RESUMEN
BACKGROUND: A stent with characteristics of a hybrid design may have advantages in improving the patency of symptomatic iliofemoral vein obstruction. This study assessed the safety and effectiveness of the V-Mixtent Venous Stent in treating symptomatic iliofemoral outflow obstruction. METHODS: Eligible patients had a Clinical-Etiologic-Anatomic-Physiologic (CEAP) C classification of ≥ 3 or a Venous Clinical Severity Score (VCSS) pain score of ≥ 2. The primary safety endpoint was the rate of major adverse events within 30 days. The primary effectiveness endpoint was the 12-month primary patency rate. Secondary endpoints included changes in VCSS from baseline to 6 and 12 months, alterations in CEAP C classification, Chronic Venous Disease Quality of Life Questionnaire (CIVIQ-14) scores at 12 months, and stent durability measures. RESULTS: Between December 2020 and November 2021, 171 patients were enrolled across 15 institutions. A total of 185 endovenous stents were placed, with 91.81% of subjects receiving one stent and 8.19% receiving 2 stents. Within 30 days, only two major adverse events occurred (1.17%; 95% confidence interval [CI], 0.14-4.16%), below the literature-defined performance goal of 11% (P < .001). The 12-month primary patency rate (91.36%; 95% CI, 85.93-95.19%; P < .001) exceeded the literature-defined performance goal. VCSS changes from baseline demonstrated clinical improvement at 6 months (- 4.30 ± 3.66) and 12 months (- 4.98 ± 3.67) (P < .001). Significant reduction in symptoms, as measured by CEAP C classification and CIVIQ-14, was observed from pre-procedure to 12 months (P < .001). CONCLUSIONS: The 12-month outcomes confirm the safety and effectiveness of the V-Mixtent Venous Stent in managing symptomatic iliofemoral venous outflow obstruction, including clinical symptom improvement compared to before treatment.
Asunto(s)
Vena Femoral , Vena Ilíaca , Stents , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Prospectivos , Vena Femoral/cirugía , Vena Ilíaca/cirugía , Resultado del Tratamiento , Adulto , Anciano , Calidad de VidaAsunto(s)
Anticuerpos Neutralizantes , Anticuerpos Neutralizantes/inmunología , Humanos , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/genética , Inmunización Secundaria , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/genética , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Animales , Anticuerpos Antivirales/inmunología , COVID-19/inmunología , COVID-19/prevención & controlRESUMEN
Metabolic diseases are a group of disorders caused by metabolic abnormalities, including obesity, diabetes, non-alcoholic fatty liver disease, and more. Increasing research indicates that, beyond inherent metabolic irregularities, the onset and progression of metabolic diseases are closely linked to alterations in the gut microbiota, particularly gut bacteria. Additionally, fecal microbiota transplantation (FMT) has demonstrated effectiveness in clinically treating metabolic diseases, notably diabetes. Recent attention has also focused on the role of gut viruses in disease onset. This review first introduces the characteristics and influencing factors of gut viruses, then summarizes their potential mechanisms in disease development, highlighting their impact on gut bacteria and regulation of host immunity. We also compare FMT, fecal filtrate transplantation (FFT), washed microbiota transplantation (WMT), and fecal virome transplantation (FVT). Finally, we review the current understanding of gut viruses in metabolic diseases and the application of FVT in treating these conditions. In conclusion, FVT may provide a novel and promising treatment approach for metabolic diseases, warranting further validation through basic and clinical research.
Asunto(s)
Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Enfermedades Metabólicas , Viroma , Humanos , Trasplante de Microbiota Fecal/métodos , Enfermedades Metabólicas/terapia , Animales , Heces/virología , Heces/microbiologíaRESUMEN
The rapid advancement of sequencing technologies has enabled the generation of vast datasets, allowing for the in-depth analysis of sequencing data. This analysis has facilitated the validation of novel pathogenesis hypotheses for understanding and treating diseases through ex vivo and in vivo experiments. Androgenetic alopecia (AGA), a common hair loss disorder, has been a key focus of investigators attempting to uncover its underlying mechanisms. Abnormal changes in mRNA, proteins, and metabolites have been identified in individuals with AGA, and future developments in sequencing technologies may reveal new biomarkers for AGA. By integrating multiple omics analysis datasets such as genomics, transcriptomics, proteomics, and metabolomics-along with clinical phenotype data-we can achieve a comprehensive understanding of the molecular underpinnings of AGA. This review summarizes the data-mining studies conducted on various omics analysis datasets as related to AGA that have been adopted to interpret the biological data obtained from different omics layers. We herein discuss the challenges of integrative omics analyses, and suggest that collaborative multi-omics studies can enhance the understanding of the complete pathomechanism(s) of AGA by focusing on the interaction networks comprising DNA, RNA, proteins, and metabolites.
