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Tumour necrosis factor (TNF) superfamily member 11 (TNFSF11), also known as RANKL, plays a crucial role in regulating several physiological and pathological activities. Additionally, it is a vital factor in bone physiology, and the sex hormone progesterone regulates the expansion of stem cells and the proliferation of mammary epithelial cells. It is essential for animal growth and reproductive physiological processes. This study aimed to evaluate the tissue-specific expression characteristics and promoter activity of the TNFSF11 gene in pigs. As a result, the study examined the presence of TNFSF11 expression in the tissues of Xiangsu pigs at 0.6 and 12 months of age. Moreover, the core promoter region of TNFSF11 was also identified by utilizing a combination of bioinformatic prediction and dual-luciferase activity tests. Finally, the effect of transcription factors on the transcriptional activity of the core promoter region was determined using site-directed mutagenesis. TNFSF11 was uniformly expressed in all tissues; however, its expression in muscles was comparatively low. The core promoter region of TNFSF11 was located in the -555 to -1 region. The prediction of the transcription start site of TNFSF11 gene-2000 â¼ + 500bp showed that there was a CpG site in 17 â¼ + 487bp. Analysis of mutations in the transcription factor binding sites revealed that mutations in the Stat5b, Myog, Trl, and EN1 binding sites had significant effects on the transcriptional activity of the TNFSF11 gene, particularly following the EN1 binding site mutation (P < 0.001). This study provides insights into both the tissue-specific expression patterns of TNFSF11 in the tissues of Xiangsu pigs and the potential regulatory effects of transcription factors on its promoter activity. These results may be helpful for future research aimed at clarifying the expression and role of the porcine TNFSF11 gene.
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Regulação da Expressão Gênica , Regiões Promotoras Genéticas , Ligante RANK , Animais , Suínos/genética , Ligante RANK/genética , Ligante RANK/metabolismoRESUMO
Microelectromechanical system (MEMS) sensors are a miniaturized sensor technology that integrates sensors with microelectronic components using microelectromechanical system manufacturing technology [...].
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Malic acid is an important flavor determinant in apple (Malus domestica Borkh.) fruit. One known variation controlling malic acid is the A/G SNP in an aluminium-activated malate transporter gene (MdMa1). Nevertheless, there are still differences in malic acid content in apple varieties with the same Ma1 genotype (Ma1/Ma1 homozygous), such as 'Honeycrisp' (high malic acid content) and 'Qinguan' (low malic acid content), indicating that other loci may influence malic acid and fruit acidity. Here, the F1 hybrid generation of 'Honeycrisp' × 'Qinguan' was used to analyze quantitative trait loci (QTLs) for malic acid content. A major locus (Ma7) was identified on chromosome 13. Within this locus, a malate dehydrogenase gene, MDH1 (MdMa7), was the best candidate for further study. Subcellular localization suggested that MdMa7 encodes a cytosolic protein. Overexpression and RNAi of MdMa7 in apple fruit increased and decreased malic acid content, respectively. An insertion / deletion (indel) in the MdMa7 promoter was found to affect MdMa7 expression and malic acid content in both hybrids and other cultivated varieties. The insertion and deletion genotypes were designated as MA7 and ma7, respectively. The transcription factor MdbHLH74 was found to stimulate MdMa7 expression in the MA7 genotype but not in the ma7 genotype. Transient transformation of fruit showed that MdbHLH74 affected MdMa7 expression and malic acid content in 'Gala' (MA7/MA7) but not in 'Fuji' (ma7/ma7). Our results indicated that genetic variation in the MdMa7 (MDH1) promoter alters the binding ability of the transcription factor MdbHLH74, which alters MdMa7 (MDH1) transcription and the malic acid content in apple fruit, especially in Ma1/Ma1 homozygous accessions.
