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The rumen undergoes developmental changes during maturation. To characterize this understudied dynamic process, we profiled single-cell transcriptomes of about 308,000 cells from the rumen tissues of sheep and goats at 17 time points. We built comprehensive transcriptome and metagenome atlases from early embryonic to rumination stages, and recapitulated histomorphometric and transcriptional features of the rumen, revealing key transitional signatures associated with the development of ruminal cells, microbiota, and core transcriptional regulatory networks. In addition, we identified and validated potential cross-talk between host cells and microbiomes and revealed their roles in modulating the spatiotemporal expression of key genes in ruminal cells. Cross-species analyses revealed convergent developmental patterns of cellular heterogeneity, gene expression, and cell-cell and microbiome-cell interactions. Finally, we uncovered how the interactions can act upon the symbiotic rumen system to modify the processes of fermentation, fiber digestion, and immune defense. These results significantly enhance understanding of the genetic basis of the unique roles of rumen.
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Metagenoma , Microbiota , Ovinos/genética , Animais , Transcriptoma , Rúmen , Ruminantes/genéticaRESUMO
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.
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Aminopiridinas , Esclerose Lateral Amiotrófica , Humanos , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/genética , Reposicionamento de Medicamentos , Análise da Randomização Mendeliana , Proteínas Serina-Treonina Quinases/genéticaRESUMO
OBJECTIVES: To investigate whether the interplay of anti-galectin-3 antibodies (anti-Gal3 Abs) with neutrophils contributes to the development of lupus cutaneous vasculitis. METHODS: Enzyme-linked immunosorbent assay was used to determine the serum level of anti-Gal3 Abs in lupus patients. Flow cytometry, quantitative PCR and western blot were performed to investigate the expression of cell surface receptors, proinflammatory cytokines and signalling molecules in neutrophils stimulated by serum from lupus patients or healthy controls (HCs) or anti-Gal3 Ab, respectively. Immunofluorescence was performed to visualise the formation of neutrophil extracellular traps (NETs). Human umbilical vein endothelial cells were co-cultured with the supernatants from neutrophils stimulated by anti-Gal3 Ab, and cytokine production was measured at mRNA and protein levels. Immunohistochemistry was adopted to reveal the distribution of Gal3, cytokines and myeloperoxidase within lupus skin lesions. REULTS: Serum levels of anti-Gal3 Abs were negatively correlated with peripheral counts of neutrophils. Anti-Gal3 Abs positive sera from SLE patients accelerated neutrophil death, altered cell phenotype and promoted formation of NETs with the involvement of p38 MAPK pathway. Supernatants collected from neutrophils co-cultured with anti-Gal3 Ab provoked endothelial cells to produce cytokines such as IL-1, ICAM-1, SELE and particularly IL-6. Consistently, IL-6 was higher in SLE patients with anti-Gal3 Ab positive sera and enriched in the area of vascular inflammation together with enhanced expression of Gal3 protein and infiltration of neutrophils. CONCLUSIONS: Overall, these findings suggested that neutrophils were crucial mediators in anti-Gal3 Ab induced lupus cutaneous vasculitis.
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Domestic sheep and their wild relatives harbor substantial genetic variants that can form the backbone of molecular breeding, but their genome landscapes remain understudied. Here, we present a comprehensive genome resource for wild ovine species, landraces and improved breeds of domestic sheep, comprising high-coverage (â¼16.10×) whole genomes of 810 samples from 7 wild species and 158 diverse domestic populations. We detected, in total, â¼121.2 million single nucleotide polymorphisms, â¼61 million of which are novel. Some display significant (P < 0.001) differences in frequency between wild and domestic species, or are private to continent-wide or individual sheep populations. Retained or introgressed wild gene variants in domestic populations have contributed to local adaptation, such as the variation in the HBB associated with plateau adaptation. We identified novel and previously reported targets of selection on morphological and agronomic traits such as stature, horn, tail configuration, and wool fineness. We explored the genetic basis of wool fineness and unveiled a novel mutation (chr25: T7,068,586C) in the 3'-UTR of IRF2BP2 as plausible causal variant for fleece fiber diameter. We reconstructed prehistorical migrations from the Near Eastern domestication center to South-and-Southeast Asia and found two main waves of migrations across the Eurasian Steppe and the Iranian Plateau in the Early and Late Bronze Ages. Our findings refine our understanding of genome variation as shaped by continental migrations, introgression, adaptation, and selection of sheep.
