and diseases. By interacting with chromatin, many lncRNAs can regulate that state of chromatin by recruiting chromatin-modifying complexes and thus control large-scale gene expression programs. However, the available information on interactions between lncRNAs and chromatin is hidden in a large amount of dispersed literature and has not been extensively collected. We established the LnChrom database, a manually curated resource of experimentally validated lncRNA-chromatin interactions. The current release of LnChrom includes 382 743 interactions in human and mouse. We also manually collected detailed metadata for each interaction pair, including those of chromatin modifying factors, epigenetic marks and disease associations. LnChrom provides a user-friendly interface to facilitate browsing, searching and retrieving of lncRNA-chromatin interaction data. Additionally, a large amount of multi-omics data was integrated into LnChrom to aid in characterizing the effects of lncRNA-chromatin interactions on epigenetic modifications and transcriptional expression. We believe that LnChrom is a timely and valuable resource that can greatly motivate mechanistic research into lncRNAs.Database URL: http://biocc.hrbmu.edu.cn/LnChrom/.

Hyperinsulinemia is the earliest symptom of insulin resistance (IR), but a causal relationship between the two remains to be established. Here we show that a protein kinase D2 (PRKD2) nonsense mutation (K410X) in two rhesus monkeys with extreme hyperinsulinemia along with IR and metabolic defects by using extreme phenotype sampling and deep sequencing analyses. This mutation reduces PRKD2 at both the mRNA and the protein levels. Taking advantage of a PRKD2-KO mouse model, we demonstrate that PRKD2 deletion triggers hyperinsulinemia which precedes to IR and metabolic disorders in the PRKD2 ablation mice. PRKD2 deficiency promotes β-cell insulin secretion by increasing the expression and activity of L-type Ca2+ channels and subsequently augmenting high glucose- and membrane depolarization-induced Ca2+ influx. Altogether, these results indicate that down-regulation of PRKD2 is involved in the pathogenesis of hyperinsulinemia which, in turn, results in IR and metabolic disorders.

A recent study analyzed 2053 multiple sclerosis (MS) cases and 799 healthy controls to investigate whether five genetic variants (rs11039149, rs12221497, rs2279238, rs7120118 and rs7114704) in NR1H3 are associated with MS risk. However this study reported negative results. It is very important that the appropriate samples and approach should be used in replication studies, which may provide the correct interpretation of the results. Here, we evaluated the above findings using large-scale MS genome-wide association studies with a total of 27,148 samples including 9772 MS cases and 17,376 controls, and multiple expression quantitative trait loci datasets. The results suggest that rs7120118 and rs2279238 variants are significantly associated with MS risk, and could significantly regulate NR1H3 expression in kinds of human tissues and cells. In summary, these findings provide important supplementary information about the association between NR1H3 variants and MS risk.

Decidual CD8+ (dCD8) T cells have been proposed to play important roles in immune protection against the invading pathogens and in tolerance toward the growing semi-allogeneic fetus during early pregnancy. However, their phenotypic and functional characteristics remain poorly defined. Here, we performed the first analysis of the transcriptional and alternative splicing (AS) signatures for human first-trimester dCD8 T cells using high-throughput mRNA sequencing. Our data revealed that dCD8 T cells have distinct transcriptional and AS landscapes when compared with their autologous peripheral blood CD8+ (pCD8) T counterparts. Furthermore, human dCD8 T cells were observed to contain CD8-Treg and effector-memory T-cell subsets, and display enhanced functionality in terms of degranulation and cytokine production on a per-cell basis. Additionally, we have identified the novel splice junctions that use a high ratio of the non-canonical splicing motif GC-AG and found that AS is not a major contributor to the gene expression-level changes between paired pCD8 and dCD8 T cells. Together, our findings not only provide a comprehensive framework of the transcriptional and AS landscapes but also reveal the functional feature of human dCD8 T cells, which are of great importance in understanding the biology of these cells and the physiology of human healthy pregnancy.

The performance of functional near-infrared spectroscopy (fNIRS) is sometimes degraded by the interference caused by the physical or the systemic physiological activities. Several interferences presented during fNIRS recordings are mainly induced by cardiac pulse, breathing, and spontaneous physiological low-frequency oscillations. In previous work, we introduced a multidistance measurement to reduce physiological interference based on recursive least squares (RLS) adaptive filtering. Monte Carlo simulations have been implemented to evaluate the performance of RLS adaptive filtering. However, its suitability and performance on human data still remain to be evaluated. Here, we address the issue of how to detect evoked hemodynamic response to auditory stimulus using RLS adaptive filtering method. A multidistance probe based on continuous wave fNIRS is devised to achieve the fNIRS measurement and further study the brain functional activation. This study verifies our previous findings that RLS adaptive filtering is an effective method to suppress global interference and also provides a practical way for real-time detecting brain activity based on multidistance measurement.

