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The primary objective of this study was to explore the extensive implications and complex molecular interactions arising from the confluence of excessive glucocorticoids and RANKL on the differentiation process of BMM into osteoclasts, profoundly impacting osteoporosis development. The methodology encompassed X-ray analysis and HE staining for evaluating bone loss in mice, while immunohistochemical staining was utilized to observe phosphorylated SHP2 (p-SHP2) expression. The assessment of several phosphorylated and total protein expression levels, including NF-κB, SHP2, SYK, JAK2, TAK1, NFATC1, c-fos, and Cathepsin K, was conducted via Western blotting. Additional experiments, involving CCK8 and monoclonal proliferation assays, were undertaken to determine BMM proliferation capacity. Immunofluorescence staining facilitated the quantification of TRAP fluorescence intensity. In vivo analysis revealed that glucocorticoid surplus triggers SHP2 signaling pathway activation, accelerating osteoporosis progression. Western blot results demonstrated that SHP2 inhibition could decrease the expression of specific proteins such as p-NF-κB and p-SHP2, with minimal effects on p-SYK levels. In vitro findings indicated that glucocorticoid and RANKL interaction activates the SHP2 pathway through NF-κB and SYK pathways, enhancing expressions of p-JAK2, p-TAK1, NFATC1, c-fos, and Cathepsin K, thereby promoting BMM to osteoclast transformation. Conclusion: Excessive glucocorticoids and RANKL interaction advance osteoclast differentiation from BMM by activating the SYK/SHP2/NF-κB signaling pathway, expediting osteoporosis progression.
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BACKGROUND: Fungal skin diseases are the most common and widespread fungal infections, exerting a significant impact on patients' socio-psychological health and the quality of life. OBJECTIVES: To assess and compare the global burden of fungal skin diseases in 2019 and over the past 30 years. METHODS: Data were retrieved from the Global Burden of Disease Study 2019. Incidence and years lived with disability (YLDs) were used to assess the burden of fungal skin diseases. A total of 204 countries and territories were hierarchically organised into 21 regions and seven super-regions. Data were presented as absolute numbers and rates per 100,000 population, stratified by sex, age, year and location. RESULTS: In 2019, the global incidence rate and YLD rate of fungal skin diseases were 21,277 (95% UI 19 298-23,399) and 42 (95% UI 17-88) per 100,000 population, respectively. Sub-Saharan Africa bore the heaviest disease burden, especially children aged 5-9 years had a significantly higher incidence rate, YLD rate and YLDs to incidence ratio compared to other regions. Moreover, more than half of the incident cases among the elderly came from high-income regions and Southeast Asia, East Asia, and Oceania. Over the past 30 years, the number of incident cases and YLDs of fungal skin diseases has been continuously increasing worldwide, but the incidence rates and YLD rates have not shown significant changes. CONCLUSIONS: The global burden of fungal skin diseases has been continuously rising. Children in Sub-Saharan Africa are experiencing higher disease incidence and severity compared to other regions.
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Dermatomicosis , Carga Global de Enfermedades , Salud Global , Humanos , Niño , Preescolar , Adolescente , Masculino , Adulto , Femenino , Incidencia , Dermatomicosis/epidemiología , Dermatomicosis/microbiología , Persona de Mediana Edad , Adulto Joven , Anciano , Lactante , Salud Global/estadística & datos numéricos , Recién Nacido , Costo de Enfermedad , Anciano de 80 o más Años , Calidad de Vida , África del Sur del Sahara/epidemiologíaRESUMEN
BACKGROUND: Arterial remodeling is a common pathophysiological change in the pathogenesis of cardiovascular diseases in which the phenotypic switch of vascular smooth muscle cells (VSMC) plays an important role. Recently, an increasing number of long non-coding RNAs(lncRNAs) have been shown to encode micropeptides that play biological roles and have great clinical transformation potential. However, the role of micropeptides encoded by lncRNAs in arterial remodeling has not been well studied and requires further exploration. METHODS AND RESULTS: Through bioinformatic analysis and experimental verification, we found that a new lncRNA, the mitochondrial function-related lncRNA (MFRL), encodes a 64-amino acid micropeptide, MFRLP. MFRL and MFRLP play important roles in the phenotypic switch of VSMC. Further experiments showed that MFRLP interacts with mitochondrial cytochrome b to reduce accumulation of reactive oxygen species, suppress mitophagy and inhibit the VSMC switch from contractile to synthetic phenotype. CONCLUSIONS: LncRNA MFRL encodes the micropeptide MFRLP, which interacts with mitochondrial cytochrome b to inhibit the VSMC switch from contractile to synthetic phenotype and improve arterial remodeling.