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Genoma , Carneiro Doméstico , Animais , Ásia , Europa (Continente) , Variação Genética , Irã (Geográfico) , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Ovinos/genética , Carneiro Doméstico/genéticaRESUMO
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.
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Galectina 3 , Queratinócitos , MicroRNAs , Psoríase , Fator de Necrose Tumoral alfa , Fator de Necrose Tumoral alfa/farmacologia , Queratinócitos/metabolismo , Células HaCaT , Humanos , MicroRNAs/genética , Quimiocina CXCL1/metabolismo , Interleucina-8/metabolismo , Galectina 3/genética , Psoríase/genética , Psoríase/patologia , NF-kappa B/metabolismo , Transdução de Sinais , Feminino , Animais , Camundongos , Camundongos Endogâmicos C57BLRESUMO
To date, surgical resection is the mainstay for the treatment of colorectal cancer (CRC). Propofol (2,6-diisopropylphenol), one of the most commonly used intravenous anaesthetic agents, has been reported to be involved in modulating the malignancy of a variety of human cancers. However, the underlying mechanisms remain poorly understood. In this study, using a cell counting kit (CCK-8), flow cytometry, and caspase-3 cleavage assays, we found that propofol promoted cell apoptosis and inhibited cell proliferation in both Colo205 and SW620 cells, through the down-regulation of HOXA11-AS and up-regulation of let-7i. Moreover, gain-of-function studies of HOXA11-AS or loss-of-function studies of let-7i also revealed a negative correlation between HOXA11-AS and let-7i in propofol-mediated biological functions of CRC cells. Furthermore, our mechanistic experiments revealed that HOXA11-AS acts as a molecular sponge for let-7i, thereby regulating the expression of ABCC10. We investigate the theory that propofol suppresses colorectal cancer tumorigenesis by modulating the HOXA11-AS-let-7i-ABCC10 regulatory network, indicating the potential for propofol to control CRC development.
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Anestésicos Intravenosos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Colorretais/patologia , Proteínas de Homeodomínio/genética , MicroRNAs/metabolismo , Propofol/farmacologia , RNA Longo não Codificante/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Oligonucleotídeos Antissenso/genética , Ligação ProteicaRESUMO
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 â¼5,000â5,700 years ago, Chinese sheep were inferred to spread in the upper and middle reaches of the Yellow River â¼3,000â5,000 years ago following the expansions of the Di-Qiang people. Afterwards, sheep were then inferred to reach the Qinghai-Tibetan and Yunnan-Kweichow plateaus â¼2,000â2,600 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 12thâ13th 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.
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Filogeografia/métodos , Carneiro Doméstico/genética , Animais , Animais Domésticos/genética , Povo Asiático/genética , Cruzamento , China , DNA Mitocondrial/genética , Ásia Oriental , Variação Genética/genética , Genoma/genética , Genômica/métodos , Haplótipos , Humanos , Filogenia , Polimorfismo de Nucleotídeo Único/genética , Ovinos/genética , Migrantes , Cromossomo Y/genéticaRESUMO
BACKGROUND: Recent studies have revealed the link between immune activation and neurodegenerative diseases. METHODS: By employing meta-analysis, we estimated the standardized mean difference (SMD) and their corresponding 95% confidence intervals (CIs) between the groups. RESULTS: According to the pre-set criteria, a total of 21 published articles including 2377 ALS patients and 1244 HCs, as well as 60 articles including 5111 PD patients and 4237 HCs, were identified. This study provided evidence of peripheral immune activation in the pathogenesis of ALS and PD. CONCLUSION: Our results suggested monitoring changes in peripheral blood immune cell populations, particularly lymphocyte subsets, will benefit understanding the developments and exploring reliable and specific biomarkers of these two diseases.