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Prostate cancer (PCa) ranks as the second most prevalent cancer among males globally. However, the exact mechanisms underlying its progression remain inadequately elucidated. The present study sought to investigate the role and underlying molecular mechanism of hsa_circ_0001671 (circ_0001671) in the pathogenic behavior of PCa cells. Guided by the ceRNA theory, miR-27b-3p was employed to identify circRNAs that could potentially regulate Bloom Syndrome Protein (BLM). A series of experimental approaches including bioinformatics, luciferase assays, Fluorescent In Situ Hybridization (FISH), RNA-pulldown, and RNA Immunoprecipitation (RIP) were utilized to validate the miRNA sponge function of circ_0001671. Divergent primer PCR, RNase R treatments, and Sanger sequencing were conducted for the identification of circ_0001671. Quantitative RT-PCR and Western blot analyses were performed to validate gene expression levels. Both in vitro and in vivo experiments were conducted to assess the functional role of circ_0001671 in PCa cells.It was observed that the expression levels of circ_0001671 and BLM were significantly elevated in PCa tissues and cell lines, whereas miR-27b-3p showed decreased expression. Circ_0001671 was found to promote cellular proliferation, migration, and invasion, while inhibiting apoptosis. In vivo assays confirmed that circ_0001671 facilitated tumor growth. Further mechanistic studies revealed that circ_0001671 acted as a competing endogenous RNA (ceRNA) for BLM by sponging miR-27b-3p. The oncogenic role of circ_0001671 in PCa was shown to be modulated through the miR-27b-3p/BLM axis. In conclusion, circ_0001671 exerts an oncogenic effect in prostate cancer through the regulation of BLM by sponging miR-27b-3p, thus suggesting a novel molecular target for the treatment of PCa.
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Proliferação de Células , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , MicroRNAs , Neoplasias da Próstata , RNA Circular , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Masculino , RNA Circular/genética , Proliferação de Células/genética , Linhagem Celular Tumoral , Animais , Camundongos , Movimento Celular/genética , Camundongos Nus , Apoptose/genéticaRESUMO
Introduction: Acetyl-Coenzyme A Acyltransferase-1 (ACAA1) is a peroxisomal acyltransferase involved in fatty acid metabolism. Current evidence does not precisely reveal the effect of the ACAA1 gene on pig growth performance. Methods: The present study assessed the mRNA expression levels of the ACAA1 gene in the heart, liver, spleen, lung, kidney of 6-month-old Xiangsu pigs and in the longissimus dorsi muscle at different growth stages (newborn, 6 months and 12 months of age) using RT-qPCR. The relationship between single-nucleotide polymorphisms (SNPs) of ACAA1 gene and growth traits in 6-month-old and 12-month-old Xiangsu pigs was investigated on 184 healthy Xiangsu pigs using Sanger sequencing. Results: The ACAA1 gene was expressed in heart, liver, spleen, lung, kidney, and longissimus dorsi muscle of 6-month-old pigs, with the highest level of expression in the liver. ACAA1 gene expression in the longissimus dorsi muscle decreased with age (p < 0.01). In addition, four SNPs were identified in the ACAA1 gene, including exon g.48810 A>G (rs343060194), intron g.51546 T>C (rs319197012), exon g.55035 T>C (rs333279910), and exon g.55088 C>T (rs322138947). Hardy-Weinberg equilibrium (p > 0.05) was found for the four SNPs, and linkage disequilibrium (LD) analysis revealed a strong LD between g.55035 T>C (rs333279910) and g.55088 C>T (rs322138947) (r 2 = 1.000). Association analysis showed that g.48810 A>G (rs343060194), g.51546 T>C (rs319197012), g.55035 T>C (rs333279910), and g.55088 C>T (rs322138947) varied in body weight, body length, body height, abdominal circumference, leg and hip circumference and living backfat thickness between 6-month-old and 12-month-old Xiangsu pigs. Conclusion: These findings strongly demonstrate that the ACAA1 gene can be exploited for marker-assisted selection to improve growth-related phenotypes in Xiangsu pigs and present new candidate genes for molecular pig breeding.