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Microtubule-severing enzymes (MTSEs) play important roles in mitosis and meiosis of the primitive organisms. However, no studies have assessed their roles in mammalian meiosis of females, whose abnormality accounts for over 80% of the cases of gamete-originated human reproductive disease. In the current study, we reported that katanin-like 2 (KL2) was the only MTSE concentrating at chromosomes. Furthermore, the knockdown of KL2 significantly reduced chromosome-based increase in the microtubule (MT) polymer, increased aberrant kinetochore-MT (K-MT) attachment, delayed meiosis, and severely affected normal fertility. Importantly, we demonstrated that the inhibition of aurora B, a key kinase for correcting aberrant K-MT attachment, eliminated KL2 from chromosomes completely. KL2 also interacted with phosphorylated eukaryotic elongation factor-2 kinase; they competed for chromosome binding. We also observed that the phosphorylated KL2 was localized at spindle poles, and that KL2 phosphorylation was regulated by extracellular signal-regulated kinase 1/2. In summary, our study reveals a novel function of MTSEs in mammalian female meiosis and demonstrates that multiple kinases coordinate to regulate the levels of KL2 at chromosomes.
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BACKGROUND: Reportedly, the stress-hyperglycemia ratio (SHR) is closely associated with poor prognosis in patients with severe acute disease. However, the community-dwelling may also be in a state of stress due to environmental exposure. Our study aimed to explore the association between SHR and all-cause mortality in the community-dwelling population. METHODS: A total of 18 480 participants were included out of 82 091 from the NHANES 1999-2014 survey. The Kaplan-Meier survival analyses were used to assess the disparities in survival rates based on SHR, and the log-rank test was employed to investigate the distinctions between groups. The multivariate Cox regression analysis and restricted cubic spline (RCS) analysis were performed to assess the association of SHR with all-cause mortality. A subgroup analysis was also conducted. RESULTS: A total of 3188 deaths occurred during a median follow-up period of 11.0 (7.7; 15.4) years. The highest risk for all-cause mortality was observed when SHR≤ 0.843 or SHR ≥0.986 (log-rank p < .001). After adjusting for the confounding factors, compared with subjects in the second SHR quartile (Q2), participants in the highest (Q4, adjusted hazard ratio [HR] 1.49, 95% confidence interval [CI] 1.28-1.73) and lowest quartiles (Q1, adjusted HR 1.37, 95% CI 1.16-1.60) have a higher probability of all-cause death. The RCS observed a dose-response U-shaped association between SHR and all-cause mortality. The U-shaped association between SHR and all-cause mortality was similar across subgroup analysis. CONCLUSIONS: The SHR was significantly associated with all-cause mortality in the community-dwelling population, and the relationship was U-shaped.
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Hiperglucemia , Vida Independiente , Encuestas Nutricionales , Humanos , Masculino , Femenino , Persona de Mediana Edad , Vida Independiente/estadística & datos numéricos , Hiperglucemia/mortalidad , Hiperglucemia/sangre , Hiperglucemia/epidemiología , Adulto , Anciano , Causas de Muerte , Factores de Riesgo , Mortalidad/tendencias , Estrés Fisiológico , Estados Unidos/epidemiología , Pronóstico , Estimación de Kaplan-MeierRESUMEN
BACKGROUND: The incidence and mortality of colorectal cancer (CRC) are among the highest in the world, and its occurrence and development are closely related to tumor neovascularization. When the balance between pigment epithelium-derived factors (PEDF) that inhibit angiogenesis and vascular endothelial growth factors (VEGF) that stimulate angiogenesis is broken, angiogenesis is out of control, resulting in tumor development. Therefore, it is very necessary to find more therapeutic targets for CRC for early intervention and later treatment. AIM: To investigate the expression and significance of PEDF, VEGF, and CD31-stained microvessel density values (CD31-MVD) in normal colorectal mucosa, adenoma, and CRC. METHODS: In this case-control study, we collected archived wax blocks of specimens from the Digestive Endoscopy Center and the General Surgery Department of Chengdu Second People's Hospital from April 2022 to October 2022. Fifty cases of specimen wax blocks were selected as normal intestinal mucosa confirmed by electronic colonoscopy and concurrent biopsy (normal control group), 50 cases of specimen wax blocks were selected as colorectal adenoma confirmed by electronic colonoscopy and pathological biopsy (adenoma group), and 50 cases of specimen wax blocks were selected as CRC confirmed by postoperative pathological biopsy after