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Esclerose Lateral Amiotrófica , Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Esclerose Lateral Amiotrófica/imunologia , Biomarcadores , Doenças Neurodegenerativas/imunologia , Doença de Parkinson/imunologiaRESUMO
OBJECTIVE: To explore the pathophysiological changes in the functional connectivity of posterior cingulate cortex (PCC) with other brain regions in children with attention-deficit or hyperactivity disorder (ADHD) on resting-state functional magnetic resonance imaging(fMRI) and explore the neural mechanisms of ADHD at the point of relationships between brain regions. METHODS: Thirty children with ADHD from the Third Affiliated Hospital of Soochow University from June 2008 to April 2010 and another 30 age-and-gender-matched controls from a normal primary school over the same period underwent resting-state fMRI scans. And blood oxygenation level dependent (BOLD) signal was acquired to calculate the functional connectivity of PCC with other brain regions controls. Significant differences of connectivity between groups were analyzed with REST software. RESULTS: The pattern of functional connectivity of PCC for the ADHD group was similar to that of the control group. Significant positive functional connectivity with PCC was observed in the default mode of network (DMN) while negative functional connectivity was present in dorsolateral prefrontal cortex, anterior cingulate, parietal cortex and basal ganglia(all P < 0.05, corrected). Compared to the controls, the ADHD group exhibited decreased positive connectivity with PCC in bilateral medial prefrontal cortex (0.07 ± 0.20 vs 0.33 ± 0.23, t = -5.47), right posterior cingulate gyrus(0.25 ± 0.28 vs 0.48 ± 0.30, t = -3.44), right inferior temporal gyrus (-0.05 ± 0.19 vs 0.22 ± 0.22, t = -4.61) and cerebellar posterior lobe (-0.04 ± 0.21 vs 0.17 ± 0.16, t = -3.99), while decreased negative functional connectivity with PCC was observed in left insula (-0.10 ± 0.26 vs -0.30 ± 0.19, t = 3.71), right inferior parietal lobule (0.02 ± 0.18 vs -0.23 ± 0.17, t = 5.20), left postcentral gyrus (0.08 ± 0.26 vs -0.17 ± 0.25, t = 4.06), left superior temporal gyrus (-0.04 ± 0.25 vs -0.27 ± 0.17, t = 4.27), right superior temporal gyrus (-0.08 ± 0.25 vs -0.31 ± 0.21, t = 3.80) and left fusiform gyrus (-0.01 ± 0.25 vs -0.18 ± 0.17, t = 3.57)(all P < 0.05, corrected). CONCLUSIONS: The connectivity of DMN between brain regions is abnormal in ADHD group. And the strengthen of negative relationship between DMN and task activated network becomes reduced. It is surmised that the decreased internal synchronization of default network and disrupted balance between DMN and prefrontal-parietal attentional networks may be important neural mechanisms of ADHD.