RESUMEN
BACKGROUND: At present, liver transplantation (LT) is one of the best treatments for hepatocellular carcinoma (HCC). Accurately predicting the survival status after LT can significantly improve the survival rate after LT, and ensure the best way to make rational use of liver organs. AIM: To develop a model for predicting prognosis after LT in patients with HCC. METHODS: Clinical data and follow-up information of 160 patients with HCC who underwent LT were collected and evaluated. The expression levels of alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin, Golgi protein 73, cytokeratin-18 epitopes M30 and M65 were measured using a fully automated chemiluminescence analyzer. The best cutoff value of biomarkers was determined using the Youden index. Cox regression analysis was used to identify the independent risk factors. A forest model was constructed using the random forest method. We evaluated the accuracy of the nomogram using the area under the curve, using the calibration curve to assess consistency. A decision curve analysis (DCA) was used to evaluate the clinical utility of the nomograms. RESULTS: The total tumor diameter (TTD), vascular invasion (VI), AFP, and cytokeratin-18 epitopes M30 (CK18-M30) were identified as important risk factors for outcome after LT. The nomogram had a higher predictive accuracy than the Milan, University of California, San Francisco, and Hangzhou criteria. The calibration curve analyses indicated a good fit. The survival and recurrence-free survival (RFS) of high-risk groups were significantly lower than those of low- and middle-risk groups (P < 0.001). The DCA shows that the model has better clinical practicability. CONCLUSION: The study developed a predictive nomogram based on TTD, VI, AFP, and CK18-M30 that could accurately predict overall survival and RFS after LT. It can screen for patients with better postoperative prognosis, and improve long-term survival for LT patients.
Asunto(s)
Biomarcadores de Tumor , Carcinoma Hepatocelular , Neoplasias Hepáticas , Trasplante de Hígado , Nomogramas , alfa-Fetoproteínas , Humanos , Carcinoma Hepatocelular/cirugía , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/sangre , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/sangre , Masculino , Trasplante de Hígado/efectos adversos , Persona de Mediana Edad , Femenino , Factores de Riesgo , alfa-Fetoproteínas/análisis , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/análisis , Pronóstico , Adulto , Estudios Retrospectivos , Anciano , Resultado del Tratamiento , Queratina-18/sangre , Queratina-18/análisis , Técnicas de Apoyo para la DecisiónRESUMEN
Exosomes derived from bone marrow-derived mesenchymal stem cells (BMSCs) can alleviate the symptoms of pelvic floor dysfunction (PFD) in rats. However, the potential therapeutical effects of exosomes derived from BMSCs treated with tumour necrosis factor (TNF)-α on the symptoms of PFD in rats are unknown. Exosomes extracted from BMSCs treated with or without TNF-α were applied to treat PFD rats. Our findings revealed a significant elevation in interleukin (IL)-6 and TNF-α, and matrix metalloproteinase-2 (MMP2) levels in the vaginal wall tissues of patients with pelvic organ prolapse (POP) compared with the control group. Daily administration of exosomes derived from BMSCs, treated either with or without TNF-α (referred to as Exo and TNF-Exo), resulted in increased void volume and bladder void pressure, along with reduced peak bladder pressure and leak point pressure in PFD rats. Notably, TNF-Exo treatment demonstrated superior efficacy in restoring void volume, bladder void pressure and the mentioned parameters compared with Exo treatment. Importantly, TNF-Exo exhibited greater potency than Exo in restoring the levels of multiple proteins (Elastin, Collagen I, Collagen III, IL-6, TNF-α and MMP2) in the anterior vaginal walls of PFD rats. The application of exosomes derived from TNF-α-treated BMSCs holds promise as a novel therapeutic approach for treating PFD.