inpatient operation of general surgery (CRC group). An immunohistochemical staining experiment was carried out to detect PEDF and VEGF expression in three groups of specimens, analyze their differences, study the relationship between the two and clinicopathological factors in CRC group, record CD31-MVD in the three groups, and analyze the correlation of PEDF, VEGF, and CD31-MVD in the colorectal adenoma group and the CRC group. The F test or adjusted F test is used to analyze measurement data statistically. Kruskal-Wallis rank sum test was used between groups for ranked data. The chi-square test, adjusted chi-square test, or Fisher's exact test were used to compare the rates between groups. All differences between groups were compared using the Bonferroni method for multiple comparisons. Spearman correlation analysis was used to test the correlation of the data. The test level (α) was 0.05, and a two-sided P< 0.05 was considered statistically significant. RESULTS: The positive expression rate and expression intensity of PEDF were gradually decreased in the normal control group, adenoma group, and CRC group (100% vs 78% vs 50%, χ2 = 34.430, P < 0.001; ++~++ vs +~++ vs -~+, H = 94.059, P < 0.001), while VEGF increased gradually (0% vs 68% vs 96%, χ2 = 98.35, P < 0.001; - vs -~+ vs ++~+++, H = 107.734, P < 0.001). In the CRC group, the positive expression rate of PEDF decreased with the increase of differentiation degree, invasion depth, lymph node metastasis, distant metastasis, and TNM stage (χ2 = 20.513, 4.160, 5.128, 6.349, 5.128, P < 0.05); the high expression rate of VEGF was the opposite (χ2 = 10.317, 13.134, 17.643, 21.844, 17.643, P < 0.05). In the colorectal adenoma group, the expression intensity of PEDF correlated negatively with CD31-MVD (r = -0.601, P < 0.001), whereas VEGF was not significantly different (r = 0.258, P = 0.07). In the CRC group, the expression intensity of PEDF correlated negatively with the expression intensity of CD31-MVD and VEGF (r = -0.297, P < 0.05; r = -0.548, P < 0.05), while VEGF expression intensity was positively related to CD31-MVD (r = 0.421, P = 0.002). CONCLUSION: It is possible that PEDF can be used as a new treatment and prevention target for CRC by upregulating the expression of PEDF while inhibiting the expression of VEGF.
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Biomarcadores , Endotelio Vascular , Péptidos y Proteínas de Señalización Intercelular , Preeclampsia , Humanos , Preeclampsia/sangre , Preeclampsia/fisiopatología , Preeclampsia/diagnóstico , Femenino , Biomarcadores/sangre , Embarazo , Endotelio Vascular/fisiopatología , Péptidos y Proteínas de Señalización Intercelular/sangre , Péptidos/sangre , Proteínas SanguíneasRESUMEN
BACKGROUND: Benefiting from rich knowledge and the exceptional ability to understand text, large language models like ChatGPT have shown great potential in English clinical environments. However, the performance of ChatGPT in non-English clinical settings, as well as its reasoning, have not been explored in depth. OBJECTIVE: This study aimed to evaluate ChatGPT's diagnostic performance and inference abilities for retinal vascular diseases in a non-English clinical environment. METHODS: In this cross-sectional study, we collected 1226 fundus fluorescein angiography reports and corresponding diagnoses written in Chinese and tested ChatGPT with 4 prompting strategies (direct diagnosis or diagnosis with a step-by-step reasoning process and in Chinese or English). RESULTS: Compared with ChatGPT using Chinese prompts for direct diagnosis that achieved an F1-score of 70.47%, ChatGPT using English prompts for direct diagnosis achieved the best diagnostic performance (80.05%), which was inferior to ophthalmologists (89.35%) but close to ophthalmologist interns (82.69%). As for its inference abilities, although ChatGPT can derive a reasoning process with a low error rate (0.4 per report) for both Chinese and English prompts, ophthalmologists identified that the latter brought more reasoning steps with less incompleteness (44.31%), misinformation (1.96%), and hallucinations (0.59%) (all P<.001). Also, analysis of the robustness of ChatGPT with different language prompts indicated significant differences in the recall (P=.03) and F1-score (P=.04) between Chinese and English prompts. In short, when prompted in English, ChatGPT exhibited enhanced diagnostic and inference capabilities for retinal vascular disease classification based on Chinese fundus fluorescein angiography reports. CONCLUSIONS: ChatGPT can serve as a helpful medical assistant to provide diagnosis in non-English clinical environments, but there are still performance gaps, language disparities, and errors compared to professionals, which demonstrate the potential limitations and the need to continually explore more robust large language models in ophthalmology practice.
