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OBJECTIVE: Our objective was to evaluate the trajectory of immunology in patients with HIV with different baseline CD4 T-cell count strata after antiretroviral therapy (ART) under long-term viral suppression. METHODS: This was a sub-analysis focused on patients with virological suppression for at least 5 years after ART. Data were obtained from the Yunnan HIV cohort in China. Patients were categorized according to prespecified baseline CD4 T-cell counts. The trajectories of CD4 T-cell count, CD8 T-cell count, and CD4/CD8 ratio changing over time were fitted using a B-spline regression model. The Cox proportional hazards regression model was used to assess the association of baseline CD4 T-cell count with the risk of both immunological responder (IR) and CD4/CD8 ratio normalization. RESULTS: A total of 2618 patients with a median follow-up of 7.25 years (interquartile range [IQR] 5.92-8.75) were included. Over a period of 12 years, the mean CD4 T-cell count remained above 500 cells/µL in all groups. The mean CD4/CD8 ratio was solely normalized in patients whose baseline CD4 T-cell counts were above 350 cells/µL. Patients with higher baseline CD4 T-cell counts showed higher risks of both IR and CD4/CD8 ratio normalization than those with the lowest (all p trend <0.001). A higher baseline CD4 T-cell count predicted a shorter time for both IR and CD4/CD8 ratio normalization. CONCLUSIONS: Long-term, sustained viral suppression may not be able to fully normalize immunological functions in patients with HIV. A high baseline CD4 T-cell count benefits IR and CD4/CD8 ratio normalization.
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Previous research identified the expression of EDN3 in granulosa cells of preovulatory follicles in chickens. Notably, the expression level of EDN3 in Silky Fowl with low egg-laying performance was significantly higher than that in high-yield laying breed White Leghorn. Given the crucial role of granulosa cells in follicular development and maturation, it is very important to study the effect of EDN3 on the biological function of granular cells. In this study, an EDN3 overexpression plasmid was constructed and transfected into granular cells. The viability of these cells was detected using quantiative (qPCR), Cell Counting Kit-8 (CCK8), and 5-Ethynyl-2'-deoxyuridine (EdU) assays. Gonadal hormone synthesis was detected using enzyme-linked immunosorbent assay (ELISA) techniques. Finally, transcriptome sequencing was employed to identify differentially expressed genes. Result showed thatoverexpression of EDN3 was observed to promote cell viability. In addition, it significantly inhibits the expressions of LHR and cAMP-PKA signaling pathways. Cell transcriptome sequencing data displayed that EDN3 can upregulate energy metabolism and immune-related signaling pathways, whereas follicle maturation and the GnRH signaling pathway were downregulated. In conclusion, this study demonstrates that EDN3 can enhance granulosa cell viability and inhibit the expression of LHCGR, a process likely mediated through the cAMP-PKA signaling pathway. However, further evidence is required to substantiate the regulatory relationship between EDN3 and the cAMP-PKA signaling pathway.
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The presence of a significant number of melanocytes in the ovary and follicular membrane of Silky Fowl suggests their potential involvement in follicle development. Currently, there is a lack of available data regarding to the isolation of primary melanocytes from adult chickens. To date, primary melanocytes and their in vitro culture system have been successfully conducted in the peritoneum of chicken embryos. Herein, melanocytes from silky fowl ovaries were isolated and identified. Silky Fowl ovaries were obtained by mixed digestion of 0.1% collagenase II and 0.25% trypsin-EDTA. Melanocytes could be further purified and cultured up to 5 generations in vitro. RNA-seq analysis was used to investigate whether there were differences in the functional status of melanocytes in different tissues and developmental stages. Consequently, differential gene expressions between peritoneal and ovarian melanocytes were compared. These findings demonstrated that the Silky Fowl ovary had higher expression levels of genes involved in the production of sexual hormones and melanogenesis, while those of melanocytes derived from the peritoneum were involved in amino acid metabolism, lipid synthesis, and overall metabolic rates. This suggests that the role of melanocytes is dependent on the origin tissue and developmental stage, and is tightly connected to the function of the specific source tissue from which the cells were derived. This study provides a method for isolating adult melanocytes and serve as a basis for further investigate the effect of SFOM on germ cells.