Asunto(s)
Exosomas , Metaloproteinasa 2 de la Matriz , Células Madre Mesenquimatosas , Prolapso de Órgano Pélvico , Factor de Necrosis Tumoral alfa , Animales , Exosomas/metabolismo , Exosomas/trasplante , Células Madre Mesenquimatosas/metabolismo , Femenino , Factor de Necrosis Tumoral alfa/metabolismo , Ratas , Humanos , Prolapso de Órgano Pélvico/terapia , Prolapso de Órgano Pélvico/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Ratas Sprague-Dawley , Interleucina-6/metabolismo , Diafragma Pélvico , Modelos Animales de Enfermedad , Células de la Médula Ósea/metabolismo , Vagina/patología , Trasplante de Células Madre Mesenquimatosas/métodos , Trastornos del Suelo Pélvico/terapia , Persona de Mediana EdadRESUMEN
BACKGROUNDS & AIMS: Portal hypertension (PH) is one of the most frequent complications of chronic liver disease. The peripheral 5-hydroxytryptamine (5-HT) level was increased in cirrhotic patients. We aimed to elucidate the function and mechanism of 5-HT receptor 1A (HTR1A) in the portal vein (PV) on PH. METHODS: PH models were induced by thioacetamide injection, bile duct ligation, or partial PV ligation. HTR1A expression was detected using real-time polymerase chain reaction, in situ hybridization, and immunofluorescence staining. In situ intraportal infusion was used to assess the effects of 5-HT, the HTR1A agonist 8-OH-DPAT, and the HTR1A antagonist WAY-100635 on portal pressure (PP). Htr1a-knockout (Htr1a-/-) rats and vascular smooth muscle cell (VSMC)-specific Htr1a-knockout (Htr1aΔVSMC) mice were used to confirm the regulatory role of HTR1A on PP. RESULTS: HTR1A expression was significantly increased in the hypertensive PV of PH model rats and cirrhotic patients. Additionally, 8-OH-DPAT increased, but WAY-100635 decreased, the PP in rats without affecting liver fibrosis and systemic hemodynamics. Furthermore, 5-HT or 8-OH-DPAT directly induced the contraction of isolated PVs. Genetic deletion of Htr1a in rats and VSMC-specific Htr1a knockout in mice prevented the development of PH. Moreover, 5-HT triggered adenosine 3',5'-cyclic monophosphate pathway-mediated PV smooth muscle cell contraction via HTR1A in the PV. We also confirmed alverine as an HTR1A antagonist and demonstrated its capacity to decrease PP in rats with thioacetamide-, bile duct ligation-, and partial PV ligation-induced PH. CONCLUSIONS: Our findings reveal that 5-HT promotes PH by inducing the contraction of the PV and identify HTR1A as a promising therapeutic target for attenuating PH. As an HTR1A antagonist, alverine is expected to become a candidate for clinical PH treatment.
RESUMEN
The electrochemical production of hydrogen peroxide (H2O2) using metal-free catalysts has emerged as a viable and sustainable alternative to the conventional anthraquinone process. However, the precise architectural design of these electrocatalysts poses a significant challenge, requiring intricate structural engineering to optimize electron transfer during the oxygen reduction reaction (ORR). Herein, we introduce a novel design of covalent organic frameworks (COFs) that effectively shift the ORR from a four-electron to a more advantageous two-electron pathway. Notably, the JUC-660 COF, with strategically charge-modified benzyl moieties, achieved a continuous high H2O2 yield of over 1200â mmol g-1 h-1 for an impressive duration of over 85â hours in a flow cell setting, marking it as one of the most efficient metal-free and non-pyrolyzed H2O2 electrocatalysts reported to date. Theoretical computations alongside in situ infrared spectroscopy indicate that JUC-660 markedly diminishes the adsorption of the OOH* intermediate, thereby steering the ORR towards the desired pathway. Furthermore, the versatility of JUC-660 was demonstrated through its application in the electro-Fenton reaction, where it efficiently and rapidly removed aqueous contaminants. This work delineates a pioneering approach to altering the ORR pathway, ultimately paving the way for the development of highly effective metal-free H2O2 electrocatalysts.
