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Despite pluripotent stem cells sharing key transcription factors, their maintenance involves distinct genetic inputs. Emerging evidence suggests that super-enhancers (SEs) can function as master regulatory hubs to control cell identity and pluripotency in humans and mice. However, whether pluripotency-associated SEs share an evolutionary origin in mammals remains elusive. Here, we performed comprehensive comparative epigenomic and transcription factor binding analyses among pigs, humans, and mice to identify pluripotency-associated SEs. Like typical enhancers, SEs displayed rapid evolution in mammals. We showed that BRD4 is an essential and conserved activator for mammalian pluripotency-associated SEs. Comparative motif enrichment analysis revealed 30 shared transcription factor binding motifs among the three species. The majority of transcriptional factors that bind to identified motifs are known regulators associated with pluripotency. Further, we discovered three pluripotency-associated SEs (SE-SOX2, SE-PIM1, and SE-FGFR1) that displayed remarkable conservation in placental mammals and were sufficient to drive reporter gene expression in a pluripotency-dependent manner. Disruption of these conserved SEs through the CRISPR-Cas9 approach severely impaired stem cell pluripotency. Our study provides insights into the understanding of conserved regulatory mechanisms underlying the maintenance of pluripotency as well as species-specific modulation of the pluripotency-associated regulatory networks in mammals.
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Elementos de Facilitación Genéticos , Células Madre Pluripotentes , Animales , Proteínas de Ciclo Celular/metabolismo , Elementos de Facilitación Genéticos/genética , Euterios/genética , Femenino , Humanos , Ratones , Proteínas Nucleares/metabolismo , Placenta/metabolismo , Células Madre Pluripotentes/metabolismo , Embarazo , Porcinos , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Spermatogonial stem cells (SSCs) play a crucial role in mammalian spermatogenesis and maintain the stable inheritance of the germline in livestock. However, stress and bacterial or viral infections can disrupt immune homeostasis of the testes, thereby leading to spermatogenesis destruction and infertility, which severely affects the health and productivity of mammals. This study aimed to explore the effect of ubiquitin C-terminal hydrolase L1 (UCHL1) knockdown (KD) in goat SSCs and mouse testes and investigate the potential anti-inflammatory function of UCHL1 in a poly(I:C)-induced inflammation model to maintain microenvironmental homeostasis. In vitro, the downregulation of UCHL1 (UCHL1 KD) in goat SSCs increased the expression levels of apoptosis and inflammatory factors and inhibited the self-renewal and proliferation of SSCs. In vivo, the structure of seminiferous tubules and spermatogenic cells was disrupted after UCHL1 KD, and the expression levels of apoptosis- and inflammation-related proteins were significantly upregulated. Furthermore, UCHL1 inhibited the TLR3/TBK1/IRF3 pathway to resist poly(I:C)-induced inflammation in SSCs by antagonizing HSPA8 and thus maintaining SSC autoimmune homeostasis. Most importantly, the results of this study showed that UCHL1 maintained immune homeostasis of SSCs and spermatogenesis. UCHL1 KD not only inhibited the self-renewal and proliferation of goat SSCs and spermatogenesis but was also involved in the inflammatory response of goat SSCs. Additionally, UCHL1 has an antiviral function in SSCs by antagonizing HSPA8, which provides an important basis for exploring the specific mechanisms of UCHL1 in goat spermatogenesis.