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OBJECTIVES: Older-adult migrants constitute a proportion of the global population, and loneliness hinders their adaptation to host areas. However, review studies on risk factors for loneliness target general older-adults without focusing on older-adult migrants. Therefore, this study systematically reviews and synthesizes the factors influencing the loneliness of older-adult migrants. METHOD: Five databases were searched and screened for quantitative studies investigating the relationship between risk factors and loneliness among older-adult migrants (over age 50). Finally, 35 articles were included. RESULTS: Factors related to loneliness in older-adult migrants were synthesized into sociodemographic, physical health, psychological, interpersonal, and acculturation-related factors. Consistent significant relationships with loneliness were found for a few risk factors, including not having spouses, low subjective financial status, poor self-rated health, poor psychological status, few non-kin ties, low quality of kin and non-kin ties, and a weak sense of belonging to either one's ethnic group or that of the host areas. CONCLUSION: This review discusses the unique findings on the risk factors for loneliness in older-adult migrants. Additionally, the current literature on loneliness in older-adult migrants has some research gaps, calling for longitudinal studies with a rigorous design.
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Solidão , Migrantes , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Aculturação , Solidão/psicologia , Fatores de Risco , Migrantes/psicologiaRESUMO
As one of the most important food and feed crops worldwide, maize suffers much more tremendous damages under heat stress compared to other plants, which seriously inhibits plant growth and reduces productivity. To mitigate the heat-induced damages and adapt to high temperature environment, plants have evolved a series of molecular mechanisms to sense, respond and adapt high temperatures and heat stress. In this review, we summarized recent advances in molecular regulations underlying high temperature sensing, heat stress response and memory in maize, especially focusing on several important pathways and signals in high temperature sensing, and the complex transcriptional regulation of ZmHSFs (Heat Shock Factors) in heat stress response. In addition, we highlighted interactions between ZmHSFs and several epigenetic regulation factors in coordinately regulating heat stress response and memory. Finally, we laid out strategies to systematically elucidate the regulatory network of maize heat stress response, and discussed approaches for breeding future heat-tolerance maize.
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In recent years, there has been an increase in the incidence and mortality rates of prostate cancer (PCa). However, the specific molecular mechanisms underlying its occurrence and development remain unclear, necessitating the identification of new therapeutic targets. Through bioinformatics analysis, we discovered a previously unstudied differential gene called HIST3H2A in prostate cancer. Our study revealed that HIST3H2A is highly expressed in PCa tissues, as confirmed by analysis of both the GEO and UALCAN databases. Further analysis using the KEGG database demonstrated that HIST3H2A regulates the pathway of programmed necroptosis in cells. Additionally, we observed significant up-regulation of HIST3H2A in PCa tissues and cell lines. HIST3H2A was found to regulate cell proliferation, migration, invasion, and the epithelial-mesenchymal transition (EMT) process in tumors. Notably, HIST3H2A's role in regulating programmed necroptosis in prostate cancer cells differs from its role in apoptosis. In vitro and in vivo experiments collectively support the key role of HIST3H2A in promoting the development of prostate cancer, highlighting its potential as a therapeutic target for patients with PCa.