Rheumatoid arthritis (RA) is a progressive autoimmune disease affecting the joints. In this study, we investigated the role of the pro-angiogenic factor leptin in regulating reactive oxygen species (ROS) to promote cell migration and angiogenesis in RA. We showed that leptin triggered RA fibroblast-like synoviocyte (FLS) migration by increased ROS expression. Additionally, leptin enhanced human umbilical vein endothelial cell (HUVEC) tube formation in a ROS/hypoxia-inducible factor-1α-dependent manner, accompanied by increased production of vascular endothelial growth factor and interleukin (IL)-6. We also revealed that antagonists of tumor necrosis factor, IL-6 and IL-1β down-regulated ROS production of RA FLS induced by leptin, which subsequently attenuated RA FLS migration and HUVEC tube formation. These findings demonstrated that leptin might play an important role in RA FLS migration and HUVEC angiogenesis.

Survival predictors are of potential use for informing on biological age and targeting prevention of aging-related morbidity. We assessed associations of 2 novel methylomic survival indicators, a methylation-based mortality risk score (MRscore) and the epigenetic clock-derived age acceleration (AA), with a well-known survival predictor, frailty index (FI), and compared the 3 indicators in mortality prediction. In a large population-based cohort with 14-year follow-up, we found both MRscore and AA to be independently associated with FI, but the association was much stronger for MRscore than for AA. Although all 3 indicators were individually associated with all-cause mortality, robust associations only persisted for MRscore and FI when simultaneously including the 3 indicators in regression models, with hazard ratios (95% CI) of 1.91 (1.63-2.22), 1.37 (1.25-1.51), and 1.05 (0.90-1.22), respectively, per standard deviation increase of MRscore, FI, and AA. Prediction error curves, Harrell's C-statistics, and time-dependent AUCs all showed higher predictive accuracy for MRscore than for FI and AA. These findings were validated in independent samples. Our study demonstrates the ability of the MRscore to strongly enhance survival prediction beyond established markers of biological age, such as FI and AA, and it thus bears potential of a surrogate endpoint for clinical research and intervention.

Insights into disease susceptibility as well as the efficacy of vaccines against typhoid and other enteric pathogens may be informed by better understanding the relationship between the effector immune response and the gut microbiota. In the present study, we characterized the composition (16S rRNA gene profiling) and function (RNA sequencing [RNA-seq]) of the gut microbiota following immunization and subsequent exposure to wild-type Salmonella enterica serovar Typhi in a human challenge model to further investigate the central hypothesis that clinical outcomes may be linked to the gut microbiota. Metatranscriptome analysis of longitudinal stool samples collected from study subjects revealed two stable patterns of gene expression for the human gut microbiota, dominated by transcripts from either Methanobrevibacter or a diverse representation of genera in the Firmicutes phylum. Immunization with one of two live oral attenuated vaccines against S. Typhi had minimal effects on the composition or function of the gut microbiota. It was observed that subjects harboring the methanogen-dominated transcriptome community at baseline displayed a lower risk of developing symptoms of typhoid following challenge with wild-type S. Typhi. Furthermore, genes encoding antioxidant proteins, metal homeostasis and transport proteins, and heat shock proteins were expressed at a higher level at baseline or after challenge with S. Typhi in subjects who did not develop symptoms of typhoid. These data suggest that functional differences relating to redox potential and ion homeostasis in the gut microbiota may impact clinical outcomes following exposure to wild-type S. Typhi.IMPORTANCES. Typhi is a significant cause of systemic febrile morbidity in settings with poor sanitation and limited access to clean water. It has been demonstrated that the human gut microbiota can influence mucosal immune responses, but there is little information available on the impact of the human gut microbiota on clinical outcomes following exposure to enteric pathogens. Here, we describe differences in the composition and function of the gut microbiota in healthy adult volunteers enrolled in a typhoid vaccine trial and report that these differences are associated with host susceptibility to or protection from typhoid after challenge with wild-type S Typhi. Our observations have important implications in interpreting the efficacy of oral attenuated vaccines against enteric pathogens in diverse populations.