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Abstract A complete goat (Capra hircus) reference genome enhances analyses of genetic variation, thus providing insights into domestication and selection in goats and related species. Here, we assemble a telomere-to-telomere (T2T) gap-free genome (2.86 Gb) from a cashmere goat (T2T-goat1.0), including a Y chromosome of 20.96 Mb. With a base accuracy of >99.999%, T2T-goat1.0 corrects numerous genome-wide structural and base errors in previous assemblies and adds 288.5 Mb of previously unresolved regions and 446 newly assembled genes to the reference genome. We sequence the genomes of five representative goat breeds for PacBio reads, and use T2T-goat1.0 as a reference to identify a total of 63,417 structural variations (SVs) with up to 4711 (7.42%) in the previously unresolved regions. T2T-goat1.0 was applied in population analyses of global wild and domestic goats, which revealed 32,419 SVs and 25,397,794 SNPs, including 870 SVs and 545,026 SNPs in the previously unresolved regions. Also, our analyses reveal a set of selective variants and genes associated with domestication (e.g., NKG2D and ABCC4) and cashmere traits (e.g., ABCC4 and ASIP).

Abstract Background There is a lack of effective therapeutic strategies for amyotrophic lateral sclerosis (ALS); therefore, drug repurposing might provide a rapid approach to meet the urgent need for treatment. Methods To identify therapeutic targets associated with ALS, we conducted Mendelian randomization (MR) analysis and colocalization analysis using cis-eQTL of druggable gene and ALS GWAS data collections to determine annotated druggable gene targets that exhibited significant associations with ALS. By subsequent repurposing drug discovery coupled with inclusion criteria selection, we identified several drug candidates corresponding to their druggable gene targets that have been genetically validated. The pharmacological assays were then conducted to further assess the efficacy of genetics-supported repurposed drugs for potential ALS therapy in various cellular models. Results Through MR analysis, we identified potential ALS druggable genes in the blood, including TBK1 [OR 1.30, 95%CI (1.19, 1.42)], TNFSF12 [OR 1.36, 95%CI (1.19, 1.56)], GPX3 [OR 1.28, 95%CI (1.15, 1.43)], TNFSF13 [OR 0.45, 95%CI (0.32, 0.64)], and CD68 [OR 0.38, 95%CI (0.24, 0.58)]. Additionally, we identified potential ALS druggable genes in the brain, including RESP18 [OR 1.11, 95%CI (1.07, 1.16)], GPX3 [OR 0.57, 95%CI (0.48, 0.68)], GDF9 [OR 0.77, 95%CI (0.67, 0.88)], and PTPRN [OR 0.17, 95%CI (0.08, 0.34)]. Among them, TBK1, TNFSF12, RESP18, and GPX3 were confirmed in further colocalization analysis. We identified five drugs with repurposing opportunities targeting TBK1, TNFSF12, and GPX3, namely fostamatinib (R788), amlexanox (AMX), BIIB-023, RG-7212, and glutathione as potential repurposing drugs. R788 and AMX were prioritized due to their genetic supports, safety profiles, and cost-effectiveness evaluation. Further pharmacological analysis revealed that R788 and AMX mitigated neuroinflammation in ALS cell models characterized by overly active cGAS/STING signaling that was induced by MSA-2 or ALS-related toxic proteins (TDP-43 and SOD1), through the inhibition of TBK1 phosphorylation. Conclusions Our MR analyses provided genetic evidence supporting TBK1, TNFSF12, RESP18, and GPX3 as druggable genes for ALS treatment. Among the drug candidates targeting the above genes with repurposing opportunities, FDA-approved drug-R788 and AMX served as effective TBK1 inhibitors. The subsequent pharmacological studies validated the potential of R788 and AMX for treating specific ALS subtypes through the inhibition of TBK1 phosphorylation.