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Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Giro do Cíngulo/fisiopatologia , Imageamento por Ressonância Magnética , Adolescente , Estudos de Casos e Controles , Criança , Humanos , Vias NeuraisRESUMO
OBJECTIVE: To explore the mathematics cognitive function of children with attention deficit hyperactivity disorder and explore neural mechanisms with event-related potential(ERP) and behaviors. METHODS: Behavior data and ERP elicited by performing mental calculation tasks were recorded in 27 children with ADHD and 29 normal controls from July to October 2012 at Third Affiliated Hospital of Soochow University.The differences of behaviors and N2 component of ERP were compared and analyzed. RESULTS: The reaction time of the children with ADHD were longer than the control group in addition, subtraction and multiplication ((949 ± 144) vs (829 ± 166) ms, (981 ± 129) vs (856 ± 170) ms, (944 ± 136) vs (825 ± 172) ms, all P < 0.05). While the correct rate were less than normal control in all three arithmetic operations (0.80% (0.72%, 0.88%) vs 0.90% (0.85%,0.96%), 0.78% (0.64%,0.85%) vs 0.90% (0.84%,0.93%), 0.86% (0.74%,0.92%) vs 0.93%(0.90%,0.98%), all P < 0.05). N2 component could be elicited by all subjects in forehead. The amplitude of N2 of children with ADHD were significantly lower than control group in all three arithmetic operations at left frontal (F3: (-3.5 ± 5.2) vs (-6.7 ± 3.5)µV, (-3.8 ± 4.0) vs (-7.4 ± 4.5)µV, -5.8 (-7.6,1.6) vs -6.4(-10.3, -4.9) µV, all P < 0.05) and Fz ((-4.3 ± 6.4) vs ( -7.4 ± 4.2) µV, (-5.0 ± 5.4) vs (-7.9 ± 4.6)µV, -5.2(-9.7, -0.6) vs -7.9 (-10.5, -5.1)µV, all P < 0.05), the latency of ADHD group were prolonger than controls in subtraction operations at right and left frontal ((328 ± 36) vs (307 ± 27)ms, 325 (307,354)vs 309 (280, 330)ms) and frontal electrodes ((331 ± 35) vs (311 ± 30) ms, all P < 0.05). In addition and multiplication operations, there was no significant difference in latency (all P > 0.05). CONCLUSIONS: The children with ADHD have weak capacities of inhibition irrelevant information and paying attention to control. Their deficits in mental arithmetics may be due to the difficulties of selecting the best strategy during cognitive tasks.
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Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Cognição , Estudos de Casos e Controles , Criança , Potenciais Evocados , Feminino , Humanos , Masculino , MatemáticaRESUMO
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 < 0.001 at 30 min, P < 0.001 at 6 h] and group RK1 [(102.86 ± 24.17) versus (114.29 ± 41.05) versus (160.00 ± 54.98) g, P < 0.001 at 30 min, P < 0.001 at 6 h] around the surgical incision, and in group C [(112.00 ± 31.78) versus (170.67 ± 56.26) g, P < 0.001 at 30 min, (118.67 ± 34.42) versus (170.67 ± 56.26) g, P = 0.001 at 6 h] and group RK1 [(114.29 ± 45.17) versus (175.71 ± 54.80) g, P = 0.001 at 30 min, (121.43 ± 38.46) versus (175.71 ± 54.80) g, P = 0.002 at 6 h] on the forearm at 30 min and 6 h after surgery; compared with group C, the mechanical pain threshold was higher in group RK2 [(142.76 ± 50.06) versus (94.67 ± 22.85) g, P < 0.001 at 30 min, (145.52 ± 49.83) versus (112.00 ± 36.62) g, P < 0.001 at 6 h] and group RK3 [(140.00 ± 40.68) versus (94.67 ± 22.85) g, P < 0.001 at 30 min, (150.67 ± 56.50) versus (112.00 ± 36.62) g, P = 0.010 at 6 h] around the surgical incision, and in group RK2 [(149.66 ± 39.50) versus (112.00 ± 31.78) g, P = 0.006 at 30 min, (156.55 ± 47.23) versus (118.67 ± 34.42) g, P = 0.005 at 6 h] and group RK3 [(145.33 ± 51.18) versus (112.00 ± 31.78) g, P = 0.018 at 30 min, (154.67 ± 47.54) versus (118.67 ± 34.42) g, P = 0.008 at 6 h] on the forearm at 30 min and 6 h after surgery. Group RK3 had more glandular secretions than the other three groups (P = 0.042). CONCLUSIONS: Intravenous injection of esketamine 0.4 mg·kg-1 before anesthesia induction is a suitable dose to reduce pain sensitivity in patients undergoing thyroidectomy without increasing adverse reactions. However, future research needs to be extended to other populations. TRIAL REGISTRATION: Registered at the Chinese Clinical Trials Registry http://www.chictr.org.cn/ (09/06/2022, ChiCTR-2200060741).
