MvMRL: a multi-view molecular representation learning method for molecular property prediction.

Effective molecular representation learning is very important for Artificial Intelligence-driven Drug Design because it affects the accuracy and efficiency of molecular property prediction and other molecular modeling relevant tasks. However, previous molecular representation learning studies often suffer from limitations, such as over-reliance on a single molecular representation, failure to fully capture both local and global information in molecular structure, and ineffective integration of multiscale features from different molecular representations. These limitations restrict the complete and accurate representation of molecular structure and properties, ultimately impacting the accuracy of predicting molecular properties. To this end, we propose a novel multi-view molecular representation learning method called MvMRL, which can incorporate feature information from multiple molecular representations and capture both local and global information from different views well, thus improving molecular property prediction. Specifically, MvMRL consists of four parts: a multiscale CNN-SE Simplified Molecular Input Line Entry System (SMILES) learning component and a multiscale Graph Neural Network encoder to extract local feature information and global feature information from the SMILES view and the molecular graph view, respectively; a Multi-Layer Perceptron network to capture complex non-linear relationship features from the molecular fingerprint view; and a dual cross-attention component to fuse feature information on the multi-views deeply for predicting molecular properties. We evaluate the performance of MvMRL on 11 benchmark datasets, and experimental results show that MvMRL outperforms state-of-the-art methods, indicating its rationality and effectiveness in molecular property prediction. The source code of MvMRL was released in https://github.com/jedison-github/MvMRL.

Role of small molecules as drug candidates for reprogramming somatic cells into induced pluripotent stem cells: A comprehensive review.

With the use of specific genetic factors and recent developments in cellular reprogramming, it is now possible to generate lineage-committed cells or induced pluripotent stem cells (iPSCs) from readily available and common somatic cell types. However, there are still significant doubts regarding the safety and effectiveness of the current genetic methods for reprogramming cells, as well as the conventional culture methods for maintaining stem cells. Small molecules that target specific epigenetic processes, signaling pathways, and other cellular processes can be used as a complementary approach to manipulate cell fate to achieve a desired objective. It has been discovered that a growing number of small molecules can support lineage differentiation, maintain stem cell self-renewal potential, and facilitate reprogramming by either increasing the efficiency of reprogramming or acting as a genetic reprogramming factor substitute. However, ongoing challenges include improving reprogramming efficiency, ensuring the safety of small molecules, and addressing issues with incomplete epigenetic resetting. Small molecule iPSCs have significant clinical applications in regenerative medicine and personalized therapies. This review emphasizes the versatility and potential safety benefits of small molecules in overcoming challenges associated with the iPSCs reprogramming process.

Identification of different myofiber types in pigs muscles and construction of regulatory networks.

BACKGROUND: Skeletal muscle is composed of muscle fibers with different physiological characteristics, which plays an important role in regulating skeletal muscle metabolism, movement and body homeostasis. The type of skeletal muscle fiber directly affects meat quality. However, the transcriptome and gene interactions between different types of muscle fibers are not well understood. RESULTS: In this paper, we selected 180-days-old Large White pigs and found that longissimus dorsi (LD) muscle was dominated by fast-fermenting myofibrils and soleus (SOL) muscle was dominated by slow-oxidizing myofibrils by frozen sections and related mRNA and protein assays. Here, we selected LD muscle and SOL muscle for transcriptomic sequencing, and identified 312 differentially expressed mRNA (DEmRs), 30 differentially expressed miRNA (DEmiRs), 183 differentially expressed lncRNA (DElRs), and 3417 differentially expressed circRNA (DEcRs). The ceRNA network included ssc-miR-378, ssc-miR-378b-3p, ssc-miR-24-3p, XR_308817, XR_308823, SMIM8, MAVS and FOS as multiple core nodes that play important roles in muscle development. Moreover, we found that different members of the miR-10 family expressed differently in oxidized and glycolytic muscle fibers, among which miR-10a-5p was highly expressed in glycolytic muscle fibers (LD) and could target MYBPH gene mRNA. Therefore, we speculate that miR-10a-5p may be involved in the transformation of muscle fiber types by targeting the MYHBP gene. In addition, PPI analysis of differentially expressed mRNA genes showed that ACTC1, ACTG2 and ACTN2 gene had the highest node degree, suggesting that this gene may play a key role in the regulatory network of muscle fiber type determination. CONCLUSIONS: We can conclude that these genes play a key role in regulating muscle fiber type transformation. Our study provides transcriptomic profiles and ceRNA interaction networks for different muscle fiber types in pigs, providing reference for the transformation of pig muscle fiber types and the improvement of meat quality.

PLZF protein forms a complex with protein TET1 to target TCF7L2 in undifferentiated spermatogonia.

The transcription factor promyelocytic leukemia zinc finger (PLZF, also known as ZBTB16) is critical for the self-renewal of spermatogonial stem cells (SSCs). However, the function of PLZF in SSCs is not clear. Here, we found that PLZF acted as an epigenetic regulator of stem cell maintenance and self-renewal of germ cells. The PLZF protein interacts with the ten-eleven translocation 1 (TET1) protein and subsequently acts as a modulator to regulate the expression of self-renewal-related genes. Furthermore, Transcription Factor 7-like 2 (TCF7L2) is promoted by the coordination of PLZF and Tri-methylation of lysine 4 on histone H3 (H3K4me3). In addition, testicular single-cell sequencing indicated that TCF7L2 is commonly expressed in the PLZF cluster. We demonstrated that PLZF directly targets TCF7L2 and alters the landscape of histone methylation in the SSCs nucleus. Meanwhile, the RD domain and Zn finger domain of PLZF synergize with H3K4me3 and directly upregulate TCF7L2 expression at the transcriptional level. Additionally, we identified a new association between PLZF and the histone methyltransferase EZH2 at the genomic level. Our study identified a new association between PLZF and H3K4me3, established the novel PLZF&TET1-H3K4me3-TCF7L2 axis at the genomic level which regulates undifferentiated spermatogonia, and provided a platform for studying germ cell development in male domestic animals.

Rapid conversion of porcine pluripotent stem cells into macrophages with chemically defined conditions.

A renewable source of porcine macrophages derived from pluripotent stem cells (PSCs) would be a valuable alternative to primary porcine alveolar macrophages (PAMs) in the research of host-pathogen interaction mechanisms. We developed an efficient and rapid protocol, within 11 days, to derive macrophages from porcine PSCs (pPSCs). The pPSC-derived macrophages (pPSCdMs) exhibited molecular and functional characteristics of primary macrophages. The pPSCdMs showed macrophage-specific surface protein expression and macrophage-specific transcription factors, similar to PAMs. The pPSCdMs also exhibited the functional characteristics of macrophages, such as endocytosis, phagocytosis, porcine respiratory and reproductive syndrome virus infection and the response to lipopolysaccharide stimulation. Furthermore, we performed transcriptome sequencing of the whole differentiation process to track the fate transitions of porcine PSCs involved in the signaling pathway. The activation of transforming growth factor beta signaling was required for the formation of mesoderm and the inhibition of the transforming growth factor beta signaling pathway at the hematopoietic endothelium stage could enhance the fate transformation of hematopoiesis. In summary, we developed an efficient and rapid protocol to generate pPSCdMs that showed aspects of functional maturity comparable with PAMs. pPSCdMs could provide a broad prospect for the platforms of host-pathogen interaction mechanisms.

Integrated analysis of the ubiquitination mechanism reveals the specific signatures of tissue and cancer.

BACKGROUND: Ubiquitination controls almost all cellular processes. The dysregulation of ubiquitination signals is closely associated with the initiation and progression of multiple diseases. However, there is little comprehensive research on the interaction and potential function of ubiquitination regulators (UBRs) in spermatogenesis and cancer. METHODS: We systematically characterized the mRNA and protein expression of UBRs across tissues and further evaluated their roles in testicular development and spermatogenesis. Subsequently, we explored the genetic alterations, expression perturbations, cancer hallmark-related pathways, and clinical relevance of UBRs in pan-cancer. RESULTS: This work reveals heterogeneity in the expression patterns of UBRs across tissues, and the expression pattern in testis is the most distinct. UBRs are dynamically expressed during testis development, which are critical for normal spermatogenesis. Furthermore, UBRs have widespread genetic alterations and expression perturbations in pan-cancer. The expression of 79 UBRs was identified to be closely correlated with the activity of 32 cancer hallmark-related pathways, and ten hub genes were screened for further clinical relevance analysis by a network-based method. More than 90% of UBRs can affect the survival of cancer patients, and hub genes have an excellent prognostic classification for specific cancer types. CONCLUSIONS: Our study provides a comprehensive analysis of UBRs in spermatogenesis and pan-cancer, which can build a foundation for understanding male infertility and developing cancer drugs in the aspect of ubiquitination.

Unveiling the multi-target compounds of Rhazya stricta: Discovery and inhibition of novel target genes for the treatment of clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a prevalent kidney malignancy with a pressing need for innovative therapeutic strategies. In this context, emerging research has focused on exploring the medicinal potential of plants such as Rhazya stricta. Nevertheless, the complex molecular mechanisms underlying its potential therapeutic efficacy remain largely elusive. Our study employed an integrative approach comprising data mining,network pharmacology,tissue cell type analysis, and molecular modelling approaches to identify potent phytochemicals from R. stricta, with potential relevance for ccRCC treatments. Initially, we collected data on R. stricta's phytochemical from public databases. Subsequently, we integrated this information with differentially expressed genes (DEGs) in ccRCC, which were derived from microarray datasets(GSE16441,GSE66270, and GSE76351). We identified potential intersections between R. stricta and ccRCC targets, which enabled us to construct a compound-genes-pathway network using Cytoscape software. This helped illuminate R. stricta's multi-target pharmacological effects on ccRCC. Moreover, tissue cell type analysis added another layer of insight into the cellular specificity of potential therapeutic targets in the kidney. Through further Kaplan-Meier survival analysis, we pinpointed MMP9,ACE,ERBB2, and HSP90AA1 as prospective diagnostic and prognostic biomarkers for ccRCC. Notably, our study underscores the potential of R. stricta derived compounds-namely quebrachamine,corynan-17-ol, stemmadenine,strictanol,rhazinilam, and rhazimolare-to impede ccRCC progression by modulating the activity of MMP9,ACE,ERBB2, and HSP90AA1 genes. Further, molecular docking and dynamic simulations confirmed the plausible binding affinities of these compounds. Despite these promising findings, we recognize the need for comprehensive in vivo and in vitro studies to further investigate the pharmacokinetics and biosafety profiles of these compounds.

SCM is potential resource for non-invasive preimplantation genetic testing based on human embryos single-cell sequencing.

The ongoing development of assisted reproductive technologies has provided hope to individuals struggling with infertility, promising the potential for a healthy pregnancy. One significant innovation in field of pre-implantation genetic screening (PGS) requires the biopsy of embryos or oocytes, which has potential implications for the health and development of the resultant offspring. Therefore, a non-invasive approach to preimplantation genetic screening is highly sought after. The clinical application of non-invasive preimplantation genetic testing (ni-PGT) is currently limited, with its sensitivity and specificity requiring further investigation. In this study, we used 218 human embryos for single-cell whole genome amplification (WGA), along with ni-PGT of blastocoele fluid (BF) and spent culture medium (SCM). Whole blastocyst (WB), trophectoderm biopsy (TB), and inner cell mass (ICM) from embryo biopsies were used as controls to track genomic signal alterations. Our results showed that the overall genome similarity between SCM and ICM was higher than that of BF. Apart from the Y chromosome, both SCM and ICM demonstrated numerous variant sites across other chromosomes.Further categorization of gene variants in these two sample types revealed that missense variants were the most prevalent, single nucleotide polymorphisms were more common than insertions or deletions, and C > T was the dominant single nucleotide variants in both ICM and SCM. Lastly, we found that the mutant genes in SCM and ICM had different biological functions and pathways. This study indicates that SCM provides a more effective source of embryonic DNA for preimplantation genetic screening, offering a novel reference point for genetic screening research.