RESUMEN
BACKGROUND: Regulatory T cells (Tregs) play vital roles in controlling immune reactions and maintaining immune tolerance in the body. The targeted destruction of epidermal melanocytes by activated CD8+T cells is a key event in the development of vitiligo. However, Tregs may exert immunosuppressive effects on CD8+T cells, which could be beneficial in treating vitiligo. METHODS: A comprehensive search of PubMed and Web of Science was conducted to gather information on Tregs and vitiligo. RESULTS: In vitiligo, there is a decrease in Treg numbers and impaired Treg functions, along with potential damage to Treg-related signaling pathways. Increasing Treg numbers and enhancing Treg function could lead to immunosuppressive effects on CD8+T cells. Recent research progress on Tregs in vitiligo has been summarized, highlighting various Treg-related therapies being investigated for clinical use. The current status of Treg-related therapeutic strategies and potential future directions for vitiligo treatment are also discussed. CONCLUSIONS: A deeper understanding of Tregs will be crucial for advancing Treg-related drug discovery and treatment development in vitiligo.
Asunto(s)
Linfocitos T Reguladores , Vitíligo , Vitíligo/inmunología , Vitíligo/terapia , Humanos , Linfocitos T Reguladores/inmunología , Animales , Linfocitos T CD8-positivos/inmunologíaRESUMEN
This study explored the mechanism of the ultrafiltration extract of Angelicae Sinensis Radix and Hedysari Radix in ameliorating renal fibrosis in the rat model of diabetic kidney disease(DKD) based on the expression of hypoxia-inducible factor-1α(HIF-1α)/vascular endothelial growth factor(VEGF) and HIF-1α/platelet-derived growth factor(PDGF)/platelet-derived growth factor receptor(PDGFR) signaling pathways in the DKD rats. After 1 week of adaptive feeding, 50 male SPF-grade Wistar rats were randomized into a blank group(n=7) and a modeling group. After 24 h of fasting, the rats in the modeling group were subjected to intraperitoneal injection of streptozocin and fed with a high-sugar and high-fat diet to establish a DKD model. After modeling, the rats were randomly assigned into model(n=7), low-dose ultrafiltration extract(n=7), medium-dose ultrafiltration extract(n=7), irbesartan(n=8), and high-dose ultrafiltration extract(n=8) groups. After intervention by corresponding drugs for 12 weeks, the general conditions of the rats were observed. The body weights and blood glucose levels of the rats were measured weekly, and the 24 h urinary protein(24hUP) was measured at the 6th and 12th weeks of drug administration. After the last drug administration, the renal function indicators were determined. Masson staining was employed to observe the pathological changes of the renal tissue. The expression of prolyl hydroxylase domain 2(PHD2) and HIF-1α in the renal tissue was detected by immunohistochemistry(IHC). Real-time qPCR was employed to determine the mRNA levels of PHD2, VEGF, PDGF, and PDGFR in the renal tissue. Western blot was employed to determine the protein levels of HIF-1α, VEGF, PDGF, and PDGFR in the renal tissue. The results showed that compared with the model group, drug administration lowered the levels of glycosylated serum protein(GSP), aerum creatinine(Scr), and blood urea nitrogen(BUN) in a dose-dependent manner(P<0.05 or P<0.01) and mitigated the pathological changes in the renal tissue. Furthermore, drug administration up-regulated mRNA level of PHD2(P<0.05 or P<0.01), down-regulated the mRNA levels of VEGF, PDGF, and PDGFR(P<0.05 or P<0.01) and the protein levels of HIF-1α, VEGF, PDGF, and PDGFR(P<0.01) in the renal tissue, and increased the rate of PHD2-positive cells(P<0.01). In conclusion, the ultrafiltration extract of Angelicae Sinensis Radix and Hedysari Radix effectively alleviated the renal fibrosis in DKD rats by inhibiting the expression of key proteins in the HIF-1α signaling pathway mediated by renal hypoxia and reducing extracellular matrix(ECM) deposition.