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Inteligencia Artificial , Errores Diagnósticos , Angiografía con Fluoresceína , Lenguaje , Enfermedades de la Retina , Enfermedades Vasculares , Humanos , Estudios Transversales , Enfermedades Vasculares/clasificación , Enfermedades Vasculares/diagnóstico , Enfermedades Vasculares/diagnóstico por imagen , Enfermedades de la Retina/clasificación , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/diagnóstico por imagenRESUMEN
Poly (ADP-ribose) polymerase inhibitors (PARPi) are selectively active in ovarian cancer (OC) with homologous recombination (HR) deficiency (HRD) caused by mutations in BRCA1/2 and other DNA repair pathway members. We sought molecular targeted therapy that induce HRD in HR-proficient cells to induce synthetic lethality with PARPi and extend the utility of PARPi. Here, we demonstrate that lysine-specific demethylase 1 (LSD1) is an important regulator for OC. Importantly, genetic depletion or pharmacological inhibition of LSD1 induces HRD and sensitizes HR-proficient OC cells to PARPi in vitro and in multiple in vivo models. Mechanistically, LSD1 inhibition directly impairs transcription of BRCA1/2 and RAD51, three genes essential for HR, dependently of its canonical demethylase function. Collectively, our work indicates combination with LSD1 inhibitor could greatly expand the utility of PARPi to patients with HR-proficient tumor, warranting assessment in human clinical trials.
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Proteína BRCA1 , Neoplasias Ováricas , Humanos , Femenino , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Regulación hacia Abajo , Reparación del ADN , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Recombinación Homóloga , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Recombinasa Rad51/genética , Recombinasa Rad51/metabolismoRESUMEN
BACKGROUND: Cholangiocarcinoma (CCA) is a serious threat to human health, and tumor development is associated with abnormal mitochondrial function. It is believed that the introduction of healthy mitochondria into tumor cells can induce the oxidative stress in tumor cells to return to normal levels, thus exerting an inhibitory effect on tumor growth. METHODS: Mitochondria isolated from 143BρW cells were co-cultured with HuCCT1 cells, and the mitochondria were stained with MitoTracker dye as a tracking label. Changes in apoptosis, proliferation, oxidative stress, and PTEN/PI3K/AKT signaling pathway were assessed. In addition, a CCA nude mouse transplantation tumor model was constructed to analyze the effects of mitochondrial transplantation on the above factors in nude mice. Furthermore, the expression of PTEN was interfered to observe the effect and mechanism of mitochondrial transplantation on the proliferation and apoptosis of CCA cells. RESULTS: Mitochondrial transplantation promoted apoptosis and inhibited cell proliferation in CCA cell line. SOD, GSH, and CAT activities were significantly increased, the expression of PTEN was activated, and the expression of p-PI3K and p-AKT were inhibited after mitochondrial transplantation. After mitochondrial transplantation + si-PTEN treatment, cell apoptosis, SOD, GSH, CAT activity, and the expression of PTEN were decreased, while the expression of p-PI3K and p-AKT were significantly enhanced. CONCLUSION: This study reveals the anti-tumor potential of mitochondrial transplantation through PTEN/PI3K/AKT signaling pathway to regulate cellular oxidative stress in CCA.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Ratones , Animales , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Ratones Desnudos , Línea Celular Tumoral , Transducción de Señal , Colangiocarcinoma/metabolismo , Proliferación Celular , Estrés Oxidativo , Conductos Biliares Intrahepáticos/metabolismo , Neoplasias de los Conductos Biliares/metabolismo , Mitocondrias/metabolismo , Superóxido Dismutasa/metabolismo , Apoptosis , Fosfohidrolasa PTEN/metabolismoRESUMEN
BACKGROUND: Apolipoprotein B (apoB) is a crucial component that directly reflects the number of atherogenic lipoprotein particles and is closely related to atherosclerosis. However, there was an inconsistency among previous studies in its relationship with mortality. Using nationally representative data, we aimed to investigate the association of apoB with cardiovascular and all-cause mortality. METHODS: We retrospectively included participants from the National Health and Nutrition Examination Survey (2007-2014), and mortality was ascertained through December 31, 2015. Hazard ratios (HRs) with 95% confidence intervals (CIs) of apoB in quartiles (Q1-Q4) for mortality risk were calculated using multivariable-adjusted Cox proportional hazards models, and restricted cubic spline regressions were performed to test dose relationships. RESULTS: We enrolled 10,375 participants with a mean age of 46.3 years, of which 47.88% were men. During a mean follow-up time of 69.2 months, 533 (5.14%) and 91 (0.88%) deaths were due to all causes and cardiovascular disease, respectively. After adjusting for confounders, per SD, increment of apoB was associated with an elevated risk of cardiovascular mortality (HR, 1.13; 95% CI, 1.03-1.24). The risk of all-cause mortality was significantly reduced in the third quartile (Q3) of apoB (HR, 0.71; 95% CI, 0.56-0.91) compared with the reference quartile (Q1). Moreover, spline analyses showed that the relationship of apoB with all-cause mortality was U-shaped, and the threshold value was 108 mg/dL. CONCLUSIONS: ApoB was linearly associated with increased risk of cardiovascular mortality and non-linearly associated with all-cause mortality in a U-shaped manner, independently of other cardiovascular risk factors.