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Proliferação de Células , Progressão da Doença , Transição Epitelial-Mesenquimal , Necroptose , Neoplasias da Próstata , Masculino , Neoplasias da Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Humanos , Necroptose/genética , Animais , Camundongos , Transição Epitelial-Mesenquimal/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , ApoptoseRESUMO
Ginger, a well-known spice plant, has been used widely in medicinal preparations for pain relief. However, little is known about its analgesic components and the underlying mechanism. Here, we ascertained, the efficacy of ginger ingredient 8-Shogaol (8S), on inflammatory pain and tolerance induced by morphine, and probed the role of TRPV1 in its analgesic action using genetic and electrophysiology approaches. Results showed that 8S effectively reduced nociceptive behaviors of mice elicited by chemical stimuli, noxious heat as well as inflammation, and antagonized morphine analgesic tolerance independent on opioid receptor function. Genetic deletion of TRPV1 significantly abolished 8S' analgesia action. Further calcium imaging and patch-clamp recording showed that 8S could specifically activate TRPV1 in TRPV1-expressing HEK293T cells and dorsal root ganglion (DRG) neurons. The increase of [Ca2+]i in DRG was primarily mediated through TRPV1. Mutational and computation studies revealed the key binding sites for the interactions between 8S and TRPV1 included Leu515, Leu670, Ile573, Phe587, Tyr511, and Phe591. Further studies showed that TRPV1 activation evoked by 8S resulted in channel desensitization both in vitro and in vivo, as may be attributed to TRPV1 degradation or TRPV1 withdrawal from the cell surface. Collectively, this work provides the first evidence for the attractive analgesia of 8S in inflammatory pain and morphine analgesic tolerance mediated by targeting pain-sensing TRPV1 channel. 8S from dietary ginger has potential as a candidate drug for the treatment of inflammatory pain.
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Catecóis , Gânglios Espinais , Canais de Cátion TRPV , Zingiber officinale , Canais de Cátion TRPV/metabolismo , Zingiber officinale/química , Animais , Humanos , Células HEK293 , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Catecóis/farmacologia , Camundongos , Masculino , Camundongos Endogâmicos C57BL , Inflamação/tratamento farmacológico , Analgésicos/farmacologia , Morfina/farmacologia , Cálcio/metabolismoRESUMO
The newborn ovary homeobox gene (NOBOX) regulates ovarian and early oocyte development, and thus plays an essential role in reproduction. In this study, the mRNA expression level and single nucleotide polymorphism (SNP) of NOBOX in various tissues of Xiangsu pigs were studied to explore the relationship between its polymorphism and litter size traits. Also, bioinformatics was used to evaluate the effects of missense substitutions on protein structure and function. The results revealed that NOBOX is preferentially expressed in the ovary. Six mutations were detected in the NOBOX sequence, including g.1624 T>C, g.1858 G>A, g.2770 G>A, g.2821 A>G, g.5659 A>G, and g.6025 T>A, of which g.1858 G>A was a missense mutation. However, only g.1858 G>A, g.5659 A>G, and g.6025 T>A were significantly associated with litter size traits (p < 0.05). Further prediction of the effect of the missense mutation g.1858 G>A on protein function revealed that p.V82M is a non-conservative mutation that significantly reduces protein stability and thus alters protein function. Overall, these findings suggest that NOBOX polymorphism is closely related to the litter size of Xiangsu pigs, which may provide new insights into pig breeding.
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To germinate in nature, orchid seeds strictly rely on seed germination-promoting orchid mycorrhizal fungi (sgOMFs) for provision of carbon nutrients. The underlying delivery pathway, however, remains elusive. We develop here a plausible model for sugar transport from sgOMFs to orchid embryonic cells to fuel germination. Orchids exploit sgOMFs to induce the formation of pelotons, elaborate intracellular hyphal coils in orchid embryos. The colonized orchid cells then obtain carbon nutrients by uptake from living hyphae and peloton lysis, primarily as glucose derived from fungal trehalose hydrolyzed by orchid-specific trehalases. The uptake of massive fungally derived glucose is likely to be mediated by two classes of membrane proteins, namely, sugars will eventually be exported transporters (SWEETs) and H+-hexose symporters. The proposed model serves as a launch pad for further research to better understand and improve orchid seed germination and conservation.