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Galinhas , Ovário , Feminino , Embrião de Galinha , Animais , Galinhas/genética , Galinhas/metabolismo , Melanócitos/metabolismo , CarneRESUMO
Primary small bowel adenocarcinoma (SBA) is a rare gastrointestinal cancer with a low incidence of ovarian metastasis. Differential diagnosis of metastatic and primary ovarian cancer is often challenging. The present study reported the case of a 45-year-old woman with jejunal adenocarcinoma who presented with right ovarian, left ovarian, abdominopelvic implant and local recurrent bowel wall metastases successively after primary tumor resection. The ovarian masses of the patient originated from SBA, which was confirmed by immunohistochemical results. Following four comprehensive evaluations by an experienced multidisciplinary team (MDT) during the disease period, the patient underwent four operations, 28 cycles of chemotherapy, 24 cycles of targeted therapy and maintenance therapy for 8 months. As of February 2023, the patient has survived for 73 months and has a high quality of life. It is suggested that when a patient with SBA presents with an ovarian mass, the differential diagnosis between metastatic ovarian cancer and primary ovarian cancer mainly relies on immunohistochemistry. After a comprehensive evaluation by an experienced MDT, surgical resection is the primary treatment for advanced SBA, thus demonstrating some benefits for patients.
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BACKGROUND: Dorper and Tan sheep are renowned for their rapid growth and exceptional meat quality, respectively. Previous research has provided evidence of the impact of gut microbiota on breed characteristics. The precise correlation between the gastrointestinal tract and peripheral organs in each breed is still unclear. Investigating the metabolic network of the intestinal organ has the potential to improve animal growth performance and enhance economic benefits through the regulation of intestinal metabolites. RESULTS: In this study, we identified the growth advantage of Dorper sheep and the high fat content of Tan sheep. A transcriptome study of the brain, liver, skeletal muscle, and intestinal tissues of both breeds revealed 3,750 differentially expressed genes (DEGs). The genes PPARGC1A, LPL, and PHGDH were found to be highly expressed in Doper, resulting in the up-regulation of pathways related to lipid oxidation, glycerophospholipid metabolism, and amino acid anabolism. Tan sheep highly express the BSEP, LDLR, and ACHE genes, which up-regulate the pathways involved in bile transport and cholesterol homeostasis. Hindgut content analysis identified 200 differentially accumulated metabolites (DAMs). Purines, pyrimidines, bile acids, and fatty acid substances were more abundant in Dorper sheep. Based on combined gene and metabolite analyses, we have identified glycine, serine, and threonine metabolism, tryptophan metabolism, bile secretion, cholesterol metabolism, and neuroactive ligand-receptor interaction as key factors contributing to the differences among the breeds. CONCLUSIONS: This study indicates that different breeds of sheep exhibit unique breed characteristics through various physiological regulatory methods. Dorper sheep upregulate metabolic signals related to glycine, serine, and threonine, resulting in an increase in purine and pyrimidine substances. This, in turn, promotes the synthesis of amino acids and facilitates body development, resulting in a faster rate of weight gain. Tan sheep accelerate bile transport, reduce bile accumulation in the intestine, and upregulate cholesterol homeostasis signals in skeletal muscles. This promotes the accumulation of peripheral and intramuscular fat, resulting in improved meat quality. This work adopts a joint analysis method of multi-tissue transcriptome and gut metabolome, providing a successful case for analyzing the mechanisms underlying the formation of various traits.
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Melhoramento Vegetal , Transcriptoma , Ovinos/genética , Animais , Metaboloma , Glicina , Serina , Treonina , ColesterolRESUMO
Municipal solid waste (MSW) is characterized by complex composition, low calorific value and high moisture content. Using a single treatment technology is costly and difficult to achieve optimal results. A poly-generation system that integrates classified waste pyrolysis and incineration is proposed, producing fuel, electricity, and steam. The system has been designed and optimized to find the optimal feed ratio and process model. However, the economic performance of the poly-generation system is still unclear. In this work, a techno-economic analysis (TEA) was conducted to evaluate the economic feasibility of the proposed MSW treatment poly-generation system. The annual electricity generated by the poly-generation system is 104.13 GWh. The annual steam generated is 4.91 kt, and the average annual diesel produced is 1.60 kt. The TEA results showed that the total capital investment of the system was 602.07 M¥, and the annual operating cost was 40.63 M¥. The net present value was 93.01 M¥, which is a positive value. The internal rate of return was 10.28 %, which is higher than the benchmark rate of return, indicating that the system is economically feasible. Sensitivity analysis indicated that the internal rate of return was extremely sensitive to fixed capital investment, price of electricity, product yield, and government subsidy. The TEA analysis of poly-generation system provides a fundamental theoretical basis for the feasibility of classified MSW treatment and offers valuable insights for policy makers and investors in the waste management field. Considering the complexity of the waste, future research can be carried out from the environmental aspect, combining both economic and environmental objectives for multi-objective optimization and conducting comprehensive evaluation of the industrial practicability of the poly-generation system.
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Beijing You Chicken, a valuable local chicken breed from Beijing, China, was once listed as an endangered breed. From the point of view of conservation, the preservation of this breed is an important task for the local researchers. Semen cryopreservation is a popular method to maintain valuable species. However, during cryopreservation, semen is susceptible to oxidative damage. Melatonin is a potent antioxidant and free radical scavenger, so it has been selected to improve the efficiency of sperm cryopreservation. In this study, the chicken semen was treated with different concentrations of melatonin in the cryopreservation solution. The results showed that melatonin at concentrations of 10-3 M and 10-5 M significantly improved sperm progressive motility and total motility, respectively, compared to the control (P < 0.05). Melatonin at 10-3 M also significantly improved the plasma membrane and acrosome integrity of spermatozoa compared to the control. The mechanisms are that melatonin significantly reduces the level of ROS and preserves sperm mitochondrial membrane potential. Most importantly, the melatonin-treated cryopreserved chicken sperm after artificial insemination significantly increased the hatching rate of chicks compared to the control (p < 0.05). The results show that melatonin has a positive effect on the quality of the cryopreserved spermatozoa. These results provide the theoretical and practical basis for using melatonin to improve Beijing You Chicken conservation, and they may also be applicable to poultry as a whole.
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Melatonina , Preservação do Sêmen , Masculino , Animais , Galinhas , Melatonina/farmacologia , Criopreservação/métodos , Sêmen , Pequim , Crioprotetores/farmacologia , Crioprotetores/metabolismo , Preservação do Sêmen/veterinária , Preservação do Sêmen/métodos , Espermatozoides , Motilidade dos Espermatozoides , Análise do SêmenRESUMO
Alopecia areata is an autoimmune disease characterized by the immune system attacking self hair follicles, mainly in the scalp. There is no complete cure, and the pathogenesis is still not fully understood. Here, sequencing of skin tissues collected from 1-month-old coarse- and fine-wool lambs identified miR-199a-3p as the only small RNA significantly overexpressed in the fine-wool group, suggesting a role in hair follicle development. MiR-199a-3p expression was concentrated in the dermal papillae cells of sheep hair follicles, along with enhanced ß-catenin expression and the inhibition of PTPRF protein expression. We also successfully constructed a mouse model of alopecia areata by intracutaneous injection with an miR-199a-3p antagomir. Injection of the miR-199a-3p agomir resulted in hair growth and earlier anagen entry. Conversely, local injection with the miR-199a-3p antagomir resulted in suppressed hair growth at the injection site, upregulation of immune system-related genes, and downregulation of hair follicle development-related genes. In vivo and in vitro analyses demonstrated that miR-199a-3p regulates hair follicle development through the PTPRF/ß-catenin axis. In conclusion, a mouse model of alopecia areata was successfully established by downregulation of a small RNA, suggesting the potential value of miR-199a-3p in the study of alopecia diseases. The regulatory role of miR-199a-3p in the PTPRF/ß-catenin axis was confirmed, further demonstrating the link between alopecia areata and the Wnt-signaling pathway.
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Alopecia em Áreas , MicroRNAs , Animais , Camundongos , Antagomirs , beta Catenina/genética , Modelos Animais de Doenças , Folículo Piloso/patologia , MicroRNAs/genética , OvinosRESUMO
BACKGROUND: Tan and Hu sheep are well-known local breeds in China, producing lamb fur with unique ornamental and practical values highly appreciated by consumers worldwide. Fur quality is optimal at one month of age and gradually declines with time. Despite active research on its genetic mechanism using transcriptomic and whole genome bisulfite sequencing analysis, the main effective gene locus has not been found, and its regulatory mechanism is still unclear, which limits the breeding and improvement of fur traits. RESULTS: Scapular skin samples from newborn (1-month old) and adult (24-month old) Tan sheep were utilized for small ribonucleic acid (RNA) sequencing Principal Component Analysis (PCA) showed that the newborn and adult groups were completely separated. Differential expression analysis of micro-RNAs (miRNAs) identified 32 up-regulated miRNAs and 48 down-regulated miRNAs in the newborn groups. All up-regulated miRNAs were located in the imprinted. Dlk1-Gtl2 locus on chromosome 18, whereas all down-regulated miRNAs were distributed across the sheep chromosomes, without a clear pattern of positional consistency. Further, by systematically analyzing the target genes and signaling pathways of all 32 up-regulated miRNAs, we found that the PI3K-AKT signaling pathway has the potential to be targeted and regulated by most of the miRNAs in the Dlk1-Gtl2 region. In addition, we also re-analyzed miRNA sequencing data from public databases on Hu lambs (full sibling Hu lambs with high- and low-quality fur characteristics). Again, it was found that most of the up-regulated miRNAs in lambs with high-quality fur were also located in the Dlk1-Gtl2 region, whereas this patter was not present for down-regulated miRNAs. CONCLUSION: Sequencing of miRNAs in conjunction with public databases was employed to identify miRNAs within the imprinted Dlk1-Gtl2 region on chromosome 18, suggesting their potential roles as epigenetic regulators of fur traits. Small RNAs located at the Dlk1-Gtl2 locus were identified as having the potential to systematically regulate the PI3K-AKT signaling pathway, thereby indicating the relevance of the Dlk1-Gtl2/PI3K-AKT axis in the context of fur traits. Selection of parental specific expressed imprinted genes in the process of conserving and exploiting lamb fur traits should be emphasized.
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MicroRNAs , RNA Longo não Codificante , Animais , Ovinos/genética , MicroRNAs/genética , Impressão Genômica , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas de Ligação ao Cálcio/genéticaRESUMO
BACKGROUND: It is not uncommon for some individuals to retain certain primitive characteristics even after domestication or long-term intensive selection. Wild ancestors or original varieties of animals typically possess strong adaptability to environmental preservation, a trait that is often lacking in highly artificially selected populations. In the case of the Merino population, a world-renowned fine wool sheep breed, a phenotype with primitive coarse wool characteristic has re-emerged. It is currently unclear whether this characteristic is detrimental to the production of fine wool or whether it is linked to the adaptability of sheep. The underlying genetic/epigenetic mechanisms behind this trait are also poorly understood. RESULTS: This study identified lambs with an ancestral-like coarse (ALC) wool type that emerged during the purebred breeding of Merino fine wool sheep. The presence of this primitive sheep characteristic resulted in better environmental adaptability in lambs, as well as improved fine wool yield in adulthood. Reciprocal cross experiments revealed that the ALC phenotype exhibited maternal genetic characteristics. Transcriptomic SNP analysis indicated that the ALC phenotype was localized to the imprinted Gtl2-miRNAs locus, and a significant correlation was found between the ALC wool type and a newly identified short Interstitial Telomeric Sequences (s-ITSs) at this locus. We further confirmed that a novel 38-nt small RNA transcribed from these s-ITSs, in combination with the previously reported 22-nt small RNAs cluster from the Gtl2-miRNAs locus, synergistically inhibited PI3K/AKT/Metabolic/Oxidative stress and subsequent apoptotic pathways in wool follicle stem cells, resulting in the ALC wool type. The necessity of Gtl2-miRNAs in controlling primary hair follicle morphogenesis, as well as the wool follicle type for ALC wool lambs, was verified using intergenic differentially methylated region-knockout mice. CONCLUSION: The ALC wool type of Merino sheep, which does not reduce wool quality but increases yield and adaptability, is regulated by epigenetic mechanisms in the imprinted Gtl2-miRNAs region on sheep chromosome 18, with the maternally expressed imprinted gene responsible for the ALC phenotype. This study highlights the significance of epigenetic regulation during embryonic and juvenile stages and emphasizes the advantages of early adaptation breeding for maternal parents in enhancing the overall performance of their offspring.
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BACKGROUND: Wool fibers are valuable materials for textile industry. Typical wool fibers are divided into medullated and non-medullated types, with the former generated from primary wool follicles and the latter by either primary or secondary wool follicles. The medullated wool is a common wool type in the ancestors of fine wool sheep before breeding. The fine wool sheep have a non-medullated coat. However, the critical period determining the type of wool follicles is the embryonic stage, which limits the phenotypic observation and variant contrast, making both selection and studies of wool type variation fairly difficult. RESULTS: During the breeding of a modern fine (MF) wool sheep population with multiple-ovulation and embryo transfer technique, we serendipitously discovered lambs with ancestral-like coarse (ALC) wool. Whole-genome resequencing confirmed ALC wool lambs as a variant type from the MF wool population. We mapped the significantly associated methylation locus on chromosome 4 by using whole genome bisulfite sequencing signals, and in turn identified the SOSTDC1 gene as exons hypermethylated in ALC wool lambs compare to their half/full sibling MF wool lambs. Transcriptome sequencing found that SOSTDC1 was expressed dozens of times more in ALC wool lamb skin than that of MF and was at the top of all differentially expressed genes. An analogy with the transcriptome of coarse/fine wool breeds revealed that differentially expressed genes and enriched pathways at postnatal lamb stage in ALC/MF were highly similar to those at the embryonic stage in the former. Further experiments validated that the SOSTDC1 gene was specifically highly expressed in the nucleus of the dermal papilla of primary wool follicles. CONCLUSION: In this study, we conducted genome-wide differential methylation site association analysis on differential wool type trait, and located the only CpG locus that strongly associated with primary wool follicle development. Combined with transcriptome analysis, SOSTDC1 was identified as the only gene at this locus that was specifically overexpressed in the primary wool follicle stem cells of ALC wool lamb skin. The discovery of this key gene and its epigenetic regulation contributes to understanding the domestication and breeding of fine wool sheep.
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PURPOSE: Despite limited genetic and histologic heterogeneity, Ewing sarcoma (EwS) tumor cells are transcriptionally heterogeneous and display varying degrees of mesenchymal lineage specification in vitro. In this study, we investigated if and how transcriptional heterogeneity of EwS cells contributes to heterogeneity of tumor phenotypes in vivo. EXPERIMENTAL DESIGN: Single-cell proteogenomic-sequencing of EwS cell lines was performed and integrated with patient tumor transcriptomic data. Cell subpopulations were isolated by FACS for assessment of gene expression and phenotype. Digital spatial profiling and human whole transcriptome analysis interrogated transcriptomic heterogeneity in EwS xenografts. Tumor cell subpopulations and matrix protein deposition were evaluated in xenografts and patient tumors using multiplex immunofluorescence staining. RESULTS: We identified CD73 as a biomarker of highly mesenchymal EwS cell subpopulations in tumor models and patient biopsies. CD73+ tumor cells displayed distinct transcriptional and phenotypic properties, including selective upregulation of genes that are repressed by EWS::FLI1, and increased migratory potential. CD73+ cells were distinguished in vitro and in vivo by increased expression of matrisomal genes and abundant deposition of extracellular matrix (ECM) proteins. In epithelial-derived malignancies, ECM is largely deposited by cancer-associated fibroblasts (CAF), and we thus labeled CD73+ EwS cells, CAF-like tumor cells. Marked heterogeneity of CD73+ EwS cell frequency and distribution was detected in tumors in situ, and CAF-like tumor cells and associated ECM were observed in peri-necrotic regions and invasive foci. CONCLUSIONS: EwS tumor cells can adopt CAF-like properties, and these distinct cell subpopulations contribute to tumor heterogeneity by remodeling the tumor microenvironment. See related commentary by Kuo and Amatruda, p. 5002.
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Fibroblastos Associados a Câncer , Sarcoma de Ewing , Humanos , Sarcoma de Ewing/patologia , Fibroblastos Associados a Câncer/metabolismo , Microambiente Tumoral/genética , Linhagem Celular Tumoral , Proteína EWS de Ligação a RNA/genética , Proteína EWS de Ligação a RNA/metabolismo , Perfilação da Expressão Gênica , Proteínas de Fusão Oncogênica/genética , Proteína Proto-Oncogênica c-fli-1/genética , Regulação Neoplásica da Expressão GênicaRESUMO
Novel small RNAs derived from tRNAs are continuously identified, however, their biological functions are rarely reported. Here, we accidentally found the reads peak at 32nt during statistical analysis on the miRNA-seq data of lamb skin tissue, and found that it was related to the wool type of lambs. This 32nt peak was composed of small tRNA fragments. The main component sequence of this peak was a novel small tRNA derived from Glycyl tRNA (tRNAGly), the expression level of tRNAGly-derived tRNA fragments (tRFGly) was 5.77 folds higher in the coarse wool lambs than that in the fine wool lambs. However, in contrast, the expression of tRNAGly in the skin of fine wool lambs is 6.28 folds more than that in coarse wool lambs. tRNAGly promoted the synthesis of high glycine protein including KAP6 in fine wool lamb skin. These proteins were reported as the major genes for fine curly wool. Integrative analysis of target gene prediction, proteomics and metabolomics results revealed that tRFGly reduced the level of reactive oxygen species (ROS) in the skin of coarse wool lambs by targeted inhibition of the Metabolic signal and the corresponding Glutathione metabolic pathway, on the contrary, the level of oxidative stress in the skin of fine wool lambs was significantly higher. This study revealed for the first time the relationship between tRNAGly and its derived tRFGly and animal traits. tRFGly has the function of targeting and regulating protein synthesis. At the same time, tRFGly can reduce the expression of its resource complete tRNA, thereby reducing its ability to transport specific amino acid and affecting the expression of corresponding proteins.
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RNA de Transferência de Glicina , Lã , Ovinos/genética , Animais , Lã/metabolismo , RNA de Transferência de Glicina/metabolismo , RNA de Transferência/metabolismo , Carneiro Doméstico/genética , Carneiro Doméstico/metabolismo , Estresse Oxidativo/genéticaRESUMO
Background: The pathogenesis of COVID-19, including thrombocytopenia, has not been fully clarified. The lungs are a major organ of platelet production and thrombocytopenia induced by severe COVID-19 was proposed. Methods: the change of platelet level was analysed with clinical parameters in 95 hospitalized COVID-19 patients in Wuhan Third Hospital. The production of platelets in the lungs was explored in an ARDS rat model. Results: The level of platelets was negatively correlated with disease severity and was recovered with disease improvement. The non-survivors were accompanied by lower levels of platelet. The odds ratio (OR) of the valley level of the platelet count (PLTlow) was greater than 1, suggesting that PLTlow could be a death exposure factor. The platelet/lymphocyte ratio (PLR) was positively associated with severity of COVID-19, and the platelet/lymphocyte ratio threshold of 248.5 was best correlated with death risk (sensitivity 0.641 and specificity 0.815). To demonstrate the possible biogenesis aberration of platelet in lungs, an LPS-induced ARDS rat model was applied. Lower level of platelet in peripheral and less production of platelet from lungs in ARDS were demonstrated. Though megakaryocyte (MK) number in ARDS lungs is higher than controls, the immature platelet fraction (IPF) in postpulmonary blood is still at the same level as prepulmonary in ARDS rat, indicating that ARDS rats generated fewer platelets in lungs. Conclusion: Our data suggested that COVID-19-induced severe lung inflammation may impair platelet production in the lung. Thrombocytopenia may be mainly caused by platelet consumption for multiorgan thrombosis; however, biogenesis aberration of platelet in the lung induced by diffuse interstitial pulmonary damage cannot be ruled out.
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Tumor heterogeneity is a major driver of cancer progression. In epithelial-derived malignancies, carcinoma-associated fibroblasts (CAFs) contribute to tumor heterogeneity by depositing extracellular matrix (ECM) proteins that dynamically remodel the tumor microenvironment (TME). Ewing sarcomas (EwS) are histologically monomorphous, mesenchyme-derived tumors that are devoid of CAFs. Here we identify a previously uncharacterized subpopulation of transcriptionally distinct EwS tumor cells that deposit pro-tumorigenic ECM. Single cell analyses revealed that these CAF-like cells differ from bulk EwS cells by their upregulation of a matrisome-rich gene signature that is normally repressed by EWS::FLI1, the oncogenic fusion transcription factor that underlies EwS pathogenesis. Further, our studies showed that ECM-depositing tumor cells express the cell surface marker CD73, allowing for their isolation ex vivo and detection in situ. Spatial profiling of tumor xenografts and patient biopsies demonstrated that CD73 + EwS cells and tumor cell-derived ECM are prevalent along tumor borders and invasive fronts. Importantly, despite loss of EWS::FLI1-mediated gene repression, CD73 + EwS cells retain expression of EWS::FLI1 and the fusion-activated gene signature, as well as tumorigenic and proliferative capacities. Thus, EwS tumor cells can be reprogrammed to adopt CAF-like properties and these transcriptionally and phenotypically distinct cell subpopulations contribute to tumor heterogeneity by remodeling the TME.
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Background: Livestock is an excellent source of high nutritional value protein for humans; breeding livestock is focused on improving meat productivity and quality. Dorper sheep is a distinguished breed with an excellent growth performance, while Tan sheep is a Chinese local breed famous for its delicious meat. Several studies have demonstrated that the composition of gut microbiome and metabolome modulate host phenotype. Methods: In the present study, we performed 16S amplicon sequencing and metabolomic analyses of the rumen and hindgut microbiome of 8-month-old Dorper and Tan sheep, raised under identical feeding and management conditions, to explore the potential effects of gut microbiome and its metabolites on growth performance and meat quality. Results: Our study identified Lactobacillus, a marker genus in the rumen, to be significantly associated with the levels of fumaric acid, nicotinic acid, and 2-deoxyadenosine (P-value < 0.05). Statistical analysis showed that nicotinic acid was significantly negatively correlated with body weight (P-value < 0.01), while 2-deoxyadenosine was significantly positively correlated with fatty acids content (P-value < 0.05). There was a biologically significant negative correlation between Phascolarctobacterium and deoxycytidine levels in the hindgut. Deoxycytidine was significantly positively correlated with body weight, protein, and amino acid content. Differences in rumen fermentation patterns that are distinctive among breeds were identified. Tan sheep mainly used Lactobacillus and fumaric acid-mediated pyruvic acid for energy supply, while Dorper sheep utilize glycogenic amino acids. The difference of iron metabolism in the hindgut of Dorper sheep affects lipid production, while Phascolarctobacterium in Tan sheep is related to roughage tolerance. The accumulation of nucleosides promotes the growth performance of Dorper sheep. Conclusion: These findings provide insights into how the microbiome-metabolome-dependent mechanisms contribute to growth rate and fat contents in different breeds. This fundamental research is vital to identifying the dominant traits of breeds, improving growth rate and meat quality, and establishing principles for precision feeding.
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Cecal microflora plays a key role in the production performance and immune function of chickens. White Leghorn (WL) is a well-known commercial layer line chicken with high egg production rate. In contrast, Silky Fowl (SF), a Chinese native chicken variety, has a low egg production rate, but good immune performance. This study analyzed the composition of cecal microbiota, metabolism, and gene expression in intestinal tissue of these varieties and the correlations among them. Significant differences were observed in the cecal microbes: Bacteroides was significantly enriched in WL, whereas Veillonellaceae and Parabacteroides were significantly enriched in SF. Carbohydrate biosynthesis and metabolism pathways were significantly upregulated in WL cecum, which might provide more energy to the host, leading to persistently high levels of egg production. The higher Parabacteroides abundance in SF increased volicitin content, enhanced α-linolenic acid metabolism, and significantly negatively correlated with metabolites of propanoate metabolism and carbohydrate metabolism. Genes related to lipid metabolism, immunity, and melanogenesis were significantly upregulated in the SF cecum, regulating lipid metabolism, and participating in the immune response, while genes related to glucose metabolism and bile acid metabolism were expressed at higher levels in WL, benefiting energy support. This study provided a mechanism for intestinal microorganisms and metabolic pathways to regulate chicken egg-laying performance and immunity.
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In our study, a set of lambs with coarse wool type all over their bodies were discovered within a full-sib family during an embryo transfer experiment of merino fine wool sheep. The difference between coarse and fine wool traits were studied from the perspective of RNA modification-N6-methyladenosine. A total of 31,153 peaks were collected, including 15,968 peaks in coarse skin samples and 15,185 peaks in fine skin samples. In addition, 7208 genes were differentially m6A methylated, including 4167 upregulated and 3041 downregulated in coarse skin samples. Four key genes (EDAR, FGF5, TCHH, KRT2) were obtained by comprehensive analysis of the MeRIP-seq and RNA sequence, which are closely related to primary wool follicle morphogenesis and development. The PI3K/AKT pathway was enriched through different m6A-related genes. These results provided new insights to understand the role of epigenetics in wool sheep domestication and breeding.
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Melanoma is known to be insensitive to radiotherapy; however, the present study reports the case of a patient with vulvar malignant melanoma in which near complete remission of the target area was observed after implementing immune checkpoint inhibitors (ICIs) and hypo-fractionated radiotherapy (HFRT). The patient was treated with an intensity-modulated radiation therapy technique that delivered a hypo-fractionated dose of 3,000 cGy in six fractions. After 3 days, the patient underwent immunotherapy with two cycles of 240 mg triprizumab every 2 weeks. Tumors that underwent radiotherapy had markedly decreased in size and a near complete remission of the melanoma was observed 4 months after radiotherapy. However, the metastases in the liver and lungs continued to grow, new metastases appeared in the abdominal subcutaneous tissue and enlarged lymph nodes were observed in the pelvic area. The results of the present study indicated that ICIs and HFRT exert a marked local effect, but no abscopal effect.
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Methods for the modification of indole derivatives are powerful techniques in organic, medicinal, and biomolecular chemistry. Here, we report a protocol for the C-H alkenylation of N-H indoles with ß-chlorovinyl dithianes to furnish alkenyl indoles through dual 1,3-sulfur rearrangements. This alkenylation protocol could selectively prepare a variety of vinyl indoles in moderate to high yields with excellent functional group tolerance.