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The fat tail of sheep is an important organ that has evolved to adapt to extreme environments. However, the genetic mechanisms underlying the fat tail phenotype remain poorly understood. Here, we characterize transcriptome and lipidome profiles and morphological changes in 250 adipose tissues from two thin-tailed and three fat-tailed sheep populations in summer and winter. We implement whole-genome selective sweep tests to identify genetic variants related to fat-tails. We identify a set of functional genes that show differential expression in the tail fat of fat-tailed and thin-tailed sheep in summer and winter. These genes are significantly enriched in pathways, such as lipid metabolism, extracellular matrix (ECM) remodeling, molecular transport, and inflammatory response. In contrast to thin-tailed sheep, tail fat from fat-tailed sheep show slighter changes in adipocyte size, ECM remodeling, and lipid metabolism, and had less inflammation in response to seasonal changes, indicating improved homeostasis. Whole-genome selective sweep tests identify genes involved in preadipocyte commitment (e.g., BMP2, PDGFD) and terminal adipogenic differentiation (e.g., VEGFA), which could contribute to enhanced adipocyte hyperplasia. Altogether, we establish a model of regulatory networks regulating adipose homeostasis in sheep tails. These findings improve our understanding of how adipose homeostasis is maintained, in response to extreme environments in animals.
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Tecido Adiposo , Multiômica , Ovinos , Animais , Tecido Adiposo/metabolismo , Adipócitos , Transcriptoma , Ambientes ExtremosRESUMO
BACKGROUND: Genome-Wide Association Studies (GWAS) have identified numerous risk genes for Amyotrophic Lateral Sclerosis (ALS); however, the mechanisms by which these loci confer ALS risk are uncertain. This study aims to identify novel causal proteins in the brains of patients with ALS using an integrative analytical pipeline. METHODS: Using the datasets of Protein Quantitative Trait Loci (pQTL) (NpQTL1 = 376, NpQTL2 = 152), expression QTL (eQTL) (N = 452), and the largest ALS GWAS (NALS=27,205, NControls = 110,881), we performed a systematic analytical pipeline including Proteome-Wide Association Study (PWAS), Mendelian Randomization (MR), Bayesian colocalization, and Transcriptome-Wide Association Study (TWAS) to identify novel causal proteins for ALS in the brain. RESULTS: Using PWAS, we found that the altered protein abundance of 12 genes in the brain was associated with ALS. Three genes (SCFD1, SARM1 and CAMLG) were identified as lead causal genes for ALS with solid evidence (False discovery rate < 0.05, in MR analysis; PPH4 > 80% for Bayesian colocalization). Specifically, an increased abundance of SCFD1 and CAMLG led to an increased risk of ALS, whereas a higher abundance of SARM1 led to a decreased risk of developing ALS. TWAS showed that SCFD1 and CAMLG were related to ALS at the transcriptional level. CONCLUSIONS: SCFD1, CAMLG, and SARM1 exhibited robust associations and causality with ALS. The study findings provide novel clues for identifying potential therapeutic targets in ALS. Further studies are required to explore the mechanisms underlying the identified genes.
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Esclerose Lateral Amiotrófica , Humanos , Esclerose Lateral Amiotrófica/genética , Estudo de Associação Genômica Ampla , Proteoma/genética , Teorema de Bayes , Encéfalo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
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.
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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.
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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.
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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.
RESUMO
Understanding the genetic changes underlying phenotypic variation in sheep (Ovis aries) may facilitate our efforts towards further improvement. Here, we report the deep resequencing of 248 sheep including the wild ancestor (O. orientalis), landraces, and improved breeds. We explored the sheep variome and selection signatures. We detected genomic regions harboring genes associated with distinct morphological and agronomic traits, which may be past and potential future targets of domestication, breeding, and selection. Furthermore, we found non-synonymous mutations in a set of plausible candidate genes and significant differences in their allele frequency distributions across breeds. We identified PDGFD as a likely causal gene for fat deposition in the tails of sheep through transcriptome, RT-PCR, qPCR, and Western blot analyses. Our results provide insights into the demographic history of sheep and a valuable genomic resource for future genetic studies and improved genome-assisted breeding of sheep and other domestic animals.