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Carbono , Germinação , Micorrizas , Orchidaceae , Sementes , Germinação/fisiologia , Orchidaceae/fisiologia , Orchidaceae/metabolismo , Orchidaceae/crescimento & desenvolvimento , Carbono/metabolismo , Sementes/crescimento & desenvolvimento , Sementes/metabolismo , Micorrizas/fisiologiaRESUMO
Bloom (BLM) helicase plays an important role in DNA replication and the maintenance of genome integrity. BLM protein deficiency, which plays a vital role in the sperm-egg union and germ-cell development during reproduction, can lead to severe DNA damage in goats. However, the effect of BLM protein deficiency on goat litter size has not been reported. Herein, we studied the association between the genetic variation in the BLM gene and the number of kids per litter in Guizhou white goats. We explored differences in the expression of the BLM protein in the follicles of single and multi-kid nanny goats. We also analyzed the effects of dysregulated BLM gene expression on the proliferation and apoptosis of ovarian granulosa cells and the expression of genes related to follicle development in goats. Five single nucleotide polymorphism (SNP) loci, including the non-synonymous mutations g.38179 A > G, g.40626 G > C and g.89621 T > G; the intron synonymous mutation g.56961 G > A and the exon synonymous mutation g.65796 C > T were found in the BLM gene. All SNPs loci were in Hardy-Weinberg equilibrium, and correlation analysis showed that the g.65796 C > T and g.89621 T > G loci polymorphism was strongly associated with litter size in the first three litters (P < 0.05). The diplogenotype Hap 2/2 (AAGGAACCTT) showed no significant difference in litter size between different births, indicating that the diploid genotype is stable in different litter sizes. Bioinformatics analysis showed that three non-synonymous mutation loci (p.T488A, p.A662S, and p.S1373A) could affect BLM protein stability, and mutations in p.T488A and p.S1373A led to changes in amino acid polarity and associated interactions. qPCR results showed that the expression level of the BLM gene in the uterus and ovaries of TT genotype nanny goats was significantly higher than that of GG genotype nanny goats. Indirect immunofluorescence assay (IF) showed that the BLM protein was significantly overexpressed in both the primordial and growing follicles of nanny goats with multiple kids (P < 0.01). Disrupting BLM gene expression in the ovarian granulosa cells down-regulated the expression of the Cyp19A1 gene. It also significantly inhibited the proliferation of follicles and induces early apoptosis of the granulosa cells. These findings confirm that polymorphism in the BLM gene is closely related to the littering traits of Guizhou white goats, and it affects the reproductive performance of nanny goats by regulating the development of the oocytes and granulosa cells. This work provides new evidence on the regulatory effect of the BLM gene on the litter size of nanny goats.
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Doenças das Cabras , Deficiência de Proteína , Masculino , Gravidez , Feminino , Animais , Ovário , Cabras/genética , Sêmen , Tamanho da Ninhada de Vivíparos/genética , Polimorfismo de Nucleotídeo Único , Genótipo , Deficiência de Proteína/veterináriaRESUMO
Actuators play a crucial role in microelectromechanical systems (MEMS) and hold substantial potential for applications in various domains, including reconfigurable metamaterials. This research aims to design, fabricate, and characterize structures for the actuation of the EMA. The electromagnetic actuator overcomes the lack of high drive voltage required by other actuators. The proposed actuator configuration comprises supporting cantilever beams with fixed ends, an integrated coil positioned above the cantilever's movable plate, and a permanent magnet located beneath the cantilever's movable plate to generate a static magnetic field. Utilizing flexible polyimide, the fabrication process of the EMA is simplified, overcoming limitations associated with silicon-based micromachining techniques. Furthermore, this approach potentially enables large-scale production of EMA, with displacement reaching up to 250 µm under a 100 mA current, thereby expanding their scope of applications in manufacturing. To demonstrate the function of the EMA, we integrated it with a metamaterial structure to form a compact, tunable terahertz absorber, demonstrating a potential for reconfigurable electromagnetic space.