Abstract Introduction Several factors may lead to increased postoperative pain sensitivity, of which remifentanil-induced hyperalgesia (RIH) is one of the main factors. High-dose remifentanil exposure during anesthesia may induce RIH. Esketamine may prevent RIH by antagonizing N-methyl-d-aspartate (NMDA) receptors, thereby reducing the postoperative pain sensitivity. This study examined the effects of different esketamine doses on pain sensitivity in patients undergoing thyroidectomy and determined the optimal dose. Methods This study included 117 patients who received elective thyroidectomy. They were randomized into four groups: saline group (group C), esketamine 0.2 mg·kg−1 group (group RK1), esketamine 0.4 mg·kg−1 group (group RK2), and esketamine 0.6 mg·kg−1 group (group RK3). Five minutes before anesthesia induction, the same volume of study drugs were injected respectively in groups C, RK1, RK2, and RK3. Remifentanil was pumped at the same rate of 0.3 µg·kg−1·min−1 during surgery to ensure uniformity. This study’s primary outcomes were the mechanical pain thresholds measured before surgery, as well as at 30 min, 6 h, 24 h, and 48 h after surgery. Hyperalgesia, rescue analgesia, numerical rating scale (NRS) score, and adverse reactions were recorded. Results Compared with baseline, the mechanical pain threshold was significantly decreased in group C [(94.67 ± 22.85) versus (112.00 ± 36.62) versus (161.33 ± 53.28) g, P

Survival in extreme environments and adaptations during seasonal shifts require specialized metabolic programing. A multi-omic analysis of how regulatory networks impact adipose homeostasis in sheep tails provides insight for how these animals survive extreme environments.

Abstract Myocardial infarction (MI) is a fatal heart disease that affects millions of lives worldwide each year. This study investigated the roles of HIF-1α/lncRNA-TUG1 in mitochondrial dysfunction and pyroptosis in MI. CCK-8, DHE, lactate dehydrogenase (LDH) assays, and JC-1 staining were performed to measure proliferation, reactive oxygen species (ROS), LDH leakage, and mitochondrial damage in hypoxia/reoxygenation (H/R)-treated cardiomyocytes. Enzyme-linked immunoassay (ELISA) and flow cytometry were used to detect LDH, creatine kinase (CK), and its isoenzyme (CK-MB) levels and caspase-1 activity. Chromatin immunoprecipitation (ChIP), luciferase assay, and RNA-immunoprecipitation (RIP) were used to assess the interaction between HIF-1α, TUG1, and FUS. Quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and immunohistochemistry were used to measure HIF-1α, TUG1 and pyroptosis-related molecules. Hematoxylin and eosin (HE), 2,3,5-triphenyltetrazolium chloride (TTC), and terminal deoxynucleotidyl transferase dUTP risk end labelling (TUNEL) staining were employed to examine the morphology, infarction area, and myocardial injury in the MI mouse model. Mitochondrial dysfunction and pyroptosis were induced in H/R-treated cardiomyocytes, accompanied by an increase in the expression of HIF-α and TUG1. HIF-1α promoted TUG1 expression by directly binding to the TUG1 promoter. TUG1 silencing inhibited H/R-induced ROS production, mitochondrial injury and the expression of the pyroptosis-related proteins NLRP3, caspase-1 and GSDMD. Additionally, H/R elevated FUS levels in cardiomyocytes, which were directly inhibited by TUG1 silencing. Fused in sarcoma (FUS) overexpression reversed the effect of TUG1 silencing on mitochondrial damage and caspase-1 activation. However, the ROS inhibitor N-acetylcysteine (NAC) promoted the protective effect of TUG1 knockdown on H/R-induced cardiomyocyte damage. The in vivo MI model showed increased infarction, myocardial injury, ROS levels and pyroptosis, which were inhibited by TUG1 silencing. HIF-1α targeting upregulated TUG1 promotes mitochondrial damage and cardiomyocyte pyroptosis by combining with FUS, thereby promoting the occurrence of MI. HIF-1α/TUG1/FUS may serve as a potential treatment target for MI.

The complete mitochondrial genome (mitogenome) of Dacus haikouensis Wang and Cheng 2002 (Diptera: Tephritidae: Dacinae) was sequenced and annotated. The mitochondrial genome is 15,291 bp (GenBank No. MZ087939), containing 73.0% AT, which is the classical structure for insect mitogenome. Additionally, the phylogenetic tree confirmed that Dacus haikouedsis clustered with Dacus longicornis and Dacus conopsoides. The current study would enrich the mitogenomes of the fruit flies.

Genetic resources for livestock are valuable for understanding their demography and past selection, and may inform future breeding programs and agricultural improvement. Here, the authors present deep resequencing of 248 wild and domestic sheep, with associated data and analysis.