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Aterosclerosis , Enfermedades Cardiovasculares , Masculino , Humanos , Adulto , Persona de Mediana Edad , Femenino , Encuestas Nutricionales , Estudios Retrospectivos , Apolipoproteínas B , Modelos de Riesgos ProporcionalesRESUMEN
INTRODUCTION: Obesity contributes to the pathogenesis of diverse metabolic diseases, yet the mechanism underlying metabolically healthy obesity (MHO) remains elusive. Thyroid hormones and sensitivity to them have a major impact on metabolism. Our study aimed to investigate the association between MHO and thyroid hormone sensitivity. METHODS: Thyroid hormone indices, including the thyroid-stimulating hormone (TSH) index (TSHI), the Thyrotroph Thyroxine Sensitivity Index (TTSI), the Thyroid Feedback Quantile-Based Index (TFQI), and the Parametric Thyroid Feedback Quantile-Based Index (PTFQI), were calculated based on a non-institutionalized US sample in the National Health and Nutrition Examination Survey (NHANES, 2007-2012). Participants were divided into four groups (metabolically healthy non-obesity [MHNO], metabolically unhealthy non-obesity [MUNO], MHO, and metabolically unhealthy obesity [MUO]) according to their body mass index and metabolic profiles. Linear regression, logistic regression, and restricted cubic splines were employed to analyze the association between thyroid hormone indices and metabolic phenotypes. RESULTS: A total of 4,857 participants (49.6% men; mean age, 42.6 years) were included, with 1,539 having obesity and 235 identified as MHO. Participants in the MHO group exhibited lower levels of TSH, TSHI, TTSI, TFQI, and PTFQI compared with the MHNO group (all p < 0.05), while the differences among MHNO, MUNO, and MUO groups were not statistically significant (all p > 0.05). Among participants with obesity, TSH, TSHI, TTSI, TFQI, and PTFQI were positively associated with metabolic abnormality (all p < 0.05). CONCLUSION: Participants with MHO exhibited higher thyroid hormone sensitivity among various obesity phenotypes, even when compared with those with MHNO. A positive association was observed between metabolic abnormality and thyroid hormone sensitivity, while the trend of TSH was observed to be consistent with sensitivity to thyroid hormone indices in discriminating metabolic abnormality. Hence, TSH has the potential to serve as a convenient index for detecting sensitivity to thyroid hormones and further metabolic conditions.