Asunto(s)
Nefropatías Diabéticas , Factor A de Crecimiento Endotelial Vascular , Ratas , Masculino , Animales , Ratas Wistar , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ultrafiltración , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Isquemia , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/genética , Fibrosis , Hipoxia , Transducción de Señal , ARN Mensajero/metabolismoRESUMEN
BACKGROUND: Alopecia areata (AA), a prevalent form of autoimmune hair loss, has a not well-defined relationship with atopic and allergic disorders, including eczema, hay fever, and asthma. OBJECTIVES: This study aims to elucidate the genetic relationship between atopy, allergies, and alopecia areata (AA) using Mendelian randomization. We hypothesize that atopic and allergic conditions contribute to the genetic predisposition of AA. METHODS: We analyzed extensive genetic data from Genome-wide Association Studies (GWAS) involving over one million individuals. This analysis focused on assessing the genetic correlation between AA and various allergic conditions, including hay fever, eczema, asthma, and allergies to pollen, dust, and cats. The inverse variance weighted method served as our primary analytical tool, complemented by sensitivity analyses to verify the robustness of our results. RESULTS: Our findings reveal a significant genetic correlation between atopy/allergies and an increased risk of AA. Notably, strong associations were observed for hay fever, eczema, asthma, and specific allergies (pollen, dust, and cats). The sensitivity analyses corroborated these associations, reinforcing the reliability of our primary results. CONCLUSIONS: This study provides compelling genetic evidence of an association between atopic and allergic conditions and the development of AA. These findings suggest that individuals with such conditions may benefit from enhanced surveillance for early signs of AA.
RESUMEN
Alopecia areata refers to an autoimmune illness indicated by persistent inflammation. The key requirement for alopecia areata occurrence is the disruption of immune-privileged regions within the hair follicles. Recent research has indicated that neuropeptides play a role in the damage to hair follicles by triggering neurogenic inflammation, stimulating mast cells ambient the follicles, and promoting apoptotic processes in keratinocytes. However, the exact pathogenesis of alopecia areata requires further investigation. Recently, there has been an increasing focus on understanding the mechanisms of immune diseases resulting from the interplay between the nervous and the immune system. Neurogenic inflammation due to neuroimmune disorders of the skin system may disrupt the inflammatory microenvironment of the hair follicle, which plays a crucial part in the progression of alopecia areata.
Asunto(s)
Alopecia Areata , Folículo Piloso , Inflamación Neurogénica , Alopecia Areata/inmunología , Alopecia Areata/etiología , Alopecia Areata/patología , Humanos , Folículo Piloso/inmunología , Folículo Piloso/patología , Inflamación Neurogénica/inmunología , Inflamación Neurogénica/etiología , Neuropéptidos/metabolismo , Neuropéptidos/inmunología , Mastocitos/inmunología , Queratinocitos/inmunología , Queratinocitos/patología , Apoptosis/inmunología , AnimalesRESUMEN
Two-dimensional (2D) covalent organic frameworks (COFs) and their derivatives have been widely applied as electrocatalysts owing to their unique nanoscale pore configurations, stable periodic structures, abundant coordination sites and high surface area. This work aims to construct a non-thermodynamically stable Pt-N2 coordination active site by electrochemically modifying platinum (Pt) single atoms into a fully conjugated 2D COF as conductive agent-free and pyrolysis-free electrocatalyst for the hydrogen evolution reaction (HER). In addition to maximizing atomic utilization, single-atom catalysts with definite structures can be used to investigate catalytic mechanisms and structure-activity relationships. In this work, in-situ characterizations and theoretical calculations reveal that a nitrogen-rich graphene analogue COF not only exhibits a favorable metal-support effect for Pt, adjusting the binding energy between Pt sites to H* intermediates by forming unique Pt-N2 instead of the typical Pt-N4 coordination environment, but also enhances electron transport ability and structural stability, showing both conductivity and stability in acidic environments.