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Cabras , Espermatogonias , Animales , Masculino , Ratones , Homeostasis , Inflamación/metabolismo , Espermatogénesis/fisiología , Espermatogonias/metabolismo , Células Madre , Testículo/metabolismoRESUMEN
BACKGROUND: Lipid metabolism plays essential roles in skin barrier formation and the regulation of skin inflammation. Moreover, lipid homeostasis regulates skin melanogenesis, although the underlying mechanism remains largely unknown. Sterol regulatory element binding protein 1 (SREBP-1) is a key transcription factor essential for cellular lipid metabolism. Loss-of-function variants in SREBF1 are responsible for autosomal-dominant ichthyosis follicularis, alopecia, and photophobia syndrome, emphasizing the significance of lipid homeostasis in skin keratinization. OBJECTIVES: To identify the genetic basis of a new entity featuring diffuse skin hyperpigmentation with congenital cataracts, and to unravel the underlying mechanism for the pathogenesis of the SREBF1 variant. METHODS: Whole-exome sequencing was performed to identify the underlying genetic variants. Quantitative PCR, western blot, and immunofluorescent staining were employed to assess the expression and the subcellular localization of the SREBF1 variant. The transcriptional activity of the mutant SREBP-1 was determined by luciferase reporter assay. A transgenic zebrafish model was constructed. RESULTS: Two patients of different ethnicities presented with generalized skin hyperpigmentation with skin xerosis, congenital cataracts, and extracutaneous symptoms. We identified a de novo nonsense variant c.1289C>A (p.Ser430*) in the SREBF1 gene in both patients. The variant encoded a truncated protein which showed preferential nucleus localization, in contrast to wild-type SREBP-1 which is mainly localized in cytoplasm in sterol-sufficient conditions. Luciferase reporter assay revealed that the Ser430* mutant exhibited an enhanced transcriptional activity. The primary cultured melanocytes from the patient showed increased melanin synthesis compared to those from normal controls. The Ser430* transgenic zebrafish model exhibited more black spots, along with upregulated expression of melanogenic genes at 35 days post-fertilization. CONCLUSIONS: We demonstrated that a gain-of-function variant in SREBF1 caused a previously undescribed disorder characterized by generalized skin hyperpigmentation and congenital cataracts. Our study reveals the involvement of SREBP-1 in melanogenesis and lens development and paves the way for developing novel therapeutic targets for skin dyspigmentation or cataracts.
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A simple, efficient, and practical method for the synthesis of S-quinolyl xanthates was developed via Ts2O-promoted deoxygenative C-H dithiocarbonation of quinoline N-oxides with various potassium O-alkyl xanthates. The reaction performed well under transition-metal-free, base-free, and room-temperature conditions with wide substrate tolerance. Employing potassium O-tert-butyl xanthate (tBuOCS2K) as a nucleophile, some valuable quinoline-2-thiones were unexpectedly obtained in a one-pot reaction without any additional base.
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A convenient, efficient and practical approach for the synthesis of S-quinolyl phosphorothioates via cheap TsCl promoted deoxygenative C2-H phosphorothiolation of quinoline N-oxides with readily available triethylammonium O,O-dialkylphosphorothioates was developed. The reaction performed well under transition-metal-free conditions at room temperature with a very short reaction time (10-20 min). Preliminary studies showed that the current transformation underwent a nucleophilic substitution process.
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BACKGROUND: Diabetes mellitus (DM) presents impediment to wound healing. While ultraviolet B (UVB) exposure showed therapeutic potential in various skin conditions, its capacity to mediate diabetic wound healing remains unclear. To investigate the efficacy of UVB on wound healing and its underlying basis. MATERIALS AND METHODS: Male C57BL/6 mice were subjected to the high-fat diet followed by streptozotocin administration to establish the diabetic model. Upon confirmation of diabetes, full-thickness wounds were inflicted and the treatment group received UVB radiation at 50 mJ/cm2 for 5 min every alternate day for 2 weeks. Wound healing rate was then assessed, accompanied by evaluations of blood glucose, lipid profiles, CD31 expression, and concentrations of ghrelin and leptin. Concurrently, in vitro studies were executed to evaluate the protective role of ghrelin on human umbilical vein endothelial cells (HUVEC) under high glucose (HG) conditions. RESULTS: Post UVB exposure, there was a marked acceleration in wound healing in DM mice without alterations in hyperglycemia and lipid profiles. Compared to non-UVB-exposed mice, the UVB group showed enhanced angiogenesis manifested by a surge in CD31 expression. This trend appeared to be in harmony with the elevated ghrelin levels. In vitro experiments indicated that ghrelin significantly enhanced the migratory pace and angiogenic properties of HUVEC under HG-induced stress, potentially mediated by an upregulation in vascular endothelial growth factor expression. CONCLUSION: UVB exposure bolstered wound healing in diabetic mice, plausibly mediated through augmented angiogenesis induced by ghrelin secretion. Such findings underscore the vast potential of UVB-induced ghrelin in therapeutic strategies targeting diabetic wound healing.
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Diabetes Mellitus Experimental , Ghrelina , Células Endoteliales de la Vena Umbilical Humana , Ratones Endogámicos C57BL , Cicatrización de Heridas , Animales , Humanos , Masculino , Ratones , Glucemia/metabolismo , Ghrelina/metabolismo , Ghrelina/efectos de la radiación , Leptina/metabolismo , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Piel/efectos de la radiación , Piel/patología , Piel/metabolismo , Rayos Ultravioleta/efectos adversos , Terapia Ultravioleta/métodos , Cicatrización de Heridas/efectos de la radiaciónRESUMEN
Ulcerative colitis (UC) is a relapsing and reoccurring inflammatory bowel disease. The treatment effect of Alhagi maurorum and stem cell extracts on UC remains unclear. The aim of the present study was to investigate the protective role of Alhagi maurorum combined with stem cell extract on the intestinal mucosal barrier in an intestinal inflammation mouse model. Sixty mice were randomly divided into a control group, model group, Alhagi group, MSC group, and MSC/Alhagi group. MSC and Alhagi extract were found to reduce the disease activity index (DAI) scores in mice with colitis, alleviate weight loss, improve intestinal inflammation in mice (p < 0.05), preserve the integrity of the ileal wall and increase the number of goblet cells and mucin in colon tissues. Little inflammatory cell infiltration was observed in the Alhagi, MSC, or MSC/Alhagi groups, and the degree of inflammation was significantly alleviated compared with that in the model group. The distribution of PCNA and TNF-alpha in the colonic tissues of the model group was more disperse than that in the normal group (p < 0.05), and the fluorescence intensity was lower. After MSC/Alhagi intervention, PCNA and TNF-alpha were distributed along the cellular membrane in the MSC/Alhagi group (p < 0.05). Compared with that in the normal control group, the intensity was slightly reduced, but it was still stronger than that in the model group. In conclusion, MSC/Alhagi can alleviate inflammatory reactions in mouse colonic tissue, possibly by strengthening the protective effect of the intestinal mucosal barrier.
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Colitis Ulcerosa , Fabaceae , Células Madre Mesenquimatosas , Animales , Ratones , Colitis Ulcerosa/tratamiento farmacológico , Factor de Células Madre , Antígeno Nuclear de Célula en Proliferación , Factor de Necrosis Tumoral alfa , Inflamación , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéuticoRESUMEN
HIV-related neuropathic pain (HRNP) is a neurodegeneration that gradually develops during the long-term course of acquired immune deficiency syndrome (AIDS) and manifests as abnormal sock/sleeve-like symmetrical pain and nociceptive hyperalgesia in the extremities, which seriously reduces patient quality of life. To date, the pathogenesis of HRNP is not completely clear. There is a lack of effective clinical treatment for HRNP and it is becoming a challenge and hot spot for medical research. In this study, we conducted a systematic review of the progress of HRNP research in recent years including (1) the etiology, classification and clinical symptoms of HRNP, (2) the establishment of HRNP pathological models, (3) the pathological mechanisms underlying HRNP from three aspects: molecules, signaling pathways and cells, (4) the therapeutic strategies for HRNP, and (5) the limitations of recent HRNP research and the future research directions and prospects of HRNP. This detailed review provides new and systematic insight into the pathological mechanism of HRNP, which establishes a theoretical basis for the future exploitation of novel target drugs. HIV infection, antiretroviral therapy and opioid abuse contribute to the etiology of HRNP with symmetrical pain in both hands and feet, allodynia and hyperalgesia. The pathogenesis involves changes in cytokine expression, activation of signaling pathways and neuronal cell states. The therapy for HRNP should be patient-centered, integrating pharmacologic and nonpharmacologic treatments into multimodal intervention.
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Infecciones por VIH , Neuralgia , Humanos , Animales , Hiperalgesia/metabolismo , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , VIH , Experimentación Humana Terapéutica , Calidad de Vida , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Modelos Animales de EnfermedadRESUMEN
A photocatalytic three-component cascade reaction of quinoxalin-2(1H)-ones, alkenes, and sulfinic acids under metal-, strong oxidant-, and external photocatalyst-free conditions was developed. The reaction was performed at room temperature using air as a green oxidant. Various sulfonated quinoxalin-2(1H)-ones were obtained in satisfactory yields with good functional group compatibility. The preliminary study showed that the current transformation was enabled by the formation of an electron donor-acceptor (EDA) complex between quinoxalin-2(1H)-ones and sulfinic acids.
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An environmentally benign protocol that provides various S-quinolyl xanthates via a ball milling enabled cross coupling reaction of haloquinolines and readily available potassium O-alkyl xanthates is first reported. The reaction proceeded well under mild, transition metal- and solvent-free conditions, making it an attractive method for the introduction of xanthates into the quinoline scaffold.
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BACKGROUND: Endometriosis, a common gynaecological disease in women, affects 10% of women of childbearing age. Among infertile women, this proportion is as high as 30-50%. Despite the high prevalence of endometriosis, the pathogenesis of endometriosis is still unclear. METHODS: In the present study, bioinformatics analysis and molecular and animal experiments were employed to explore the functions of PCGEM1 in the pathogenesis of endometriosis. We established an endometriosis rat model and isolated endometrial stromal cells (ESCs) and primary normal ESCs (NESCs). Bioinformatics analysis was adopted to study the roles of PCGEM1 in promoting the pathogenesis of endometriosis. Luciferase reporter assays and RNA pull-down assays were carried out to study the mechanism by which PCGEM1 regulates ANTXR2. RESULTS: Our results indicated that PCGEM1 promoted the motility and proliferation of ectopic endometrial cells, and the underlying mechanism was due to the direct binding of PCGEM1 to miR-124-3p to modulate ANTXR2 expression. CONCLUSION: PCGEM1 can influence endometrial stromal cell proliferation and motility and may be a novel therapeutic target for endometriosis.
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Endometriosis , Infertilidad Femenina , MicroARNs , Humanos , Femenino , Ratas , Animales , Endometriosis/patología , Infertilidad Femenina/metabolismo , MicroARNs/genética , Proliferación Celular/genética , Endometrio/metabolismo , Receptores de Péptidos/metabolismoRESUMEN
BACKGROUND: Developing Internet+home care (IHC) services is a promising way to address the problems related to population aging, which is an important global issue. However, IHC services are in their infancy in China. Limited studies have investigated the willingness and demand of nurses in municipal hospitals to provide IHC services. OBJECTIVE: This study aims to investigate the willingness and demand of nurses in municipal hospitals in China to provide IHC services and analyze the factors to promote IHC development in China. METHODS: This cross-sectional study used multistage sampling to recruit 9405 nurses from 10 hospitals in 5 regions of China. A self-designed questionnaire with good reliability and validity was used to measure nurses' willingness and demand for providing IHC services. Data analysis used the chi-square test, Welch t test, binary logistic regression analysis, and multiple linear regression analysis. RESULTS: Nurses were highly willing to provide IHC services and preferred service distances of <5 km and times from 8 AM to 6 PM. An individual share >60% was the expected service pay sharing. Job title, educational level, monthly income, and marital status were associated with nurses' willingness to provide IHC services in binary logistic regression analysis. Supervising nurses were 1.177 times more likely to express a willingness to provide IHC services than senior nurses. Nurses with a bachelor's degree had a 1.167 times higher likelihood of expressing willingness to provide IHC services than those with a junior college education or lower. Married nurses were 1.075 times more likely to express a willingness than unmarried nurses. A monthly income >¥10,000 increased the likelihood of nurses' willingness to provide IHC services, by 1.187 times, compared with an income <¥5000. Nurses' total mean demand score for IHC services was 17.38 (SD 3.67), with the highest demand being privacy protection. Multiple linear regression analysis showed that job title, monthly income, and educational level were associated with nurses' demand for IHC services. Supervising nurses (B=1.058, P<.001) and co-chief nurses or those with higher positions (B=2.574, P<.001) reported higher demand scores than senior nurses. Monthly incomes of ¥5000 to ¥10,000 (B=0.894, P<.001) and >¥10,000 (B=1.335, P<.001), as well as a bachelor's degree (B=0.484, P=.002) and at least a master's degree (B=1.224, P=.02), were associated with higher demand scores compared with a monthly income <¥5000 and junior college education or lower, respectively. CONCLUSIONS: Nurses in municipal hospitals showed a high willingness and demand to provide IHC services, with differences in willingness and demand by demographic characteristics. Accordingly, government and hospitals should regulate the service period, service distance, and other characteristics according to nurses' willingness and demand and establish relevant laws and regulations to ensure the steady and orderly development of IHC services.
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Servicios de Atención a Domicilio Provisto por Hospital , Hospitales Municipales , Enfermeras y Enfermeros , Telemedicina , Humanos , China/epidemiología , Estudios Transversales , Reproducibilidad de los Resultados , Encuestas y CuestionariosRESUMEN
BACKGROUND: Cancer indeed represents a significant public health challenge, and unplanned extubation of peripherally inserted central catheter (PICC-UE) is a critical concern in patient safety. Identifying independent risk factors and implementing high-quality assessment tools for early detection in high-risk populations can play a crucial role in reducing the incidence of PICC-UE among patients with cancer. Precise prevention and treatment strategies are essential to improve patient outcomes and safety in clinical settings. OBJECTIVE: This study aims to identify the independent risk factors associated with PICC-UE in patients with cancer and to construct a predictive model tailored to this group, offering a theoretical framework for anticipating and preventing PICC-UE in these patients. METHODS: Prospective data were gathered from January to December 2022, encompassing patients with cancer with PICC at Xiangya Hospital, Central South University. Each patient underwent continuous monitoring until the catheter's removal. The patients were categorized into 2 groups: the UE group (n=3107) and the non-UE group (n=284). Independent risk factors were identified through univariate analysis, the least absolute shrinkage and selection operator (LASSO) algorithm, and multivariate analysis. Subsequently, the 3391 patients were classified into a train set and a test set in a 7:3 ratio. Utilizing the identified predictors, 3 predictive models were constructed using the logistic regression, support vector machine, and random forest algorithms. The ultimate model was selected based on the receiver operating characteristic (ROC) curve and TOPSIS (Technique for Order Preference by Similarity to Ideal Solution) synthesis analysis. To further validate the model, we gathered prospective data from 600 patients with cancer at the Affiliated Hospital of Qinghai University and Hainan Provincial People's Hospital from June to December 2022. We assessed the model's performance using the area under the curve of the ROC to evaluate differentiation, the calibration curve for calibration capability, and decision curve analysis (DCA) to gauge the model's clinical applicability. RESULTS: Independent risk factors for PICC-UE in patients with cancer were identified, including impaired physical mobility (odds ratio [OR] 2.775, 95% CI 1.951-3.946), diabetes (OR 1.754, 95% CI 1.134-2.712), surgical history (OR 1.734, 95% CI 1.313-2.290), elevated D-dimer concentration (OR 2.376, 95% CI 1.778-3.176), targeted therapy (OR 1.441, 95% CI 1.104-1.881), surgical treatment (OR 1.543, 95% CI 1.152-2.066), and more than 1 catheter puncture (OR 1.715, 95% CI 1.121-2.624). Protective factors were normal BMI (OR 0.449, 95% CI 0.342-0.590), polyurethane catheter material (OR 0.305, 95% CI 0.228-0.408), and valved catheter (OR 0.639, 95% CI 0.480-0.851). The TOPSIS synthesis analysis results showed that in the train set, the composite index (Ci) values were 0.00 for the logistic model, 0.82 for the support vector machine model, and 0.85 for the random forest model. In the test set, the Ci values were 0.00 for the logistic model, 1.00 for the support vector machine model, and 0.81 for the random forest model. The optimal model, constructed based on the support vector machine, was obtained and validated externally. The ROC curve, calibration curve, and DCA curve demonstrated that the model exhibited excellent accuracy, stability, generalizability, and clinical applicability. CONCLUSIONS: In summary, this study identified 10 independent risk factors for PICC-UE in patients with cancer. The predictive model developed using the support vector machine algorithm demonstrated excellent clinical applicability and was validated externally, providing valuable support for the early prediction of PICC-UE in patients with cancer.
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Extubación Traqueal , Cateterismo Venoso Central , Neoplasias , Humanos , Cateterismo Venoso Central/efectos adversos , Catéteres , Aprendizaje Automático , Neoplasias/terapia , Estudios Prospectivos , Factores de RiesgoRESUMEN
A convenient and practical method for the synthesis of bioactive ester-containing chroman-4-ones through the cascade radical cyclization of 2-(allyloxy)arylaldehydes and oxalates is described. The preliminary studies suggest that an alkoxycarbonyl radical might be involved in the current transformation, which was generated via the decarboxylation of oxalates in the presence of (NH4)2S2O8.
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Ésteres , Oxalatos , Metales , Ciclización , CromanosRESUMEN
The existing treatment modalities for skin injuries mainly include dressings, negative-pressure wound treatment, autologous skin grafting, and high-pressure wound treatment. All of these therapies have limitations such as high time cost, the inability to remove inactivated tissue in a timely manner, surgical debridement, and oxygen toxicity. Mesenchymal stem cells have a unique self-renewal ability and wide differentiation potential, and they are one of the most promising stem cell types in cell therapy and have great application prospects in the field of regenerative medicine. Collagen exerts structural roles by promoting the molecular structure, shape, and mechanical properties of cells, and adding it to cell cultures can also promote cell proliferation and shorten the cell doubling time. The effects of collagen on MSCs were examined using Giemsa staining, EdU staining, and growth curves. Mice were subjected to allogeneic experiments and autologous experiments to reduce individual differences; all animals were separated into four groups. Neonatal skin sections were detected by HE staining, Masson staining, immunohistochemical staining, and immunofluorescence staining. We found that the MSCs pretreated with collagen accelerated the healing of skin wounds in mice and canines by promoting epidermal layer repair, collagen deposition, hair follicle angiogenesis, and an inflammatory response. Collagen promotes the secretion of the chemokines and growth factors associated with skin healing by MSCs, which positively influences skin healing. This study supports the treatment of skin injuries with MSCs cultured in medium with collagen added.
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Células Madre Mesenquimatosas , Cicatrización de Heridas , Ratones , Animales , Perros , Cicatrización de Heridas/fisiología , Piel/lesiones , Colágeno , Proliferación CelularRESUMEN
Household inputs and consumption play important roles in driving carbon emissions in China. However, existing studies have mainly studied consumption-based household carbon emissions in specific years to highlight consumption guidance and management, and little attention has been given to income-based accounting and policy-making focused on primary input behaviors and product allocation behaviors. In the quest for more coordinated and efficient mitigation strategies, we applied input-output analysis (IOA) combined with the biproportional scaling method (RAS) to obtain both income- and consumption-based annual accounting of rural and urban household carbon emissions from 2010 to 2017 and then used structural decomposition analysis (SDA) to determine key driving factors and sectors. Our results revealed that the proportions of income-based household emissions in gross emissions were higher than that of consumption-based household emissions. In terms of driving factors, per capita income/consumption contributed the largest increase in household emissions for most of the period, and population changes also showed a weak positive effect. However, intermediate input/output structure and carbon emission intensity were the main offsetting factors for household emissions. Compared with the consumption-based results, the income-based results can identify some new critical sectors that lead to household emission changes. Furthermore, the discrepant results for rural and urban household carbon emissions from both income and consumption perspectives suggest that differentiated measures of rural and urban households in key sectors are necessary. Finally, we propose industrial chain adjustment strategies and household input and consumption behavior recommendations in the context of urbanization.
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Carbono , Renta , Carbono/análisis , China , Urbanización , Composición Familiar , Dióxido de Carbono/análisisRESUMEN
BACKGROUND: Depression is a recurrent and devastating mental disease that is highly prevalent worldwide. Prolonged exposure to stressful events or a stressful environment is detrimental to mental health. In recent years, an inflammatory hypothesis has been implicated in the pathogenesis of stress-induced depression. However, less attention has been given to the initial phases, when a series of stress reactions and immune responses are initiated. Peripheral CD4+ T cells have been reported as the major contributors to the occurrence of mental disorders. Chronic stress exposure-evoked release of cytokines can promote the differentiation of peripheral CD4+ cells into various phenotypes. Among them, Th17 cells have attracted much attention due to their high pathogenic potential in central nervous system (CNS) diseases. Thus, we intended to determine the crucial role of CD4+ Th17 cells in the development of specific subtypes of depression and unravel the underpinnings of their pathogenetic effect. METHODS: In the present research, a daily 6-h restraint stress paradigm was employed in rats for 28 successive days to mimic the repeated mild and predictable, but inevitable environmental stress in our daily lives. Then, depressive-like symptoms, brain-blood barrier (BBB) permeability, neuroinflammation, and the differentiation and functional changes of CD4+ cells were investigated. RESULTS: We noticed that restrained rats showed significant depressive-like symptoms, concomitant BBB disruption and neuroinflammation in the dorsal striatum (DS). We further observed a time-dependent increase in thymus- and spleen-derived naïve CD4+ T cells, as well as the aggregation of inflammatory Th17 cells in the DS during the period of chronic restraint stress (CRS) exposure. Moreover, increased Th17-derived cytokines in the brain can further impair the BBB integrity, thus allowing more immune cells and cytokines to gain easy access to the CNS. Our findings suggested that, through a complex cascade of events, peripheral immune responses were propagated to the CNS, and gradually exacerbated depressive-like symptoms. Furthermore, inhibiting the differentiation and function of CD4+ T cells with SR1001 in the early stages of CRS exposure ameliorated CRS-induced depressive-like behaviour and the inflammatory response. CONCLUSIONS: Our data demonstrated that inflammatory Th17 cells were pivotal in accelerating the onset and exacerbation of depressive symptoms in CRS-exposed rats. This subtype of CD4+ T cells may be a promising therapeutic target for the early treatment of stress-induced depression.
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Depresión , Células Th17 , Animales , Encéfalo , Citocinas , Depresión/etiología , Humanos , Ratas , Restricción Física , Células TH1RESUMEN
The pluripotency gene regulatory network of porcine induced pluripotent stem cells(piPSCs), especially in epigenetics, remains elusive. To determine the biological function of epigenetics, we cultured piPSCs in different culture conditions. We found that activation of pluripotent gene- and pluripotency-related pathways requires the erasure of H3K9 methylation modification which was further influenced by mouse embryonic fibroblast (MEF) served feeder. By dissecting the dynamic change of H3K9 methylation during loss of pluripotency, we demonstrated that the H3K9 demethylases KDM3A and KDM3B regulated global H3K9me2/me3 level and that their co-depletion led to the collapse of the pluripotency gene regulatory network. Immunoprecipitation-mass spectrometry (IP-MS) provided evidence that KDM3A and KDM3B formed a complex to perform H3K9 demethylation. The genome-wide regulation analysis revealed that OCT4 (O) and SOX2 (S), the core pluripotency transcriptional activators, maintained the pluripotent state of piPSCs depending on the H3K9 hypomethylation. Further investigation revealed that O/S cooperating with histone demethylase complex containing KDM3A and KDM3B promoted pluripotency genes expression to maintain the pluripotent state of piPSCs. Together, these data offer a unique insight into the epigenetic pluripotency network of piPSCs.
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Regulación del Desarrollo de la Expresión Génica , Redes Reguladoras de Genes , Células Madre Pluripotentes Inducidas/metabolismo , Histona Demetilasas con Dominio de Jumonji/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Factores de Transcripción SOXB1/metabolismo , Animales , Metilación de ADN , Epigénesis Genética , Células Madre Pluripotentes Inducidas/citología , Histona Demetilasas con Dominio de Jumonji/genética , Factor 3 de Transcripción de Unión a Octámeros/genética , Factores de Transcripción SOXB1/genética , PorcinosRESUMEN
Pregnancy loss (PL) is one of the common complications that women can experience during pregnancy, with an occurrence rate of 1 to 5%. The potential causes of pregnancy loss are unclear, with no effective treatment modalities being available. It has been previously reported that the level of miR-125b was significantly increased in placentas of PL patients. However, the role of miR-125b in the development of PL still remains unknown. In the current study, an miR-125b placenta-specific over-expression model was constructed by lentiviral transfecting zona-free mouse embryos followed by embryo transfer. On gestation day 15, it was observed that the placenta was significantly smaller in the miR-125b placenta-specific overexpression group than the control group. Additionally, the abortion rate of the miR-125b placenta-specific overexpression group was markedly higher than in the control group. The blood vessel diameter was larger in the miR-125b-overexpressing specific placenta. In addition, miR-125b-overexpressing HTR8 and JEG3 cell lines were also generated to analyze the migration and invasion ability of trophoblasts. The results showed that miR-125b overexpression significantly suppressed the migration and invasion ability of HTR8 and JEG3 cells. Overall, our results demonstrated that miR-125b can affect embryo implantation through modulating placenta angiogenesis and trophoblast cell invasion capacity that can lead to PL.
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Aborto Espontáneo/genética , MicroARNs/genética , Placenta/química , Regulación hacia Arriba , Animales , Estudios de Casos y Controles , Línea Celular , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Especificidad de Órganos , EmbarazoRESUMEN
Ferroptosis is a relatively novel form of regulated cell death that was discovered in 2012. With the increasing research related to the mechanisms of ferroptosis, previous studies have demonstrated that the inactive of the intracellular antioxidant system and iron overload can result in the accumulation of reactive oxygen species (ROS), which can ultimately cause lipid peroxidation in the various cell types of the body. ROS accumulation can cause sperm damage by attacking the plasma membrane and damaging DNA. Acute ferroptosis causes oxidative damage to sperm DNA and testicular oxidative stress, thereby causing male reproductive dysfunction. This review aims to discuss the metabolic network of ferroptosis, summarize and analyze the relationship between male reproductive diseases caused by iron overload as well as lipid peroxidation, and provide a novel direction for the research and prevention of various male reproductive diseases.