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Enfermedades Metabólicas , Obesidad Metabólica Benigna , Masculino , Humanos , Adulto , Femenino , Encuestas Nutricionales , Factores de Riesgo , Obesidad/complicaciones , Obesidad Metabólica Benigna/complicaciones , Hormonas Tiroideas , Enfermedades Metabólicas/complicaciones , TirotropinaRESUMEN
Background: China has approximately 300 million current smokers, and smoking cessation services are limited. This study aimed to assess the efficacy of a Cognitive Behavioral Theory-based smoking cessation intervention ('WeChat WeQuit') via the most popular social media platform in China, WeChat. Methods: A parallel, single-blind, two-arm randomised controlled trial was conducted via WeChat between March 19, 2020 and November 16, 2022. Chinese-speaking adult smokers (n = 2000) willing to quit within one month were recruited and randomised in a 1:1 ratio. The intervention group (n = 1005) received the 'WeChat WeQuit' program and the control group (n = 955) received control messages for 14 weeks (2-week prequit and 12-week postquit). Participants were followed up to 26 weeks after the quit date. The primary outcome was self-reported continuous smoking abstinence rate, biochemically validated at 26 weeks. The secondary outcomes were self-reported 7-day and continuous abstinence rates at 6 months. All analyses were by intention to treat. The trial is registered at ClinicalTrials.gov (NCT03169686). Findings: By intention-to-treat analysis, the biochemically verified 26-week continuous abstinence rate was 11.94% in the intervention group and 2.81% in the control group (OR = 4.68, 95% CI: 3.07-7.13, p < 0.0001). The self-reported 7-day abstinence rates ranged from 39.70% at week 1-32.04% at week 26 for the intervention group and 14.17%-11.86% in the control group for weeks 1 and 26, respectively; the self-reported continuous abstinence rates at weeks 1 and 26 ranged from 34.33% to 24.28% and 9.65% to 6.13% in the intervention group and the control group respectively (all p < 0.0001). Participants with low nicotine dependence or previous quit attempts were more likely to successfully quit smoking. Interpretation: The 'WeChat WeQuit' intervention significantly increased smoking abstinence rates at 6 months and should be considered for treatment-seeking smokers in China. Funding: The research is supported by the Natural Science Foundation of Hunan Province (2020JJ4794, YLiao), the K.C. Wong Postdoctoral Fellowship for YLiao to study at King's College London, and China Medical Board (CMB) Open Competition Program (grant no. 15-226, 22-485, YLiao).
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The expression of linear DNA sequence is precisely regulated by the three-dimensional (3D) architecture of chromatin. Morphine-induced aberrant gene networks of neurons have been extensively investigated; however, how morphine impacts the 3D genomic architecture of neurons is still unknown. Here, we applied digestion-ligation-only high-throughput chromosome conformation capture (DLO Hi-C) technology to investigate the effects of morphine on the 3D chromatin architecture of primate cortical neurons. After receiving continuous morphine administration for 90 days on rhesus monkeys, we discovered that morphine re-arranged chromosome territories, with a total of 391 segmented compartments being switched. Morphine altered over half of the detected topologically associated domains (TADs), most of which exhibited a variety of shifts, followed by separating and fusing types. Analysis of the looping events at kilobase-scale resolution revealed that morphine increased not only the number but also the length of differential loops. Moreover, all identified differentially expressed genes from the RNA sequencing data were mapped to the specific TAD boundaries or differential loops, and were further validated for changed expression. Collectively, an altered 3D genomic architecture of cortical neurons may regulate the gene networks associated with morphine effects. Our finding provides critical hubs connecting chromosome spatial organization and gene networks associated with the morphine effects in humans.
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Cromatina , Cromosomas , Humanos , Animales , Cromatina/genética , Genoma , Primates/genética , Derivados de la MorfinaRESUMEN
Sepsis is a leading cause of fatality in invasive candidiasis. The magnitude of the inflammatory response is a determinant of sepsis outcomes, and inflammatory cytokine imbalances are central to the pathophysiological processes. We previously demonstrated that a Candida albicans F1Fo-ATP synthase α subunit deletion mutant was nonlethal to mice. Here, the potential effects of the F1Fo-ATP synthase α subunit on host inflammatory responses and the mechanism were studied. Compared with wild-type strain, the F1Fo-ATP synthase α subunit deletion mutant failed to induce inflammatory responses in Galleria mellonella and murine systemic candidiasis models and significantly decreased the mRNA levels of the proinflammatory cytokines IL-1ß, IL-6 and increased those of the anti-inflammatory cytokine IL-4 in the kidney. During C. albicans-macrophage co-culture, the F1Fo-ATP synthase α subunit deletion mutant was trapped inside macrophages in yeast form, and its filamentation, a key factor in inducing inflammatory responses, was inhibited. In the macrophage-mimicking microenvironment, the F1Fo-ATP synthase α subunit deletion mutant blocked the cAMP/PKA pathway, the core filamentation-regulating pathway, because it failed to alkalinize environment by catabolizing amino acids, an important alternative carbon source inside macrophages. The mutant downregulated Put1 and Put2, two essential amino acid catabolic enzymes, possibly due to severely impaired oxidative phosphorylation. Our findings reveal that the C. albicans F1Fo-ATP synthase α subunit induces host inflammatory responses by controlling its own amino acid catabolism and it is significant to find drugs that inhibit F1Fo-ATP synthase α subunit activity to control the induction of host inflammatory responses.