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Soluble sugar content is a key component in controlling fruit flavor, and its accumulation in fruit is largely determined by sugar metabolism and transportation. When the diurnal temperature range is greater, the fleshy fruits accumulated more soluble sugars and become more sweeter. However, the molecular mechanism underlying this response remains largely unknown. In this study, we verified that low-temperature treatment promoted soluble sugar accumulation in apple fruit and found that this was due to the upregulation of the Tonoplast Sugar Transporter genes MdTST1/2. A combined strategy using assay for transposase-accessible chromatin (ATAC) sequencing and gene expression and cis-acting elements analyses, we identified two C-repeat Binding Factors, MdCBF1 and MdCBF2, that were induced by low temperature and that might be upstream transcription factors of MdTST1/2. Further studies established that MdCBF1/2 could bind to the promoters of MdTST1/2 and activate their expression. Overexpression of MdCBF1 or MdCBF2 in apple calli and fruit significantly upregulated MdTST1/2 expression and increased the concentrations of glucose, fructose, and sucrose. Suppression of MdTST1 and/or MdTST2 in an MdCBF1/2-overexpression background abolished the positive effect of MdCBF1/2 on sugar accumulation. In addition, simultaneous silencing of MdCBF1/2 downregulated MdTST1/2 expression and apple fruits failed to accumulate more sugars under low-temperature conditions, indicating that MdCBF1/2-mediated sugar accumulation was dependent on MdTST1/2 expression. Hence, we concluded that the MdCBF1/2-MdTST1/2 module is crucial for sugar accumulation in apples in response to low temperatures. Our findings provide mechanistic components coordinating the relationship between low temperature and sugar accumulation as well as new avenues to improve fruit quality.
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Temperatura Baixa , Frutas , Regulação da Expressão Gênica de Plantas , Malus , Proteínas de Plantas , Malus/genética , Malus/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Frutas/genética , Frutas/metabolismo , Açúcares/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Plantas Geneticamente Modificadas , Metabolismo dos Carboidratos/genéticaRESUMO
BACKGROUND: The AHA has recently introduced a novel metric, Life's Essential 8, to assess cardiovascular health (CVH). Nevertheless, the association between varying levels of LE8 and the propensity for CKD is still unclear from a large prospective cohort. Our objective is to meticulously examine the relationship between LE8 and its associated susceptibilities to CKD. METHODS: A total of 251,825 participants free of CKD from the UK Biobank were included. Cardiovascular health was scored using LE8 and categorized as low, moderate, and high. Cox proportional hazard models were employed to evaluate the associations of LE8 scores with new-onset CKD. The genetic risk score for CKD was calculated by a weighted method. RESULTS: Over a median follow-up of 12.8 years, we meticulously documented 10,124 incident cases of CKD. Remarkably, an increased LE8 score correlated with a significant reduction of risk in new-onset CKD (high LE8 score vs. low LE8 score: HR = 0.300, 95% CI 0.270-0.330, p < 0.001; median LE8 score vs. low LE8 score: HR = 0.531, 95% CI 0.487-0.580, p < 0.001). This strong LE8-CKD association remained robust in extensive subgroup assessments and sensitivity analysis. Additionally, these noteworthy associations between LE8 scores and CKD remained unaffected by genetic predispositions to CKD. CONCLUSIONS: An elevated degree of CVH, as delineated by the discerning metric LE8, exhibited a pronounced and statistically significant correlation with a marked reduction in the likelihood of CKD occurrence.
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Doenças Cardiovasculares , Insuficiência Renal Crônica , Humanos , Estados Unidos , Biobanco do Reino Unido , Bancos de Espécimes Biológicos , Estudos Prospectivos , Predisposição Genética para Doença , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/genética , Fatores de RiscoRESUMO
Cathepsin S (CTSS) is a member of the cysteine protease family closely related to reproductive regulation in goats. However, its effect on litter size in goats remains unclear. In this study, the relationship between CTSS gene polymorphisms and litter size was revealed by analyzing the DNA sequence and mRNA expression of CTSS in the gonadal axis of Qianbei Ma goats. In addition, bioinformatics methods were used to evaluate the effect of non-synonymous mutations on CTSS protein structure and function. CTSS was expressed in all parts of the gonadal axis of Qianbei Ma goats, with the highest expression in the uterus in the multi-lamb group and in the fallopian tube in the single-lamb group. The sequencing results showed that four SNPs in CTSS, including g.7413C â T, g.8816A â T, g.9191 T â G and g.10193G â A, were significantly correlated with litter size (p < 0.05). All four analyzed mutation sites were in strong linkage disequilibrium (r2 > 0.33, D' > 0.70). Additionally, the haplotype Hap1/2 had a significantly higher frequency than the other haplotypes (p < 0.05). g.7413C â T and g.8816A â T were non-synonymous mutations. The g.7413C â T mutation resulted in the substitution of serine 161 of the CTSS protein with phenylalanine (p.S161F), and the g.8816A â T mutation resulted in the substitution of aspartate 219 with tyrosine (p.N219Y). p.S161F was highly conserved across 13 species and that p.N219Y was relatively conserved in cloven-hoofed species. Mutations at two sites changed the local conformation of the CTSS protein, reduced its stability, and affected its function and goat breed evolution. These findings confirm that CTSS affects the lambing traits of goats and provide a theoretical basis for the regulatory mechanism of CTSS in affecting litter size.