The cigarette beetle Lasioderma serricorne (Fabricius) is a major pest of stored products worldwide, especially tobacco and foods, causing huge economic losses. This study aimed to experimentally investigate the population dynamics of this pest at different temperatures and provide theoretical input for its control. Populations of L. serricorne were established under laboratory conditions at five temperatures (21 °C, 24 °C, 27 °C, 30 °C, and 33 °C). Results showed that an increasing temperature significantly affected the developmental time, longevity, oviposition period, and fecundity of L. serricorne. Both the longevity and fecundity of adult beetles were significantly reduced as the temperature increased. High temperatures significantly reduced the total duration of the preoviposition period but prolonged the oviposition period of L. serricorne. Increasing the temperatures from 21 °C to 33 °C significantly influenced the life table parameters of L. serricorne. The intrinsic increase rate (r), finite increase rate (λ), and gross reproductive rate (GRR) all increased with a greater rearing temperature, but mean generation time (T) was significantly shortened. To our best knowledge, this is the first report to detail the entire life history of the cigarette beetle in response to different temperatures when reared on tobacco dry leaves. This finding may provide basic information on the occurrence of L. serricorne in a warehouse setting and its mass rearing.

The complete mitochondrial genome (mitogenome) of the Bactrocera rubigina (Diptera: Tephritidae: Dacinae) was sequenced and annotated. The mitochondrial genome was 15,285 bp (GenBank No. MN714223), containing 73.1% of A + T with A 39.3%; C 16.9%; G10.1% and T 33.8%, respectively, which is the classical structure for insect mitogenome. All PCGs started with ATN and stopped with TAD. The phylogenetic tree in the current study confirms that B. rubigina clustered with other Bactrocera species, and this study would enrich the mitogenomes of the fruit flies.

The complete mitochondrial genome (mitogenome) of Bactrocera proprediaphora (Diptera: Tephritidae: Dacinae) was sequenced and annotated. The mitochondrial genome is 15,829 bp (GenBank No. MN688227) long, containing 73.9% A + T (A 39.5%, C 16.3%, G 9.8%, and T 34.3%), which is the classical structure for insect mitogenome. All PCGs were started with ATN, except ND1 which started with TTG, and 13 PCGs were stopped using TAR (TAA/TAG) as the stop codon. Additionally, the phylogenetic tree confirmed that B. proprediaphora was closely related to B. diaphorus. The current study will enrich the mitogenomes of the fruit flies.

The complete mitochondrial genome (mitogenome) of Bactrocera caudata (Diptera: Tephritidae: Dacinae) was sequenced and annotated. The mitochondrial genome is 15,311 bp (GenBank No. MT180970), containing 72.7% A + T (A 39.1%, C 17.0%, G 10.3%, and T 33.6%), which is the classical structure for insect mitogenome. All PCGs were started with ATN (ATA/ATG/ATT/ATC) and terminated with TAA except ND3, which ends with TAG. Additionally, the phylogenetic tree confirmed that Bactrocera caudata was closely related to Bactrocera dorsalis and Bactrocera correcta. The current study would enrich the mitogenomes of the fruit flies.

The complete mitochondrial genome (mitogenome) of the Bactrocera cheni (Diptera: Tephritidae: Dacinae) are sequenced and annotated. The mitochondrial genome is 15,945 bp (GenBank No. MN883026), with A + T% for the whole sequence = 73.0% (38.9% A, 16.4% C, 10.6% G, and 34.1% T), which is the classical structure for insect mitogenome. All PCGs started with ATN except ATP8; 9 PCGs use TAA as the stop codon, and others use TAG as the stop codon. The phylogenetic tree confirms that B. cheni and B. tsuneonis are not clade into one branch with strongly supported. And Pairwise Identity is 80.0% between B. cheni and B. tsuneonis. Based this study, we supported that B. cheni and B. tsuneonis are two different species clearly.