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Candida albicans , Citocinas , Ratones , Animales , Candida albicans/genética , Candida albicans/metabolismo , Citocinas/genética , Citocinas/metabolismo , Adenosina Trifosfato/metabolismo , AminoácidosRESUMEN
Background: Dieulafoy's lesion is an uncommon cause of hemorrhage of the digestive tract. It often presents with urgent and massive bleeding usually leading to shock, even death. Dieulafoy's lesions have been reported throughout the digestive tract but which occurred on duodenal papilla were particularly rare and presented challenges in the choice of hemostasis. Case presentation: A 66-year-old man with melena for 2 days was admitted. Gastrointestinal endoscopy revealed blood clots covering the duodenal papilla with oozing blood. During the procedure of trying to place a plastic stent into the duodenal papilla first, the hemorrhage began to present pulsating bleeding. The patient went into shock. With consent, two titanium clips were inserted to clamp the bleeding site to stop the bleeding. The patient complained of epigastric pain 14 h after the endoscopy. An abdominal CT scan showed signs of acute pancreatitis. Endoscopy was performed to remove the titanium clips and showed a vessel stump on the duodenal papilla. The patient was discharged from the hospital on the 14th day and followed for 6 months with no recurrence. Conclusion: This case was diagnosed with a Dieulafoy's lesion on the duodenal papilla, which has rarely been reported. Hematemesis was stopped by clamping the vessel stump with titanium clips but caused acute pancreatitis. Reviewing the treatment, electrocoagulation might be a better choice, and life support treatment, including central vena catheterization and an adequate supply of blood products, should be prepared in advance to provide extra time for the stent placement or vascular intervention treatment.
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OBJECTIVE: To investigate the prognostic value of early serum lactate, albumin, and lactate/albumin ratio (L/A) on the 28-day prognosis of adult patients with sepsis. METHODS: A retrospective cohort study was conducted among adult patients with sepsis admitted to the First Affiliated Hospital of Xinjiang Medical University from January to December in 2020. Gender, age, comorbidities, lactate within 24 hours of admission, albumin, L/A, interleukin-6 (IL-6), procalcitonin (PCT), C-reactive protein (CRP) and 28-day prognosis were recorded. The receiver operator characteristic curve (ROC curve) was drawn to analyze the predictive value of lactate, albumin and L/A for 28-day mortality in patients with sepsis. Subgroup analysis of patients was performed according to the best cut-off value, Kaplan-Meier survival curves were drawn, and the 28-day cumulative survival of patients with sepsis was analyzed. RESULTS: A total of 274 patients with sepsis were included, and 122 patients died at 28 days, with a 28-day mortality of 44.53%. Compared with the survival group, the age, the proportion of pulmonary infection, the proportion of shock, lactate, L/A and IL-6 in the death group were significantly increased, and albumin was significantly decreased [age (years): 65 (51, 79) vs. 57 (48, 73), pulmonary infection: 75.4% vs. 53.3%, shock: 37.7% vs. 15.1%, lactate (mmol/L): 4.76 (2.95, 9.23) vs. 2.21 (1.44, 3.19), L/A: 0.18 (0.10, 0.35) vs. 0.08 (0.05, 0.11), IL-6 (ng/L): 337.00 (97.73, 2 318.50) vs. 55.88 (25.26, 150.65), albumin (g/L): 27.68 (21.02, 33.03) vs. 29.62 (25.25, 34.23), all P < 0.05]. The area under the ROC curve (AUC) and 95% confidence interval (95%CI) of lactate, albumin, and L/A were 0.794 (95%CI was 0.741-0.840), 0.589 (95%CI was 0.528-0.647), 0.807 (95%CI was 0.755-0.852) for predicting 28-day mortality in sepsis patients. The optimal diagnostic cut-off value of lactate was 4.07 mmol/L, the sensitivity was 57.38%, the specificity was 92.76%. The optimal diagnostic cut-off value of albumin was 22.28 g/L, the sensitivity was 31.15%, the specificity was 92.76%. The optimal diagnostic cut-off of L/A was 0.16, the sensitivity was 54.92%, and the specificity was 95.39%. Subgroup analysis showed that the 28-day mortality of sepsis patients in the L/A > 0.16 group was significantly higher than that in the L/A ≤ 0.16 group [90.5% (67/74) vs. 27.5% (55/200), P < 0.001]. The 28-day mortality of sepsis patients in the albumin ≤ 22.28 g/L group was significantly higher than that in the albumin > 22.28 g/L group [77.6% (38/49) vs. 37.3% (84/225), P < 0.001]. The 28-day mortality in the group with lactate > 4.07 mmol/L was significantly higher than that in the group with lactate ≤ 4.07 mmol/L [86.4% (70/81) vs. 26.9% (52/193), P < 0.001]. The three were consistent with the analysis results of Kaplan-Meier survival curve. CONCLUSIONS: The early serum lactate, albumin, and L/A were all valuable in predicting the 28-day prognosis of patients with sepsis, and L/A was better than lactate and albumin.