RESUMEN
OBJECTIVES: To explore the clinical manifestations, endoscopic findings, histopathological changes, treatment, and prognosis of eosinophilic gastrointestinal disease (EGID) in children, with the aim of enhancing awareness among pediatricians about this condition. METHODS: Data of 267 children with EGID were prospectively collected from January 2019 to July 2022 at Jiangxi Children's Hospital, Hunan Children's Hospital, and Henan Children's Hospital. The age of onset, symptoms, physical signs, laboratory examination results, endoscopic findings, histopathological changes, and treatment outcomes were observed. RESULTS: Among the 267 children with EGID, the majority had mild (164 cases, 61.4%) or moderate (96 cases, 35.6%) clinical severity. The disease occurred at any age, with a higher prevalence observed in school-age children (178 cases). The main symptoms in infants were vomiting and hematemesis, while in toddlers, vomiting and bloody stools were prominent. Abdominal pain and vomiting were the primary symptoms in preschool and school-age children. Nearly half (49.4%) of the affected children showed elevated platelet counts on hematological examination, but there was no significant difference in platelet counts among children with mild, moderate, and severe EGID (P>0.05). Endoscopic findings in EGID children did not reveal significant specificity, and histopathological examination showed no specific structural damage. Among them, 85.0% (227 cases) received acid suppression therapy, 34.5% (92 cases) practiced dietary avoidance, 20.9% (56 cases) received anti-allergic medication, and a small proportion (24 cases, 9.0%) were treated with prednisone. Clinical symptoms were relieved in all patients after treatment, but three cases with peptic ulcers experienced recurrence after drug discontinuation. CONCLUSIONS: Mild and moderate EGID are more common in children, with no specific endoscopic findings. Dietary avoidance, acid suppression therapy, and anti-allergic medication are the main treatment methods. The prognosis of EGID is generally favorable in children.
Asunto(s)
Antialérgicos , Enteritis , Eosinofilia , Gastritis , Lactante , Preescolar , Humanos , Eosinofilia/diagnóstico , Eosinofilia/tratamiento farmacológico , VómitosRESUMEN
BACKGROUND: We devoted ourselves to proving that the initial transthoracic echocardiography score (TTES) had predictive significance for patients with continuous ambulatory peritoneal dialysis (CAPD). METHODS: In this retrospective analysis, 274 CAPD patients who had PD therapy were recruited sequentially. TTE exams were performed three months following the start of PD therapy. All patients were divided into two groups based on the strength of their TTES levels. TTES's predictive value for CAPD patients was then determined using LASSO regression and Cox regression. RESULTS: During a median of 52 months, 46 patients (16.8%) died from all causes, and 32 patients (11.7%) died from cardiovascular disease (CV). The TTES was computed as follows: 0.109 × aortic root diameter (ARD, mm) - 0.976 × LVEF (> 55%, yes or no) + 0.010 × left ventricular max index, (LVMI, g/m2) + 0.035 × E/e' ratio. The higher TTES value (≥ 3.7) had a higher risk of all-cause death (hazard ratio, HR, 3.70, 95% confidence index, 95%CI, 1.45-9.46, P = 0.006) as well as CV mortality (HR, 2.74, 95%CI 1.15-19.17, P = 0.042). Moreover, the TTES had an attractive predictive efficiency for all-cause mortality (AUC = 0.762, 95%CI 0.645-0.849) and CV mortality (AUC = 0.746, 95%CI 0.640-0.852). The introduced nomogram, which was based on TTES and clinical variables, exhibited a high predictive value for all-cause and CV mortality in CAPD patients. CONCLUSION: TTES is a pretty good predictor of clinical outcomes, and the introduced TTES-based nomogram yields an accurate prediction value for CAPD patients.
Asunto(s)
Enfermedades Cardiovasculares , Fallo Renal Crónico , Diálisis Peritoneal Ambulatoria Continua , Humanos , Diálisis Peritoneal Ambulatoria Continua/efectos adversos , Pronóstico , Estudios Retrospectivos , Ecocardiografía , Fallo Renal Crónico/diagnóstico por imagen , Fallo Renal Crónico/terapia , Fallo Renal Crónico/etiologíaRESUMEN
BACKGROUND: PRAME constitutes one of the largest multi-copy gene families in Eutherians, encoding cancer-testis antigens (CTAs) with leucine-rich repeats (LRR) domains, highly expressed in cancer cells and gametogenic germ cells. This study aims to elucidate genetic interactions between two members, Pramex1 and Pramel1, in the mouse Prame family during gametogenesis using a gene knockout approach. RESULT: Single-gene knockout (sKO) of either Pramex1 or Pramel1 resulted in approximately 7% of abnormal seminiferous tubules, characterized by a Sertoli-cell only (SCO) phenotype, impacting sperm count and fecundity significantly. Remarkably, sKO female mice displayed normal reproductive functions. In contrast, Pramex1/Pramel1 double knockout (dKO) mice exhibited reduced fecundity in both sexes. In dKO females, ovarian primary follicle count decreased by 50% compared to sKO and WT mice, correlating with a 50% fecundity decrease. This suggested compensatory roles during oogenesis in Pramex1 or Pramel1 sKO females. Conversely, dKO males showed an 18% frequency of SCO tubules, increased apoptotic germ cells, and decreased undifferentiated spermatogonia compared to sKO and WT testes. Western blot analysis with PRAMEX1- or PRAMEL1-specific antibodies on sKO testes revealed compensatory upregulation of each protein (30-50%) in response to the other gene's deletion. Double KO males exhibited more severe defects in sperm count and litter size, surpassing Pramex1 and Pramel1 sKO accumulative effects, indicating a synergistic enhancement interaction during spermatogenesis. Additional experiments administering trans-retinoic acid (RA) and its inhibitor (WIN18,446) in sKO, dKO, and WT mice suggested that PRAMEX1 and PRAMEL1 synergistically repress the RA signaling pathway during spermatogenesis. CONCLUSION: Data from sKO and dKO mice unveil a synergistic interaction via the RA signaling pathway between Pramex1 and Pramel1 genes during gametogenesis. This discovery sets the stage for investigating interactions among other members within the Prame family, advancing our understanding of multi-copy gene families involved in germ cell formation and function.