Reproduction is an important trait in sheep breeding as well as in other livestock. However, despite its importance the genetic mechanisms of litter size in domestic sheep (Ovis aries) are still poorly understood. To explore genetic mechanisms underlying the variation in litter size, we conducted multiple independent genome-wide association studies in five sheep breeds of high prolificacy (Wadi, Hu, Icelandic, Finnsheep, and Romanov) and one low prolificacy (Texel) using the Ovine Infinium HD BeadChip, respectively. We identified different sets of candidate genes associated with litter size in different breeds: BMPR1B, FBN1, and MMP2 in Wadi; GRIA2, SMAD1, and CTNNB1 in Hu; NCOA1 in Icelandic; INHBB, NF1, FLT1, PTGS2, and PLCB3 in Finnsheep; ESR2 in Romanov and ESR1, GHR, ETS1, MMP15, FLI1, and SPP1 in Texel. Further annotation of genes and bioinformatics analyses revealed that different biological pathways could be involved in the variation in litter size of females: hormone secretion (FSH and LH) in Wadi and Hu, placenta and embryonic lethality in Icelandic, folliculogenesis and LH signaling in Finnsheep, ovulation and preovulatory follicle maturation in Romanov, and estrogen and follicular growth in Texel. Taken together, our results provide new insights into the genetic mechanisms underlying the prolificacy trait in sheep and other mammals, suggesting targets for selection where the aim is to increase prolificacy in breeding projects.

The complete mitochondrial genome (mitogenome) of the fruit fly species Dacus trimacula (Diptera: Tephritidae: Dacinae) are sequenced and annotated. The mitochondrial genome is 15,851 bp (GenBank No. MK940811) has an A + T content of 72.8% (A 39.2%; C 17.0%; G 10.2%, and T 33.6%), which is the classical structure for insect mitogenome. All PCGs started with ATN and stopped with TAN. The phylogenetic tree confirms that D. trimacula clustered with D. longicornis as the sister group to Zeugodacus. This study enriches the mitogenomes of the fruit flies.

The complete mitochondrial genome (mitogenome) of the Bactrocera ruiliensis (Diptera: Tephritidae: Dacinae) is sequenced and annotated. The mitochondrial genome is 15,870 bp (GenBank No. MN477221) and has an A + T content of 73.3% (A 39.2%; C 16.2%; G 10.3%, and T 34.4%), which is the classical structure for insect mitogenome. All PCGs started with ATN, except ATP8, which is started with TTG; 12 PCGs use TAR (TAA/TAG) as the stop codon, except COX1, which ends with single T––. The phylogenetic tree confirms that B. ruiliensis clustered with other Bactrocera species. This study enriches the mitogenomes of the fruit flies.

Objective: Treatment with TNF-α inhibitors improve psoriasis with minimize/minor neutrophils infiltration and CXCL-1/8 expression in psoriatic lesions. However, the fine mechanism of TNF-α initiating psoriatic inflammation by tuning keratinocytes is unclear. Our previous research identified the deficiency of intracellular galectin-3 was sufficient to promote psoriasis inflammation characterized by neutrophil accumulation. This study aims to investigate whether TNF-α participated in psoriasis development through dysregulating galectin-3 expression. Methods: mRNA levels were assessed through quantitative real-time PCR. Flow cytometry was used to detect cell cycle/apoptosis. Western blot was used to evaluate the activation of the NF-κB signaling pathway. HE staining and immunochemistry were used to detect epidermal thickness and MPO expression, respectively. Specific small interfering RNA (siRNA) was used to knock down hsa-miR-27a-3p while plasmids transfection was used to overexpress galectin-3. Further, the multiMiR R package was utilized to predict microRNA-target interaction. Results and discussion: We found that TNF-α stimulation altered cell proliferation and differentiation and promoted the production of psoriasis-related inflammatory mediators along with the inhibition of galectin-3 expression in keratinocytes. Supplement of galectin-3 could counteract the rise of CXCL-1/8 but not the other phenotypes of keratinocytes induced by TNF-α. Mechanistically, inhibition of the NF-κB signaling pathway could counteract the decrease of galectin-3 and the increase of hsa-miR-27a-3p expression whereas silence of hsa-miR-27a-3p could counteract the decrease of galectin-3 expression induced by TNF-α treatment in keratinocytes. Intradermal injection of murine anti-CXCL-2 antibody greatly alleviated imiquimod-induced psoriasis-like dermatitis. Conclusion: TNF-α initiates psoriatic inflammation by increasing CXCL-1/8 in keratinocytes mediated by the axis of NF-κB-hsa-miR-27a-3p-galectin-3 pathway. [ABSTRACT FROM AUTHOR]

