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In this editorial, we comment on an article by Alhammad et al that was published in a recent issue of the World Journal of Clinical Cases (Manuscript No.: 91134). We specifically focus on the mental health problems caused by coronavirus disease 2019 (COVID-19), their mechanisms, and targeted rehabilitation strategies. Severe acute respiratory syndrome coronavirus 2, via its spike protein, binds to angiotensin-converting enzyme 2 and other receptors prior to infiltrating diverse cells within the central nervous system, including endothelial cells, neurons, astrocytes, and oligodendrocytes, thereby contributing to the development of mental illnesses. Epidemiological data from 2020 underscored the global upsurge in major depressive and anxiety disorders by 27.6% and 25.6%, respectively, during the pandemic. The commented research show that 30% of post-intensive care unit discharge patients with COVID-19 in the Arabic region exhibited Hospital Anxiety and Depression Scale scores that were indicative of anxiety and depression. While acknowledging psychosocial factors, such as grief and loss, it is crucial to recognize the potential neurological impact of the virus through various mechanisms. Accordingly, interventions that encompass dietary measures, health supplements, and traditional Chinese medicine with neuroprotective properties are necessary. This editorial underscores the urgency to implement comprehensive rehabilitation approaches to address the intricate interplay between COVID-19 and mental well-being.
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Evidence on the link of long-term exposure to ozone (O3) with childhood asthma, rhinitis, conjunctivitis and eczema is inconclusive. We did a population-based cross-sectional survey, including 177,888 children from 173 primary and middle schools in 14 Chinese cities. A satellite-based spatiotemporal model was employed to assess four-year average O3 exposure at both residential and school locations. Information on asthma, allergic rhinitis, eczema and conjunctivitis was collected by a standard questionnaire developed by the American Thoracic Society. We used generalized non-linear and linear mixed models to test the associations. We observed linear exposure-response associations between O3 and all outcomes. The odds ratios of doctor-diagnosed asthma, rhinitis, eczema, and conjunctivitis associated with per interquartile increment in home-school O3 concentration were 1.31 (95 % confidence interval [CI]: 1.28, 1.34), 1.25 (95 %CI: 1.23, 1.28), 1.19 (95 %CI: 1.16, 1.21), and 1.28 (95 %CI: 1.21, 1.34), respectively. Similar associations were observed for asthma-related outcomes including current asthma, wheeze, current wheeze, persistent phlegm, and persistent cough. Moreover, stronger associations were observed among children who were aged > 12 years, physically inactive, and exposed to higher temperature. In conclusion, long-term O3 exposure was associated with higher risks of asthma, allergic rhinitis, conjunctivitis and eczema in children.
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BACKGROUND & AIMS: Patients with intrahepatic cholangiocarcinoma (iCCA) respond poorly to immune checkpoint blockades (ICBs). In this study, we aimed to dissect the potential mechanisms underlying poor response to ICBs and explore a rational ICB-based combination therapy in iCCA. METHODS: scRNA-seq dataset GSE151530 was analyzed to investigate the differentially expressed genes in malignant cells following ICBs therapy. RNA-seq analysis and western blot assays were performed to examine the upstream and downstream signaling pathways of CD73. Subcutaneous tumor xenograft models were utilized to investigate the impact of CD73 on iCCA growth. Plasmid AKT/NICD-induced spontaneous murine iCCAs were used to explore the therapeutic efficacy of CD73 enzymatic inhibitor AB680 combined with PD-1 blockade. Time-of-flight mass cytometry (CyTOF) was conducted to identify the tumor-infiltrating immune cell populations and their functional changes in murine iCCAs treated with AB680 in combination with PD-1 antibody. RESULTS: scRNA-seq analysis identified elevated CD73 expression in malignant cells in response to ICBs therapy. Mechanistically, ICBs therapy upregulated CD73 expression in malignant cells via TNF-α/NF-κB signaling pathway. In vivo studies revealed that CD73 inhibition suppressed the growth of subcutaneous tumors, and achieved synergistic depression effects with gemcitabine and cisplatin (GC). Adenosine produced by CD73 activates AKT/GSK3ß/ß-catenin signaling axis in iCCA cells. CD73 inhibitor AB680 potentiates anti-tumor efficacy of PD-1 antibody in murine iCCAs. CyTOF analysis showed that AB680 combined with anti-PD-1 therapy promoted the infiltration of CD8+ T, CD4+ T cells, and NK cells in murine iCCAs, while simultaneously decreased the proportions of macrophages and neutrophils. Moreover, AB680 combined with anti-PD-1 significantly upregulated the expression of Granzyme B, Tbet and co-stimulatory molecule ICOS in infiltrating CD8+ T cells. CONCLUSIONS: CD73 inhibitor AB680 limits tumor progression and potentiates therapeutic efficacy of GC chemotherapy or anti-PD-1 treatment in iCCA. AB680 combined with anti-PD-1 therapy effectively elicits anti-tumor immune response.
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5'-Nucleotidasa , Neoplasias de los Conductos Biliares , Colangiocarcinoma , Inhibidores de Puntos de Control Inmunológico , Receptor de Muerte Celular Programada 1 , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/patología , Colangiocarcinoma/inmunología , Animales , 5'-Nucleotidasa/antagonistas & inhibidores , 5'-Nucleotidasa/metabolismo , Ratones , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/inmunología , Neoplasias de los Conductos Biliares/metabolismo , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas Ligadas a GPI/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Línea Celular Tumoral , Progresión de la EnfermedadRESUMEN
Hyperuricemia (HUA), a metabolic disease caused by excessive production or decreased excretion of uric acid (UA), has been reported to be closely associated with a variety of UA transporters. Clerodendranthus spicatus (C. spicatus) is an herbal widely used in China for the treatment of HUA. However, the mechanism has not been clarified. Here, the rat model of HUA was induced via 10% fructose. The levels of biochemical indicators, including UA, xanthine oxidase (XOD), adenosine deaminase (ADA), blood urea nitrogen (BUN), and creatinine (Cre), were measured. Western blotting was applied to explore its effect on renal UA transporters, such as urate transporter1 (URAT1), glucose transporter 9 (GLUT9), and ATP-binding cassette super-family G member 2 (ABCG2). Furthermore, the effect of C. spicatus on plasma metabolites was identified by metabolomics. Our results showed that C. spicatus could significantly reduce the serum levels of UA, XOD, ADA and Cre, and improve the renal pathological changes in HUA rats. Meanwhile, C. spicatus significantly inhibited the expression of URAT1 and GLUT9, while increased the expression of ABCG2 in a dose-dependent manner. Metabolomics showed that 13 components, including 1-Palmitoyl-2-Arachidonoyl-sn-glycero-3-PE, Tyr-Leu and N-cis-15-Tetracosenoyl-C18-sphingosine, were identified as potential biomarkers for the UA-lowering effect of C. spicatus. In addition, pathway enrichment analysis revealed that arginine biosynthesis, biosynthesis of amino acids, pyrimidine metabolism and other metabolic pathways might be involved in the protection of C. spicatus against HUA. This study is the first to explore the mechanism of anti-HUA of C. spicatus through molecular biology and metabolomics analysis, which provides new ideas for the treatment of HUA.
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Hiperuricemia , Metabolómica , Ácido Úrico , Animales , Hiperuricemia/tratamiento farmacológico , Hiperuricemia/metabolismo , Ratas , Metabolómica/métodos , Ácido Úrico/sangre , Masculino , Riñón/metabolismo , Riñón/efectos de los fármacos , Riñón/patología , Transportadores de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico/genética , Ratas Sprague-Dawley , Extractos Vegetales/farmacología , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Xantina Oxidasa/metabolismo , Modelos Animales de EnfermedadRESUMEN
Diabetic retinopathy (DR), a well-known microvascular complication of diabetes mellitus, remains the main cause of vision loss in working-age adults worldwide. Up to now, there is a shortage of information in the study regarding the contributing factors of DR in diabetes. Accumulating evidence has identified glycemic variability (GV), referred to fluctuations of blood glucose levels, as a risk factor for diabetes-related complications. Recent reports demonstrate that GV plays an important role in accounting for the susceptibility to DR development. However, its exact role in the pathogenesis of DR is still not fully understood. In this review, we highlight the current landscape and relevant mechanisms of GV in DR, as well as address the mechanism-based therapeutic strategies, aiming at better improving the quality of DR management in clinical practice.
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Glucemia , Retinopatía Diabética , Humanos , Retinopatía Diabética/terapia , Retinopatía Diabética/sangre , Glucemia/metabolismo , Factores de RiesgoRESUMEN
Modifications at different positions on the aloperine molecule were performed to improve its anticancer activity and develop anticancer drugs. The in vitro anticancer activities of 44 synthesized compounds were evaluated. The effect of modification positions on anticancer activity was discussed and a structure-activity relationship analysis was established. A novel series of compounds with modifications at the N12 position showed much higher cytotoxicity than aloperine. Among them, compound 22 displayed promising in vitro anticancer activity against PC9 cells with a median inhibitory concentration (IC50) of 1.43 µM. The mechanism studies indicated that compound 22 induced cell apoptosis and cell cycle arrest in PC9 cells. These results demonstrate the potential of aloperine thiourea derivatives in anticancer activity.
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Antineoplásicos , Apoptosis , Ensayos de Selección de Medicamentos Antitumorales , Piperidinas , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Humanos , Relación Estructura-Actividad , Estructura Molecular , Apoptosis/efectos de los fármacos , Piperidinas/farmacología , Piperidinas/química , Piperidinas/síntesis química , Diseño de Fármacos , Quinolizidinas/farmacología , Quinolizidinas/química , Quinolizidinas/síntesis química , Línea Celular Tumoral , Puntos de Control del Ciclo Celular/efectos de los fármacosRESUMEN
PURPOSE: Hepatocellular carcinoma (HCC) is a critical global health concern, with existing treatments benefiting only a minority of patients. Recent findings implicate the chemokine ligand 17 (CCL17) and its receptor CCR4 as pivotal players in the tumor microenvironment (TME) of various cancers. This investigation aims to delineate the roles of CCL17 and CCR4 in modulating the tumor's immune landscape, assessing their potential as therapeutic interventions and prognostic markers in HCC. METHODS: 873 HCC patients post-radical surgery from 2008 to 2012 at Zhongshan Hospital, Fudan University were retrospectively examined. These individuals were stratified into a training cohort (n = 354) and a validation cohort (n = 519). Through immunohistochemical analysis on HCC tissue arrays, the expressions of CCL17, CCR4, CD73, CD47, HHLA2, and PD-L1 were quantified. Survival metrics were analyzed using the Cox model, and a prognostic nomogram was devised via R software. RESULTS: The investigation confirmed the presence of CCL17 and CCR4 within the cancerous and stromal compartments of HCC tissues, associating their heightened expression with adverse clinical markers and survival outcomes. Notably, the interplay between CD73 and CCR4 expression in tumor stroma highlighted a novel cellular entity, CCR4 + CD73 + stromal cells, impacting overall and relapse-free survival. A prognostic nomogram amalgamating these immunological markers and clinical variables was established, offering refined prognostic insights and aiding in the management of HCC. The findings suggest that reduced CCR4 and CCR4 + CD73 + cell prevalence may forecast improved outcomes post-TACE. CONCLUSION: This comprehensive evaluation of CCR4, CCL17, and associated markers introduces a nuanced understanding of the HCC immunological milieu, proposing CCR4 + CD73 + stromal cells as critical to HCC pathogenesis and patient stratification.
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5'-Nucleotidasa , Biomarcadores de Tumor , Carcinoma Hepatocelular , Quimiocina CCL17 , Proteínas Ligadas a GPI , Neoplasias Hepáticas , Receptores CCR4 , Microambiente Tumoral , Humanos , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/inmunología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/inmunología , Quimiocina CCL17/metabolismo , Femenino , Masculino , Pronóstico , Receptores CCR4/metabolismo , Persona de Mediana Edad , Biomarcadores de Tumor/metabolismo , 5'-Nucleotidasa/metabolismo , Estudios Retrospectivos , Microambiente Tumoral/inmunología , Proteínas Ligadas a GPI/metabolismo , Anciano , AdultoRESUMEN
Lymph node metastasis (LNM) facilitates distant tumor colonization and leads to the high mortality in patients with intrahepatic cholangiocarcinoma (ICC). However, it remains elusive how ICC cells subvert immune surveillance within the primary tumor immune microenvironment (TIME) and subsequently metastasize to lymph nodes (LNs). In this study, scRNA-seq and bulk RNA-seq analyses identified decreased infiltration of dendritic cells (DCs) into primary tumor sites of ICC with LNM, which was further validated via dual-color immunofluorescence staining of 219 surgically resected ICC samples. Tumor-infiltrating DCs correlated with increased CD8+ T cell infiltration and better prognoses in ICC patients. Mechanistically, ß-catenin-mediated CXCL12 suppression accounted for the impaired DC recruitment in ICC with LNM. Two mouse ICC cell lines MuCCA1 and mIC-23 cells were established from AKT/NICD or AKT/YAP-induced murine ICCs respectively and were utilized to construct the footpad tumor LNM model. We found that expansion and activation of conventional DCs (cDCs) by combined Flt3L and poly(I:C) (FL-pIC) therapy markedly suppressed the metastasis of mIC-23 cells to popliteal LNs. Moreover, ß-catenin inhibition restored the defective DC infiltration into primary tumor sites and reduced the incidence of LNM in ICC. Collectively, our findings identify tumor cell intrinsic ß-catenin activation as a key mechanism for subverting DC-mediated anti-tumor immunity in ICC with LNM. FL-pIC therapy or ß-catenin inhibitor could merit exploration as a potential regimen for mitigating ICC cell metastasis to LNs and achieving effective tumor immune control.
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[This corrects the article DOI: 10.3389/fncel.2022.878673.].
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Evaluating the effects of temperature variations on animals plays an important role in understanding the threat of climate warming. The effects of developmental temperature on offspring performance are critical in evaluating the effects of warming temperatures on the fitness of oviparous species, but the physiological and biochemical basis of this developmental plasticity is largely unknown. In this study, we incubated eggs of the turtle Pelodiscus sinensis at low (24 °C), medium (28 °C), and high (32 °C) temperatures, and evaluated the effects of developmental temperature on offspring fitness, and metabolic enzymes in the neck and limb muscles of hatchlings. The hatchlings from eggs incubated at the medium temperature showed better fitness-related performance (righting response and swimming capacity) and higher activities of metabolic enzymes (hexokinase, HK; lactate dehydrogenase, LDH) than hatchlings from the eggs incubated at high or low temperatures. In addition, the swimming speed and righting response were significantly correlated with the HK activities in limb (swimming speed) and neck (righting response) muscles, suggesting that the developmental plasticity of energy metabolic pathway might play a role in determining the way incubation temperature affects offspring phenotypes. Integrating the fitness-related performance and the activities of metabolic enzymes, we predict that the P. sinensis from high latitude would not face the detrimental effects of climate warming until the average nest temperatures reach 32 °C.
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BACKGROUND: Studies have shown that RASGRP1 was potently associated with the onset of type 2 diabetes mellitus (T2DM), and RASGRP1 rs7403531 was significantly correlated with islet function in T2DM patients. However, the effect of RASGRP1 polymorphism on blood glucose and blood pressure in T2DM patients after continuous treatment has yet to be fully elucidated. OBJECTIVE: This study aimed to explore the association between RASGRP1 genetic polymorphism and cardiovascular complications in T2DM patients, so as to provide more evidence for the individualized treatment of T2DM patients. METHODS: We retrospectively analyzed a large-scale multicenter drug clinical study cohort that based on a 2 × 2 factorial (glucose control axis and blood pressure lowering axis) randomized controlled design, with follow-up for 5 years. The major vascular endpoint events included cardiovascular death, non-fatal stroke, coronary heart disease, new-onset or worsening renal disease, and diabetic retinopathy. RASGRP1 rs12593201, rs56254815 and rs7403531 were finally selected as candidate single nucleotide polymorphisms. Mixed linear model and Cox hazard ratio (HR) model were used for data analysis with IBM SPSS (version 20.0 for windows; Chicago, IL). RESULTS: Our study enrolled 1357 patients with high-risk diabetes, with a mean follow-up duration of 4.8 years. RASGRP1 rs7403531 was associated with vascular events in hypoglycemic and antihypertensive therapy. Specifically, compared with CC carriers, patients with CT/TT genotype had fewer major microvascular events (HR = 0.41, 95% confidence interval (CI) 0.21-0.80, P = 0.009), and reduced the risk of major eye disease events (HR = 0.44, 95% CI 0.20-0.94, P = 0.03). For glucose lowering axis, CT/TT carriers had a lower risk of secondary nephropathy (HR = 0.48, 95% CI 0.25-0.92, P = 0.03) in patients with standard glycemic control. For blood pressure lowering axis, all cerebrovascular events (HR = 2.24, 95% CI 1.11-4.51, P = 0.025) and stroke events (HR = 2.07, 95% CI 1.03-4.15, P = 0.04) were increased in patients with CC genotype compared to those with CT/TT genotype in the placebo group, respectively. