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Structural variations (SVs) are a major contributor to genetic diversity and phenotypic variations, but their prevalence and functions in domestic animals are largely unexplored. Here we generated high-quality genome assemblies for 15 individuals from genetically diverse sheep breeds using Pacific Biosciences (PacBio) high-fidelity sequencing, discovering 130.3 Mb nonreference sequences, from which 588 genes were annotated. A total of 149,158 biallelic insertions/deletions, 6531 divergent alleles, and 14,707 multiallelic variations with precise breakpoints were discovered. The SV spectrum is characterized by an excess of derived insertions compared to deletions (94,422 vs. 33,571), suggesting recent active LINE expansions in sheep. Nearly half of the SVs display low to moderate linkage disequilibrium with surrounding single-nucleotide polymorphisms (SNPs) and most SVs cannot be tagged by SNP probes from the widely used ovine 50K SNP chip. We identified 865 population-stratified SVs including 122 SVs possibly derived in the domestication process among 690 individuals from sheep breeds worldwide. A novel 168-bp insertion in the 5′ untranslated region (5′ UTR) ofHOXB13is found at high frequency in long-tailed sheep. Further genome-wide association study and gene expression analyses suggest that this mutation is causative for the long-tail trait. In summary, we have developed a panel of high-quality de novo assemblies and present a catalog of structural variations in sheep. Our data capture abundant candidate functional variations that were previously unexplored and provide a fundamental resource for understanding trait biology in sheep.

Herein, the defect-related properties of an AlN sample prepared based on the optimal process parameters by metal nitride vapor phase epitaxy (MNVPE) were investigated. The FWHM values of the (0002)/(101̅2) planes of the sample by MNVPE are 397/422 arcsec; the advantages of similar FWHM values of (0002) and (101̅2) planes will have a huge advantage over other preparation methods such as MOCVD. From the cross-sectional TEM images of the AlN sample, it is found that the fusion of a large number of a + c type dislocations occur at the interface of the low temperature buffer layer and the epitaxial layer, which affects the growth mode of the epitaxial layer. The lower FHWM value of the

Exposed to the natural light-dark cycle, 24 h rhythms exist in behavioral and physiological processes of living beings. Interestingly, under constant darkness or constant light, living beings can maintain a robust endogenous rhythm with a free running period (FRP) close to 24 h. In mammals, the circadian rhythm is coordinated by a master clock located in the suprachiasmatic nucleus (SCN) of the brain, which is composed of about twenty thousand self-oscillating neurons. These SCN neurons form a heterogenous network to output a robust rhythm. Thus far, the exact network topology of the SCN neurons is unknown. In this article, we examined the effect of the SCN network structure on the FRP when exposed to constant light by a Poincaré model. Four typical network structures were considered, including a Nearest-neighbor coupled network, a Newman-Watts (NW) small world network, an Erdös-Rényi (ER) random network and a Barabási-Albert (BA) scale free network. The results show that the FRP is longest in the BA network, because the BA network is characterized by the most heterogeneous structure among these four types of networks. These findings are not affected by the average node degree of the SCN network or the value of relaxation rate of the SCN neuronal oscillators. Our findings contribute to the understanding of how the network structure of the SCN neurons influences the FRP.

Objective: We used Mendelian randomization to examine the causal effects of physical activity (PA) and leisure sedentary behaviour (LSB) on the risk of knee and hip osteoarthritis (KOA/HOA). Methods: We used large-scale datasets of PA (N=377,000) and LSB (N=422,218) as exposures, and KOA (N=403,124), HOA (N=398,873), and KOA and/or HOA (N=417,596) as outcomes. We applied inverse-variance weighted, MR-Egger and weighted median methods to estimate causal effects. The validity of the instrumental variables was assessed using Cochran’s Q test, MR-Egger intercept test and MR-PRESSO test. We performed leave-one-out analysis and funnel plot to examine the influence of individual variants and potential publication bias. We also conducted risk factor analyses to explore possible mediators. Results: The genetic prediction of PA increased the risk of KOA (OR: 1.29; P: 0.02). Television viewing raised the risk of KOA (OR: 1.34; P: 5.30e-5) and HOA (OR: 1.66; P: 1.77e-15). However, computer use lowered the risk of KOA (OR: 0.80; P: 0.01) and KOA and/or HOA (OR: 0.83; P: 0.01). No effect of PA, fraction of accelerations >425 milli-gravities and driving on KOA/HOA was observed. Risk factor analysis indicated that multiple risk factors may mediate the above causal relationships.

The epitaxial aluminum nitride (AlN) crystals were grown on c-plane sapphire using high-temperature metal nitride vapor phase epitaxy at the source materials' different molar flow ratios (V/III ratios). The effects of various V/III ratios on the surface morphology, crystalline quality, material straining, and optical properties of heteroepitaxial AlN thin films were studied using X-ray diffraction, scanning electron microscopy, Raman spectroscopy, and photoluminescence (PL). With the increase in the V/III ratio from 1473 to 7367, the substrate surface underwent changes that vary from whiskers to three-dimensional island structures, two-dimensional layered stack structures, and stacked sheet structures. Additionally, due to the presence of nanoscale pits on the substrate surface, almost all samples were tensile stressers. The PL spectra demonstrated the defect luminescence of the epitaxial films, indicating that nitrogen vacancies and oxygen impurities were the samples' main defects.

Due to long-term exposure to the natural environment, insulators are prone to self-blast, threatening the safety and reliability of transmission lines. Because of the different sizes of the insulator self-blast area and the complicated background, it is inevitable that the missed and false detections occur. To solve this problem, this paper proposes a deep neural network called Mina-Net (Multi-Layer INformation Fusion and Attention Mechanism Network). Mina-Net is based on YOLOv4. First, the shallow feature map with more detailed texture information is fused into the feature pyramid. Then, an improved SENet is applied to recalibrate the features of different levels in the channel direction. The experimental results on the actual dataset show that Mina-Net has increased the average precision by 4.78% compared with the YOLOv4.

Background Regional anesthesia appears to reduce cancer recurrence, but the optimal anesthesia modality for non-muscle invasive bladder cancer (NMIBC) were still under debate. Therefore, we sought to assess the effect of regional and GA only upon the recurrence and long-term prognosis of NMIBC through this meta-analysis. Methods We performed an extensive literature search of PubMed, Embase, Web of Science, the Cochrane Library and China National Knowledge Infrastructure (up to October 30, 2022) to identify eligible articles on the possible impact of different anesthetic modalities for the recurrence rate of NMIBC. Results Eight studies comprising 3764 participants, including 2117 subjects with RA and 1647 with GA, were finally enrolled. Cancer recurrence rate was significantly lower in subjects with RA than those with GA. (RR 0.84, 95%CI 0.72–0.98, P = 0.031). Significant differences were not detected between GA and RA in the time of recurrence (SMD 2.07, 95% CI -0.49-4.64, P = 0.113) and cancer progression (RR 1.14, 95%CI 0.71–1.84, P = 0.589). Results from subgroup analysis demonstrated that spinal anesthesia could significantly decrease the incidence of cancer recurrence in comparison with general anesthesia (RR 0.80, 95%CI 0.72–0.88, P

Nanoparticles for immuno-photothermal therapy were constructed by encapsulating photosensitizers and aluminum ions into zeolitic imidazolate framework-8, which significantly inhibited the growth of primary and rechallenged tumors.

Male infertility may be caused by genetic and/or environmental factors that impair spermatogenesis and sperm maturation. High-altitude (HA) hypoxic environments represent one of the most serious challenges faced by humans that reside in these areas. To assess the influence of the plateau environment on semen parameters, 2,798 males, including 1,111 native Tibetans and 1,687 Han Chinese individuals living in the plains (HCILP) who underwent pre-pregnancy checkups, were enrolled in this study. The semen samples of males were evaluated to determine conventional sperm parameters, sperm morphology, and sperm movement. Reproductive endocrine hormones (REHs) were detected in 474 males, including 221 Tibetans and 253 HCILP. Due to recurrent abortions in partners, the DNA fragmentation index (DFI) of 133 native Tibetans and 393 HCILP individuals was further compared. Luteinizing hormone (LH) (4.94 ± 2.12 vs. 3.29 ± 1.43 U/L), prolactin (11.34 ± 3.87 vs. 8.97 ± 3.48 nmol/L), E2/T (0.22 ± 0.11 vs 0.11 ± 0.05), median total sperm motility (61.20% vs. 51.56%), and DFI (23.11% vs. 7.22%) were higher in males from plateau areas while median progressive motility (PR) (35.60% vs. 41.12%), total number of PR sperms (51.61 vs. 59.63 mil/ejaculate), percentage of normal form sperms (3.70% vs. 6.00%), curvilinear velocity (36.10 vs. 48.97 μm/s), straight-line (rectilinear) velocity (14.70 vs. 31.52 μm/s), estradiol (103.82 ± 45.92 vs. 146.01 ± 39.73 pmol/L), progesterone (0.29 ± 0.27 vs. 2.22 ± 0.84 nmol/L), testosterone (4.90 ± 1.96 vs. 14.36 ± 5.24 nmol/L), and testosterone secretion index (ratio of testosterone to LH) (33.45 ± 22.86 vs 145.78 ± 73.41) were lower than those in males from the plains. There was no difference in median total sperm number (157.76 vs. 151.65 mil/mL), sperm concentration (52.40 vs. 51.79 mil/mL), volume (3.10 vs. 3.10 mL), total normal form sperms (5.91 vs. 6.58 mil/ejaculate, p50), and follicle-stimulating hormone (FSH) levels (4.13 ± 2.55 U/L vs 3.82 ± 2.35 U/L) between the two groups of males. The REH and sperm parameters of males from HA hypoxic environments were adaptively altered. Although the total number of PR sperm decreased and DFI increased, the Tibetan population that lives at HAs has been found to grown continuously and rapidly. These results supplement prior findings regarding the impact of HA on male reproductive function.

Background Renal cell carcinoma (RCC) contributed to 403,262 new cases worldwide in 2018, which constitutes 2.2% of global cancer, nevertheless, sunitinib, one of the major targeted therapeutic agent for RCC, often developed invalid due to resistance. Emerging evidences suggested sunitinib can impact tumor environment which has been proven to be a vital factor for tumor progression. Methods In the present study, we used ssGSEA to extract the immune infiltrating abundance of clear cell RCC (ccRCC) and normal control samples from GSE65615, TCGA, and GTEx; key immune cells were determined by Student's t‐test and univariable Cox analysis. Co‐expression network combined with differentially expressed analysis was then applied to derive key immune‐related genes for ccRCC, followed by the identification of hub genes using differential expression analysis. Subsequently, explorations and validations of the biological function and the immune‐related and sunitinib‐related characteristics were conducted in KEGG, TISIDB, Oncomine, ICGC, and GEO databases. Results We refined immature dendritic cells and central memory CD4 T cells which showed associations with sunitinib and ccRCC. Following, five hub genes (CRYBB1, RIMBP3C, CEACAM4, HAMP, and LYL1) were identified for their strong relationships with sunitinib and immune infiltration in ccRCC. Further validations in external data refined CRYBB1, CEACAM4, and HAMP which play a vital role in sunitinib resistance, immune infiltrations in ccRCC, and the development and progression of ccRCC. In conclusion, our findings could shed light on the resistance of sunitinib in ccRCC and provide novel biomarkers or drug targets for ccRCC., We identified five hub genes (CRYBB1, RIMBP3C, CEACAM4, HAMP, and LYL1) related to immune infiltration, sunitinib in renal carcinoma. External validation refined CRYBB1, CEACAM4 and HAMP which played a vital role in the development and progression of ccRCC and implicated in sunitinib resistance and immune infiltrations in ccRCC.

To explore the effectiveness of vitamin E in male infertility, a systematic review and meta-analysis was conducted.The retrieval time was from January 1947 to May 2021, without language restriction. Stata 12.0 was used for the meta-analysis.A total of 8 randomized controlled trials involving 459 patients were included. The results showed that after vitamin E treatment, semen volume was reduced (95% CI: - 0.55 to - 0.06, SMD = - 0.30, p = 0.015), total sperm count was increased (95% CI: 0.02-0.45, SMD = 0.23, p = 0.035), and the differences were statistically significant. There were no statistically significant differences in increasing sperm concentration (95% CI: -0.21-0.29, SMD = 0.04, p = 0.769), total sperm motility (95% CI: -0.01-0.42, SMD = 0.20, p = 0.061) or sperm forward motility rate (95% CI: -0.06-0.65, SMD = 0.29, p = 0.106). Subgroup analysis showed that vitamin E treatment for six months could improve sperm forward motility (95% CI: 0.46-1.14, SMD = 0.80, p0.001).Vitamin E could increase the total sperm count and reduce the volume of semen in male infertility patients, and long-term treatment could improve the forward motility rate of sperm. The decrease of semen volume may be the result of different abstinence time before and after the test.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy. Even with complete tumor resection and adjuvant therapies, the prognosis of patients with ACC remains unsatisfactory. In the microtumor environment, the impact of a disordered immune system and abnormal immune responses is enormous. To improve treatment, novel prognostic predictors and treatment targets for ACC need to be identified. Hence, credible prognostic biomarkers of immune-associated genes (IRGs) should be explored and developed.We downloaded RNA-sequencing data and clinical data from The Cancer Genome Atlas (TCGA) data set, Genotype-Tissue Expression data set, and Gene Expression Omnibus data set. Gene set enrichment analysis (GSEA) was applied to reveal the potential functions of differentially expressed genes.GSEA indicated an association between ACC and immune-related functions. We obtained 332 IRGs and constructed a prognostic signature on the strength of 3 IRGs (INHBA, HELLS, and HDAC4) in the training cohort. The high-risk group had significantly poorer overall survival than the low-risk group (p .001). Multivariate Cox regression was performed with the signature as an independent prognostic indicator for ACC. The testing cohort and the entire TCGA ACC cohort were utilized to validate these findings. Moreover, external validation was conducted in the GSE10927 and GSE19750 cohorts. The tumor-infiltrating immune cells analysis indicated that the quantity of T cells, natural killer cells, macrophage cells, myeloid dendritic cells, and mast cells in the immune microenvironment differed between the low-risk and high-risk groups.Our three-IRG prognostic signature and the three IRGs can be used as prognostic indicators and potential immunotherapeutic targets for ACC. Inhibitors of the three novel IRGs might activate immune cells and play a synergistic role in combination therapy with immunotherapy for ACC in the future.

Progranulin (PGRN) is an autocrine growth factor that regulates cell proliferation, migration, wound healing, and tissue repair in mammals. Lamprey is the most primitive of the extant vertebrates and is regarded as the survivor of a once flourishing group of paleozoic vertebrates, with a history of more than 500 million years. To date, the evolutionary dynamics and the underlying function of the PGRNs remain largely unclear in lamprey. Here, we screened four genes encoding PGRNs from the genomes of Lethenteron reissneri and Petromyzon marinus, including one long form (named Lr-PGRN-L) and three short forms (named Lr-PGRN-S1, Lr-PGRN-S2, and Lr-PGRN-S3), and performed phylogenetic tree, functional domain, and synteny analyses to identify the evolutionary history of the four Lr-PGRNs. In addition, the expressions of the four Lr-pgrn family genes and the immune response against various pathogenic challenges were also investigated. We found that these genes were widely distributed in various tissues of lamprey and performed a variety of functions. Moreover, our results suggest that Lr-PGRN-S1 induces cell migration and proliferation, and is involved in repair after skin and spinal cord injury under appropriate conditions. Our findings are valuable because they improve the understanding of the evolutionary relationship of vertebrate pgrn genes, as well as providing new insights into the diverse and important roles of Lr-PGRNs.

Endometrial development is a complicated process involving numerous regulatory factors. Circular RNAs (circRNAs) have been known as a member of the naturally occurring non-coding RNA family, and are reportedly crucial for a variety of physiological processes. This study investigated the circRNA landscape of non-pregnant endometrium of dairy goats during estrus. Non-pregnant endometrial samples of goats at estrus day 5 (Ed5) and estrus day 15 (Ed15) were used to methodically analyze the circRNA landscape using strand-specific Ribo-Zero RNA-Seq. A total of 2 331 differentially expressed (P

Background Immune checkpoint blockade (ICB) therapy has become a first-line treatment option for metastatic urothelial carcinoma (mUC) patients who do not meet the criteria of cisplatin. Still, only a few people can benefit from it, so useful predictive markers are needed. Methods Download the ICB-based mUC and chemotherapy-based bladder cancer cohorts, and extract the expression data of pyroptosis-related genes (PRG). The LASSO algorithm was used to construct the PRG prognostic index (PRGPI) in the mUC cohort, and we verified the prognostic ability of PRGPI in two mUC and two bladder cancer cohorts. Results Most of the PRG in the mUC cohort were immune-activated genes, and a few were immunosuppressive genes. The PRGPI composed of GZMB, IRF1, and TP63 can stratify the risk of mUC. In IMvigor210 and GSE176307 cohorts, the P-values of Kaplan Meier analysis was

Tamoxifen is a first-line therapeutic drug for oestrogen-receptor positive breast cancer; however, like other therapeutics, its clinical use is limited by acquired resistance. Tamoxifen-resistant cells have demonstrated enhanced aerobic glycolysis; however, the mechanisms underlying this upregulation remain unclear. Here, we demonstrated that G-protein coupled oestrogen receptor (GPER) was involved in the upregulation of aerobic glycolysis via induction of hypoxia-inducible factor-1α (HIF-1α) expression and transcriptional activity in tamoxifen-resistant cells. Additionally, GPER stabilized HIF-1α through inhibiting its hydroxylation and ubiquitin-mediated degradation, which were associated with upregulation of C-terminal hydrolase-L1 (UCH-L1), downregulation of prolyl hydroxylase 2 (PHD2) and von Hippel-Lindau tumour suppressor protein (pVHL), induction of HIF-1α/UCH-L1 interaction, and suppression of HIF-1α/PHD2-pVHL association. The GPER/HIF-1α axis was functionally responsible for regulating tamoxifen sensitivity both in vitro and in vivo. Moreover, there was a positive correlation between GPER and HIF-1α expression in clinical breast cancer tissues, and high levels of GPER combined with nuclear HIF-1α indicated poor overall survival. High levels of the GPER/HIF-1α axis were also correlated with shorter relapse-free survival in patients receiving tamoxifen. Hence, our findings support a critical role of GPER/HIF-1α axis in the regulation of aerobic glycolysis in tamoxifen-resistant cells, offering a potential therapeutic target for tamoxifen-resistant breast cancer.

Varicocele (VC) is the most common treatable cause of infertility, but it is difficult to distinguish fertile from infertile VC populations because the pathogenesis is unclear. In order to study the related mechanism of VC causing male sterility, we made VC rats model by surgery, analyzed the rat epididymal sperm, and use the transcriptome sequencing compared all the miRNA expression differences in testicular tissue between VC rats, surgical treatment rats and control rats. The differentially expressed miRNAs (DEMs) of testicular tissue were also screened by the edgeR package in R software. We found that rno-miR-210-3p, rno-miR-6316, rno-miR-190a-5p and rno-miR-135b-5p were key miRNAs for VC and they were all up-regulated in VC samples and they are enriched in regulation of immune system process (GO:0002683), innate immune system (R-RNO-168,249) and apoptotic signaling pathway (GO:0097190). We hypothesize that negative regulation of immune system and apoptosis play an important role in the occurrence and development of VC, and it is induced the abnormal expression of target genes (such as Kitlg, Cxcl12) may involve in the development of VC associated infertility. Four key miRNAs, rno-miR-210-3p, rno-miR-6316, rno-miR-190a-5p and rno-miR-135b-5p, as well as their target genes are critical in VC, which could have attractive applications to provide new biomarkers for VC.

In this study, we used bioinformatics tools to analyze transcriptome data from cholangiocarcinoma (CCA) patients in multiple datasets (Sun Yat-sen University, TCGA and GSE32225 cohorts) to identify mechanisms that regulate tumor infiltration by immune cells and survival outcomes. We identified 96 differentially expressed genes (DEGs), including 13 upregulated and 83 downregulated genes, in CCA tissues as regulatory T cells were significantly higher and the proportions of activated natural killer cells and monocytes were significantly lower in CCA tissues than the precancerous tissues. The survival outcomes of CCA patients were associated with the TP53 gene mutation status, levels of Oncostatin M (OSM) expression, and the proportions of tumor-infiltrating immune cell types, including dendritic cells, monocytes, and T follicular helper cells. Functional enrichment analysis of the DEGs in the high OSM-expressing CCA tissues showed that pathways related to tumor progression and immune response were significantly upregulated. Our study demonstrates that OSM expression and TP53 mutation status regulate the tumor infiltration by immune cells and survival outcomes in CCA. OSM is thus a potential prognostic biomarker and therapeutic target in cholangiocarcinoma.

We conducted the study to investigate the relationship between anogenital distance (AGD) and benign prostatic hyperplasia (BPH) related lower urinary tract symptoms (LUTS). From May 2018 to January 2020, 220 subjects: 110 men with BPH-related LUTS (BPH-LUTS group) and 110 men without any urination complaints (control group) were selected. Clinical questionnaires, detailed physical examinations, including AGDas (distance between the anus and posterior base of the scrotum) and AGDap (distance between the anus and upper penis) measurements, and blood tests were all assessed. The two groups were similar in terms of basic features (P > 0.05). The AGDap and AGDas in the control group were significantly shorter than the BPH-LUTS group (P 0.05 for all). The associations between TT and BPH-LUTS related evaluations were also negligible (P > 0.05 for all). Furthermore, the study revealed that the AGDas cut-off values for mild, moderate, and severe symptom (based on IPSS score) in BPH-LUTS cases were 27.4 mm and 46.8 mm [area under curve (AUC): 0.802 and AUC: 0.779, respectively], respectively. Longer AGDas was related to more severe BPH related symptoms. It may be useful to consider AGD as a marker for BPH-LUTS. Further well-designed studies are remained to be done to explore the intriguing problem.

The present study aimed to assess the value of human umbilical cord mesenchymal stem cells (hUC-MSCs) for the treatment of diabetes-induced erectile dysfunction (DMED). We established a type 1 diabetes model through intra-abdominal streptozotocin injection. After 10 weeks, an apomorphine test was performed to screen the rats for erectile dysfunction (ED). The rats were divided into three groups: normal control group (n = 10), DMED group (n = 9) and DMED+hUC-MSC group (n = 9). After 4 weeks of hUC-MSC therapy, erectile function was evaluated by intracavernous pressure measurements, and penile tissue collagen and smooth muscle were examined by haematoxylin-eosin and Masson's trichrome staining. In addition, western blotting, immunohistochemistry and RT-PCR analysis of TLR4, VEGF and eNOS were performed. The results showed that hUC-MSC treatment restored erectile function (p .05) and reversed the smooth muscle/collagen ratio changes of DMED rats (p .05). Furthermore, hUC-MSC treatment inhibited the expression of TLR4 (p .05) and enhanced VEGF and eNOS expression (p .05). In conclusion, hUC-MSC treatment restored the erectile function of diabetic rats by inhibiting TLR4, improving corpora cavernosa fibrosis, and increasing VEGF and eNOS expression.

To evaluate the expression, potential functions and mechanisms of long noncoding RNAs (lncRNAs) in the pathogenesis of varicocele (VC)-induced spermatogenic dysfunction.We established a rat model with left experimental VC and divided rats into the sham group, the VC group, and the surgical treatment group (each group, n = 10). Haematoxylin and eosin (HE) staining and sperm quality were analysed to evaluate spermatogenesis function. LncRNA expression profiles were analysed using lncRNA-Seq (each group n = 3) and validated using quantitative real-time polymerase chain reaction (each group n = 10). Correlation analysis and gene target miRNA prediction were used to construct competing endogenous RNA network. The regulated signalling pathway and spermatogenic dysfunction of differentially expressed lncRNAs (DE lncRNAs) were validated by Western blot.HE detection and sperm quality analysis showed that VC could induce spermatogenic dysfunction. Eight lncRNAs were upregulated and three lncRNAs were downregulated in the VC group compared with the sham group and surgical treatment group. The lncRNA of NONRATG002949.2, NONRATG001060.2, NONRATG013271.2, NONRATG022879.2, NONRATG023424.2, NONRATG005667.2 and NONRATG010686.2 were significantly negatively related to sperm quality, while NONRATG027523.1, NONRATG017183.2 and NONRATG023747.2 were positively related to sperm quality. The lncRNAs promote spermatogenic cell apoptosis and inhibit spermatogonia and spermatocyte proliferation and meiotic spermatocytes by regulating the PI3K-Akt signalling pathway.DE lncRNAs may be potential biomarkers for predicting the risk of spermatogenic dysfunction in VC and the effect of surgical repair. These DE lncRNAs promote spermatogenic dysfunction by regulating the PI3K-Akt signalling pathway.