Bone marrow stromal cells (BMSCs) can differentiate into osteoblasts. The present study investigated the osteogenic effects of estradiol, as well as the role of the c-Jun N-terminal kinase (JNK) signaling pathway in promoting estradiol-enhanced osteogenesis of rat (r)BMSCs. rBMSCs were treated for 7 days with or without estradiol and further treated with or without the JNK-specific inhibitor SP600125. The role of estrogen during rBMSC osteogenesis was evaluated by alkaline phosphatase activity and mineralized nodule formation using the Gomori method and Alizarin red S staining, respectively. Subsequently, the mRNA expression levels of transforming growth factor-β1 (TGF-β1) and core-binding factor a1 (Cbfa1) were evaluated by reverse transcription-quantitative polymerase chain reaction, and TGF-β1, Cbfa1 and phosphorylated (p)-JNK protein expression was detected by western blotting. All groups treated with SP600125 expressed low levels of TGF-β1 and Cbfa1 mRNA and protein, and low p-JNK protein expression. Compared with the control cells, rBMSCs cultured with estradiol exhibited a significant upregulation in the expression levels of osteogenic genes and proteins. The present study demonstrated that estradiol enhanced osteogenic differentiation of rBMSCs and that the JNK signaling pathway was involved in this process, providing insights into the molecular mechanisms involved in rBMSC osteogenesis upon estradiol stimulation. [ABSTRACT FROM AUTHOR]

China has a rich resource of native sheep (Ovis aries) breeds associated with historical movements of several nomadic societies. However, the history of sheep and the associated nomadic societies in ancient China remains poorly understood. Here, we studied the genomic diversity of Chinese sheep using genome-wide SNPs, mitochondrial and Y-chromosomal variations in > 1,000 modern samples. Population genomic analyses combined with archeological records and historical ethnic demographics data revealed genetic signatures of the origins, secondary expansions and admixtures, of Chinese sheep thereby revealing the peopling patterns of nomads and the expansion of early pastoralism in East Asia. Originating from the Mongolian Plateau ~5,000-5,700 years ago, Chinese sheep were inferred to spread in the upper and middle reaches of the Yellow River ~3,000-5,000 years ago following the expansions of the Di-Qiang people. Afterwards, sheep were then inferred to reach the Qinghai-Tibetan and Yunnan-Kweichow plateaus ~2,000-2,600 years ago by following the north-to-southwest routes of the Di-Qiang migration. We also unveiled two subsequent waves of migrations of fat-tailed sheep into northern China, which were largely commensurate with the migrations of ancestors of Hui Muslims eastward and Mongols southward during the 12th-13th centuries. Furthermore, we revealed signs of argali introgression into domestic sheep, extensive historical mixtures among domestic populations and strong artificial selection for tail type and other traits, reflecting various breeding strategies by nomadic societies in ancient China. [ABSTRACT FROM AUTHOR]

Several biological properties of icariin have been identified, including its anticancer effect. However, the potential mechanisms underlying the effect of icariin on HepG2 hepatocellular carcinoma cells remain to be elucidated. The aim of the present study was to examine the effects of icariin on the proliferation and cytoskeleton of HepG2 cells. A 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay was used to assess the antiproliferative effects of icariin and to determine the optimal concentration and treatment schedule of icariin on the HepG2 cells. Cell cycle analysis was performed using fluorescence activated cell sorting, the protein expression of B-cell lymphoma (Bcl)-2 was determined using immunohistochemical and western blot analyses, and F-actin in the cells was examined using confocal microscopy. The chemotherapeutic drug, oxaliplatin, was used as a positive control. The results demonstrated that the optimal concentration of icarrin to produce an antiproliferative effect on HepG2 cells was 10-5 mol/l, and the optimal treatment duration was 72 h. The icariin group had a significantly higher proportion of cells in the G0/G1 phase, compared with the control group, treated with high glucose Dulbecco's modified Eagles medium with 10% fetal bovine serum (P<0.05). The proportion of HepG2 cells in the S phase was significantly lower in the oxaliplatin (24.19%; P<0.05) and icariin (21.07%; P<0.01) groups, compared with the control group (28.62%). Icariin markedly decreased the expression of Bcl-2, compared with the control (P<0.01), and disrupted the polymerization of F-actin filaments in the HepG2 cells. Therefore, the present study demonstrated that, at an optimum concentration of 10-5 mol/l, icariin inhibited the proliferation of the HepG2 cells, promoted apoptosis by decreasing the expression of Bcl-2, and disrupted the actin cytoskeleton. [ABSTRACT FROM AUTHOR]