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Ni90%Cr10% and Ni97%Si3% thin-film thermocouples (TFTCs) were fabricated on a silicon substrate using magnetron sputtering technology. Static calibration yielded a Seebeck coefficient of 23.00 µV/°C. During staged temperature elevation of the TFTCs while continuously monitoring their thermoelectric output, a rapid decline in thermoelectric potential was observed upon the hot junction reaching 600 °C; the device had failed. Through three cycles of repetitive static calibration tests ranging from room temperature to 500 °C, it was observed that the thermoelectric performance of the TFTCs deteriorated as the testing progressed. Utilizing the same methodology, Ni-Cr and Ni-Si thin films corresponding to the positive and negative electrodes of the TFTCs were prepared. Their resistivity after undergoing various temperature annealing treatments was measured. Additionally, their surfaces were characterized using Scanning Electron Microscopy (SEM) and X-ray Photoelectron Spectroscopy (XPS). The causes behind the decline in thermoelectric performance at elevated temperatures were analyzed from both chemical composition and microstructural perspectives.
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Current small-molecule PD-1/PD-L1 inhibitors are mainly based on the arylmethylamine/biphenyl core scaffold. Herein, we designed for the first time a series of non-arylmethylamine analogues (oxadiazole thioether derivatives) as small-molecule PD-1/PD-L1 inhibitors. Among them, compound LP23 exhibited the most potent PD-L1 inhibitory activity with an IC50 of 16.7 nM, 3.2-fold better than the lead BMS-202 (IC50 = 53.6 nM). The X-ray crystal structure of LP23 in complex with PD-L1 was solved at a resolution of 2.6 Å, which further confirmed the high binding affinity of LP23 to PD-L1. In the HepG2/Jurkat T cell co-culture model, LP23 effectively promoted HepG2 cell death by restoring the immune function of T cells. In addition, LP23 showed excellent in vivo antitumor efficacy (TGI = 88.6% at 30 mg/kg) and benign toxicity profiles in a B16-F10 tumor model by modulating PD-L1. In summary, LP23 represents the first non-arylmethylamine-based small-molecule PD-1/PD-L1 inhibitor worthy of further investigation.
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An observer-based control method with parallel Q-filter is proposed to reject unknown multiple narrow-band disturbances for line of sight stabilization in telescope systems. In general, wide-band or multiple narrow-band disturbances rejection of observer-based control can be transformed into designing Q-filter, which could be too high-order to achieve fully-accuracy digital implementation, resulting in degrading the closed-loop performance or even causing instability. Therefore, a new parallel type of Q-filters is proposed to flexibly adjust the number of Q-filter in the sensitivity function and effectively reduce the computational complexity. A sufficient condition of the effectiveness for the parallel Q-filter and the closed-loop stability is derived and verified through simulations. Furthermore, disturbance frequencies can be on-line identified to adaptively optimize the Q-filter parameters. The effectiveness of the proposed method is validated on the image-based stabilization subsystem of a segmented lightweight large-scaled diffractive telescope.