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Ácido Láctico , Sepsis , Adulto , Humanos , Interleucina-6 , Estudios Retrospectivos , Albúminas , Pronóstico , Sepsis/diagnósticoRESUMEN
BACKGROUND: This study aimed to evaluate the cut-off value of anti-Müllerian hormone (AMH) combined with body mass index (BMI) in the diagnosis of polycystic ovary syndrome (PCOS) and polycystic ovary morphology (PCOM). METHODS: This retrospective study included 15,970 patients: 3775 women with PCOS, 2879 women with PCOM, and 9316 patients as controls. Multivariate logistic regression analysis was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for AMH. We randomly divided the patients into two data sets. In dataset 1, a receiver operating characteristic (ROC) curve was generated to analyze the accuracy of basic AMH levels in diagnosing PCOS and PCOM. The optimal cut-off value was calculated in dataset 1 and validated in dataset 2, expressed as sensitivity and specificity. RESULTS: In the PCOS group, obese patients had the lowest AMH levels, while underweight patients had the highest AMH level (P < 0.001). After adjusting for age, the ratio of luteinizing hormone (LH) and follicle stimulating hormone (FSH), serum testosterone level, and BMI, AMH was an independent predictor of PCOS and PCOM. In the group with BMI < 18.5 kg/m2, the optimistic AMH cut-off value was 5.145 ng/mL with a sensitivity of 84.3% and specificity of 89.1%, whereas in the BMI ≥ 28 kg/m2 group, the optimistic AMH cut-off value was 3.165 ng/mL with a sensitivity of 88.7% and specificity of 74.6%. For the BMI range categories of 18.5-24, 24.0-28 kg/m2, the optimistic AMH cut-off values were 4.345 ng/mL and 4.115 ng/mL, respectively. The tendency that the group with lower weight corresponded to higher AMH cut-off values was also applicable to PCOM. In the same BMI category, patients with PCOM had a lower AMH diagnosis threshold than those with PCOS (< 18.5 kg/m2, 5.145 vs. 4.3 ng/mL; 18.5-24 kg/m2, 4.345 vs. 3.635 ng/mL; 24.0-28 kg/m2, 4.115 vs. 3.73 ng/mL; ≥ 28 kg /m2, 3.165 vs. 3.155 ng/mL). These cut-off values had a good diagnostic efficacy in the validation dataset. Based on different phenotypes and severity of ovulation disorders, the distribution of AMH in PCOS were also significantly different (P < 0.001). CONCLUSIONS: AMH is a potential diagnostic indicator of PCOS and is adversely associated with BMI. The AMH cut-off value for diagnosing PCOS was significantly higher than that for PCOM.
Asunto(s)
Síndrome del Ovario Poliquístico , Humanos , Femenino , Síndrome del Ovario Poliquístico/diagnóstico , Estudios Retrospectivos , Hormona Antimülleriana , Índice de Masa Corporal , Valores de ReferenciaRESUMEN
BACKGROUND: Serum sodium level is associated with cardiovascular and endocrine health. Though decreased serum sodium is considered to be associated with reduced hypertension risk, some studies also found that it may increase the risk of diabetes. This study aimed to investigate the association of serum sodium with new-onset diabetes in hypertensive patients. METHODS: Based on the annual health examinations from 2011 to 2016 in Dongguan City, Guangdong, China, hypertensive patients without diabetes at baseline were selected. Logistic regression and restricted cubic spline were used to evaluate the association between serum sodium level and new-onset diabetes. Subgroup analysis was also conducted. RESULTS: A total of 4438 hypertensive patients with a mean age of 58.65 years were included, of whom 48.9% were male. During a median follow-up of 35.1 months, 617 (13.9%) of the subjects developed new-onset diabetes. Per 1-SD (3.39 mmol/L) increment of serum sodium was associated with a 14% lower risk of new-onset diabetes (odds ratio = 0.86; 95% CI: 0.78, 0.97; p = 0.01). The lowest quartile of serum sodium was associated with the lowest diabetes risk. The restricted cubic spline showed a linear inverse relationship (nonlinear p = 0.72). Across all the subgroups, the inverse association was consistent (p for interaction >0.05). CONCLUSION: An inverse association of serum sodium with new-onset diabetes in hypertensive patients was observed.