RESUMEN
Chemotherapy-related cognitive deficits (CRCI) as one of the common adverse drug reactions during chemotherapy that manifest as memory, attention, and executive function impairments. However, there are still no effective pharmacological therapies for the treatment of CRCI. Natural compounds have always inspired drug development and numerous natural products have shown potential therapeutic effects on CRCI. Nevertheless, improving the brain targeting of natural compounds in the treatment of CRCI is still a problem to be overcome at present and in the future. Accumulated evidence shows that nose-to-brain drug delivery may be an excellent carrier for natural compounds. Therefore, we reviewed natural products with potential anti-CRCI, focusing on the signaling pathway of these drugs' anti-CRCI effects, as well as the possibility and prospect of treating CRCI with natural compounds based on nose-to-brain drug delivery in the future. In conclusion, this review provides new insights to further explore natural products in the treatment of CRCI.
RESUMEN
Despite their ubiquitous use, information regarding the presence of quaternary ammonium compounds (QACs) in various microenvironments remains scarce and only a small subset of QACs has been monitored using targeted chemical analysis. In this study, a total of 111 dust samples were collected from homes and various public settings in South China during the COVID-19 pandemic and were analyzed for traditional and emerging QACs using high-resolution mass spectrometry. The total traditional QAC concentrations in residential dust (∑traditional QAC, sum of 18 traditional QACs) ranged from 13.8 to 150 µg/g with a median concentration of 42.2 µg/g. Twenty-eight emerging QACs were identified in these samples, and the composition of ∑emerging QAC (sum of emerging QACs) to ∑QAC (sum of traditional and emerging QACs) ranged from 19 to 42% across various microenvironments, indicating the widespread existence of emerging QACs in indoor environments. Additionally, dust samples from cinemas exhibited higher ∑QAC concentrations compared to homes (medians 65.9 µg/g vs 58.3 µg/g, respectively), indicating heavier emission sources of QACs in these places. Interestingly, significantly higher ∑QAC concentrations were observed in dust from the rooms with carpets than those without (medians 65.6 µg/g vs 32.6 µg/g, p < 0.05, respectively). Overall, this study sheds light on the ubiquitous occurrence of QACs in indoor environments in South China.
RESUMEN
Single-cell technologies offer unprecedented opportunities to dissect gene regulatory mechanisms in context-specific ways. Although there are computational methods for extracting gene regulatory relationships from scRNA-seq and scATAC-seq data, the data integration problem, essential for accurate cell type identification, has been mostly treated as a standalone challenge. Here we present scTIE, a unified method that integrates temporal multimodal data and infers regulatory relationships predictive of cellular state changes. scTIE uses an autoencoder to embed cells from all time points into a common space by using iterative optimal transport, followed by extracting interpretable information to predict cell trajectories. Using a variety of synthetic and real temporal multimodal data sets, we show scTIE achieves effective data integration while preserving more biological signals than existing methods, particularly in the presence of batch effects and noise. Furthermore, on the exemplar multiome data set we generated from differentiating mouse embryonic stem cells over time, we show scTIE captures regulatory elements highly predictive of cell transition probabilities, providing new potentials to understand the regulatory landscape driving developmental processes.