Identification of molecular mechanisms underlying the therapeutic effects of Celosia Cristata on immunoglobulin nephropathy.

Immunoglobulin A (IgA) nephropathy also known as Berger's disease, is a silent monster and perhaps the most prevalent glomerulonephritis that often accounts for end-stage kidney failure, thereby signifying a growing public health problem worldwide. The limited amount of available data and a broad spectrum of dysregulated physiological processes of IgAN make it a challenging task and a disproportionate economic load on the community health sector. Celosia cristata is an Amaranthaceous plant with attractive colorful inflorescences that are used in various regions of earth for the treatment of numerous ailments. A list of studies evidences the therapeutic efficacy of C. cristata against complicated disorders, but the precise molecular mechanism is yet to be discovered. This study is attributed to the identification of bioactive compounds, pathways, and target genes for the better treatment of IgAN. In the current analysis, compound-target genes-pathway networks were explored which uncovered that isorhamnetin, stigmasterol, luteolin, amaranthin, and ß-sitosterol may serve as a magic bullet against IgAN by influencing the targets genes involved in the disease pathogenesis. Later, the expression of hub genes was then further analyzed using a microarray dataset (GSE93798). Through expression analysis, it is worth noting that FOS, JUN, and EGFR were considerably upregulated, and at the same moment, AKT1 was considerably downregulated in IgAN patients. Lastly, docking analysis further strengthened the current findings by validating the effective activity of the active ingredients against putative target genes. In summary, we propose that five key compounds including, isorhamnetin, stigmasterol, luteolin, amaranthin, and ß-sitosterol, aid in the regulation of JUN, FOS, AKT1, and EGFR, which may serve as a promising and enthralling therapeutic option for IgAN. The overall integration of network pharmacology with molecular docking unveiled the multi-target pharmacological mechanisms of C. cristata against IgAN. This study provides convincing evidence that C. cristata might partially alleviate the IgAN and ultimately lays a foundation for further experimental research on the anti-IgAN activity of C. cristata.

Super-enhancers conserved within placental mammals maintain stem cell pluripotency.

Despite pluripotent stem cells sharing key transcription factors, their maintenance involves distinct genetic inputs. Emerging evidence suggests that super-enhancers (SEs) can function as master regulatory hubs to control cell identity and pluripotency in humans and mice. However, whether pluripotency-associated SEs share an evolutionary origin in mammals remains elusive. Here, we performed comprehensive comparative epigenomic and transcription factor binding analyses among pigs, humans, and mice to identify pluripotency-associated SEs. Like typical enhancers, SEs displayed rapid evolution in mammals. We showed that BRD4 is an essential and conserved activator for mammalian pluripotency-associated SEs. Comparative motif enrichment analysis revealed 30 shared transcription factor binding motifs among the three species. The majority of transcriptional factors that bind to identified motifs are known regulators associated with pluripotency. Further, we discovered three pluripotency-associated SEs (SE-SOX2, SE-PIM1, and SE-FGFR1) that displayed remarkable conservation in placental mammals and were sufficient to drive reporter gene expression in a pluripotency-dependent manner. Disruption of these conserved SEs through the CRISPR-Cas9 approach severely impaired stem cell pluripotency. Our study provides insights into the understanding of conserved regulatory mechanisms underlying the maintenance of pluripotency as well as species-specific modulation of the pluripotency-associated regulatory networks in mammals.

EPI-Mind: Identifying Enhancer-Promoter Interactions Based on Transformer Mechanism.

MOTIVATION: Enhancer-Promoter Interactions (EPIs) is an essential step in the gene regulation process. However, the detection of EPIs by traditional wet experimental techniques is time-consuming and expensive. Thus, computational methods would be very useful for understanding the mechanism of EPIs. A number of approaches have been proposed to address this problem. Nevertheless, there is room for exploration and improvement for the existing research methods. METHODS: In this study, a novel deep-learning model named EPI-Mind was proposed to predict EPIs with sequences features. First, we encoded enhancers and promoters sequences with pre-trained DNA vectors. Then, the Convolutional Neural Network (CNN) was utilized to rough extract the global and local features. Finally, the transformer mechanism was introduced to further extract the feature. We first trained a model named EPI-Mind_spe which can predict EPIs in one cell line. To achieve general prediction across different cell lines and further improve the performance of the model, a second-time training was carried on. The redivided dataset were used to train a new model called EPI-Mind_gen which can predict EPIs across different cell lines. To further improve the accuracy, a new model named EPI-Mind_best was trained which used the EPI-Mind_gen as a pre-trained model. RESULTS: EPI-Mind_spe has the ability of predict EPIs with average AUROC above 90% and average AUPR above 70% but with cell lines specificity. EPI-Mind_gen can predict EPIs across different cell lines and its average AUROC is higher than the EPI-Mind_spe about 4.8%. EPI-Mind_best is superior to the state-of-the-art predictors on benchmarking datasets. EPI-Mind_best achieved best in 5 indicators within 12 indicators consists of AUPR and AUROC which is better than pioneers. CONCLUSION: This research proposed a method, which was called EPI-Mind, to predict EPIs only with enhancer and promoters sequences, the framework of which was based on deep learning. This manuscript may provide a new route to solve the problem.

Comprehensive comparison of two types of algorithm for circRNA detection from short-read RNA-Seq.

MOTIVATION: Circular RNA is generally formed by the 'back-splicing' process between the upstream splice acceptor and the downstream donor in/not in the regulation of the corresponding RNA-binding proteins or cis-elements. Therefore, more and more software packages have been developed and they are mostly based on the identification of the back-spliced junction reads. However, recent studies developed two software tools that can detect circRNA candidates by constructing k-mer table or/and de Bruijn graph rather than reads mapping. RESULTS: Here, we compared the precision, sensitivity and detection efficiency between software tools based on different algorithms. Eleven representative detection tools with two types of algorithm were selected for the overall pipeline analysis of RNA-seq datasets with/without RNase R treatment in two cell lines. Precision, sensitivity, AUC, F1 score and detection efficiency metrics were assessed to compare the prediction tools. Meanwhile, the sensitivity and distribution of highly expressed circRNAs before and after RNase R treatment were also revealed by their enrichment, unaffected and depleted candidate frequencies. Eventually, we found that compared to the k-mer based tools, CIRI2 and KNIFE based on reads mapping had relatively superior and more balanced detection performance regardless of the cell line or RNase R (-/+) datasets. AVAILABILITY AND IMPLEMENTATION: All predicted results and source codes can be retrieved from https://github.com/luffy563/circRNA_tools_comparison. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Single-cell transcriptome analysis of Bisphenol A exposure reveals the key roles of the testicular microenvironment in male reproduction.

Testicular development during juvenile is crucial for subsequent male reproductive function. However, it remains poorly understood about the contribution of the testis microenvironment to human germ cell maturation. Therefore, we systematically analyzed scRNA-seq transcriptome and found the dramatic changes in cell-type composition in human testis during puberty. Then we constructed cell-cell communication networks between germ cells and somatic cells in the juvenile testis, which may be achieved via immune-related pathways. Our results showed that maturation-promoting factors are the switches of the Sertoli cells that drive sperm maturation. Furthermore, we found that Bisphenol A(BPA) enhanced the maturation and growth of germ cells through the Sertoli cell's secretory protein. Finally, our results indicate Bisphenol A would lead to the dysregulation of secreted protein expression in Sertoli cells during spermatogenesis, which in turn has direct cytotoxicity to Sertoli cells. Bisphenol A is one of the underlying causes of non-obstructive azoospermia (NOA). In summary, our results reveal the reproductive toxicity and molecular mechanism of Bisphenol A in Sertoli cells and male reproduction. Provide a reference for the toxicity of Bisphenol A to human reproduction.

Ten Years of EWAS.

Epigenome-wide association study (EWAS) has been applied to analyze DNA methylation variation in complex diseases for a decade, and epigenome as a research target has gradually become a hot topic of current studies. The DNA methylation microarrays, next-generation, and third-generation sequencing technologies have prepared a high-quality platform for EWAS. Here, the progress of EWAS research is reviewed, its contributions to clinical applications, and mainly describe the achievements of four typical diseases. Finally, the challenges encountered by EWAS and make bold predictions for its future development are presented.

Persulfidation-induced structural change in SnRK2.6 establishes intramolecular interaction between phosphorylation and persulfidation.

Post-translational modifications (PTMs), including phosphorylation and persulfidation, regulate the activity of SNF1-RELATED PROTEIN KINASE2.6 (SnRK2.6). Here, we report how persulfidations and phosphorylations of SnRK2.6 influence each other. The persulfidation of cysteine C131/C137 alters SnRK2.6 structure and brings the serine S175 residue closer to the aspartic acid D140 that acts as ATP-γ-phosphate proton acceptor, thereby improving the transfer efficiency of phosphate groups to S175 to enhance the phosphorylation level of S175. Interestingly, we predicted that S267 and C137 were predicted to lie in close proximity on the protein surface and found that the phosphorylation status of S267 positively regulates the persulfidation level at C137. Analyses of the responses of dephosphorylated and depersulfidated mutants to abscisic acid and the H2S-donor NaHS during stomatal closure, water loss, gas exchange, Ca2+ influx, and drought stress revealed that S175/S267-associated phosphorylation and C131/137-associated persulfidation are essential for SnRK2.6 function in vivo. In light of these findings, we propose a mechanistic model in which certain phosphorylations facilitate persulfidation, thereby changing the structure of SnRK2.6 and increasing its activity.

Single-cell RNA sequencing reveals atlas of dairy goat testis cells.

Single-cell RNA sequencing (scRNA-seq) is useful for exploring cell heterogeneity. For large animals, however, little is known regarding spermatogonial stem cell (SSC) self-renewal regulation, especially in dairy goats. In this study, we described a high-resolution scRNA-seq atlas derived from a dairy goat. We identified six somatic cell and five spermatogenic cell subtypes. During spermatogenesis, genes with significantly changed expression were mainly enriched in the Notch, TGF-ß, and Hippo signaling pathways as well as the signaling pathway involved in the regulation of stem cell pluripotency. We detected and screened specific candidate marker genes ( TKTL1 and AES) for spermatogonia. Our study provides new insights into goat spermatogenesis and the development of testicular somatic cells.

Histone demethylase complexes KDM3A and KDM3B cooperate with OCT4/SOX2 to define a pluripotency gene regulatory network.

The pluripotency gene regulatory network of porcine induced pluripotent stem cells(piPSCs), especially in epigenetics, remains elusive. To determine the biological function of epigenetics, we cultured piPSCs in different culture conditions. We found that activation of pluripotent gene- and pluripotency-related pathways requires the erasure of H3K9 methylation modification which was further influenced by mouse embryonic fibroblast (MEF) served feeder. By dissecting the dynamic change of H3K9 methylation during loss of pluripotency, we demonstrated that the H3K9 demethylases KDM3A and KDM3B regulated global H3K9me2/me3 level and that their co-depletion led to the collapse of the pluripotency gene regulatory network. Immunoprecipitation-mass spectrometry (IP-MS) provided evidence that KDM3A and KDM3B formed a complex to perform H3K9 demethylation. The genome-wide regulation analysis revealed that OCT4 (O) and SOX2 (S), the core pluripotency transcriptional activators, maintained the pluripotent state of piPSCs depending on the H3K9 hypomethylation. Further investigation revealed that O/S cooperating with histone demethylase complex containing KDM3A and KDM3B promoted pluripotency genes expression to maintain the pluripotent state of piPSCs. Together, these data offer a unique insight into the epigenetic pluripotency network of piPSCs.

LIN28A inhibits DUSP family phosphatases and activates MAPK signaling pathway to maintain pluripotency in porcine induced pluripotent stem cells.

LIN28A, an RNA-binding protein, plays an important role in porcine induced pluripotent stem cells (piPSCs). However, the molecular mechanism underlying the function of LIN28A in the maintenance of pluripotency in piPSCs remains unclear. Here, we explored the function of LIN28A in piPSCs based on its overexpression and knockdown. We performed total RNA sequencing (RNA-seq) of piPSCs and detected the expression levels of relevant genes by quantitative real-time polymerase chain reaction (qRT-PCR), western blot analysis, and immunofluorescence staining. Results indicated that piPSC proliferation ability decreased following LIN28A knockdown. Furthermore, when LIN28A expression in the shLIN28A2 group was lower (by 20%) than that in the negative control knockdown group ( shNC), the pluripotency of piPSCs disappeared and they differentiated into neuroectoderm cells. Results also showed that LIN28A overexpression inhibited the expression of DUSP (dual-specificity phosphatases) family phosphatases and activated the mitogen-activated protein kinase (MAPK) signaling pathway. Thus, LIN28A appears to activate the MAPK signaling pathway to maintain the pluripotency and proliferation ability of piPSCs. Our study provides a new resource for exploring the functions of LIN28A in piPSCs.

Dmrt1 regulates the immune response by repressing the TLR4 signaling pathway in goat male germline stem cells.

Double sex and mab-3-related transcription factor 1 (Dmrt1), which is expressed in goat male germline stem cells (mGSCs) and Sertoli cells, is one of the most conserved transcription factors involved in sex determination. In this study, we highlighted the role of Dmrt1 in balancing the innate immune response in goat mGSCs. Dmrt1 recruited promyelocytic leukemia zinc finger (Plzf), also known as zinc finger and BTB domain-containing protein 16 (Zbtb16), to repress the Toll-like receptor 4 (TLR4)-dependent inflammatory signaling pathway and nuclear factor (NF)-κB. Knockdown of Dmrt1 in seminiferous tubules resulted in widespread degeneration of germ and somatic cells, while the expression of proinflammatory factors were significantly enhanced. We also demonstrated that Dmrt1 stimulated proliferation of mGSCs, but repressed apoptosis caused by the immune response. Thus, Dmrt1 is sufficient to reduce inflammation in the testes, thereby establishing the stability of spermatogenesis and the testicular microenvironment.

FifBase: a comprehensive fertility-associated indicators factor database for domestic animals.

Fertility refers to the ability of animals to maintain reproductive function and give birth to offspring, which is an important indicator to measure the productivity of animals. Fertility is affected by many factors, among which environmental factors may also play key roles. During the past years, substantial research studies have been conducted to detect the factors related to fecundity, including genetic factors and environmental factors. However, the identified genes associated with fertility from countless previous studies are randomly dispersed in the literature, whereas some other novel fertility-related genes are needed to detect from omics-based datasets. Here, we constructed a fertility index factor database FifBase based on manually curated published literature and RNA-Seq datasets. During the construction of the literature group, we obtained 3301 articles related to fecundity for 13 species from PubMed, involving 2823 genes, which are related to 75 fecundity indicators or 47 environmental factors. Eventually, 1558 genes associated with fertility were filtered in 10 species, of which 1088 and 470 were from RNA-Seq datasets and text mining data, respectively, involving 2910 fertility-gene pairs and 58 fertility-environmental factors. All these data were cataloged into FifBase (http://www.nwsuaflmz.com/FifBase/), where the fertility-related factor information, including gene annotation and environmental factors, can be browsed, retrieved and downloaded with the user-friendly interface.