Assuntos
Criação de Animais Domésticos/métodos , Animais Selvagens/genética , Fator de Crescimento Derivado de Plaquetas/metabolismo , Carneiro Doméstico/genética , Alelos , Animais , Cruzamento , Feminino , Frequência do Gene , Variação Genética , Genética , Genômica , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Desequilíbrio de Ligação , Mutação , Fenótipo , Polimorfismo de Nucleotídeo Único , Seleção Genética , Análise de Sequência de DNA , Ovinos , Especificidade da Espécie , Sequenciamento Completo do GenomaRESUMO
The domestication and subsequent global dispersal of livestock are crucial events in human history, but the migratory episodes during the history of livestock remain poorly documented [1-3]. Here, we first developed a set of 493 novel ovine SNPs of the male-specific region of Y chromosome (MSY) by genome mapping. We then conducted a comprehensive genomic analysis of Y chromosome, mitochondrial DNA, and whole-genome sequence variations in a large number of 595 rams representing 118 domestic populations across the world. We detected four different paternal lineages of domestic sheep and resolved, at the global level, their paternal origins and differentiation. In Northern European breeds, several of which have retained primitive traits (e.g., a small body size and short or thin tails), and fat-tailed sheep, we found an overrepresentation of MSY lineages y-HC and y-HB, respectively. Using an approximate Bayesian computation approach, we reconstruct the demographic expansions associated with the segregation of primitive and fat-tailed phenotypes. These results together with archaeological evidence and historical data suggested the first expansion of early domestic hair sheep and the later expansion of fat-tailed sheep occurred â¼11,800-9,000 years BP and â¼5,300-1,700 years BP, respectively. These findings provide important insights into the history of migration and pastoralism of sheep across the Old World, which was associated with different breeding goals during the Neolithic agricultural revolution.
Assuntos
DNA Mitocondrial/genética , Genoma/genética , Polimorfismo de Nucleotídeo Único/genética , Carneiro Doméstico/genética , Cromossomo Y/genética , Animais , Cruzamento , Linhagem da Célula/genética , Mapeamento Cromossômico , Variação Genética/genética , Masculino , Mitocôndrias/genética , Fenótipo , Filogenia , Ovinos , Carneiro Doméstico/classificação , Sequenciamento Completo do GenomaRESUMO
OBJECTIVE: To investigate the cognitive event related potentials in Chinese character priming effect of children with attention deficit hyperactivity disorder (ADHD) and to analyze the neural mechanism of the priming effect. METHODS: Fifty-two ADHD children aged (9.5 +/- 1.7) and 45 age-matched children without ADHD were asked to perform a Chinese character semantic priming task while electroencephalogram was recorded. During the Chinese character semantic priming task the subjects were instructed to judge whether the presented target word was a related word, unrelated word, or a pseudoword and event-related potentials (ERPs) were elicited and analyzed with the brain electricity source analysis (BESA) software. RESULTS: (1) The behavioral results showed that the reaction time to the unrelated character stimuli in the ADHD children was (1252 +/- 256) ms, significantly longer than that in the normal control [(1131 +/- 194) ms, P < 0.05]. (2) The amplitude of the character related N2 at the Cz lead in the ADHD children was -7.7 (-12.8, -5.0) microV, significantly larger than that of the normal controls [-5.6 (-9.4, -3.2) microV, P < 0.05]. (3) The amplitude of character unrelated stimuli P3 at the Cz lead of the ADHD children was 5.4 (2.0, 9.5) microV, significantly lower than that of the normal control [9.5 (4.2, 16.9) microV, P < 0.01]. CONCLUSION: There is a positive correlation between the amplitude of N2 and the difficulty in character semantic priming. It is more difficult for the ADHD children than normal controls to accomplish the same semantic task. ADHD children need more attention resources than normal controls. The amplitudes of character related-N2 and unrelated-P3 may become markers to measure the development of recognition in the ADHD children, thus being helpful in the ADHD diagnosis.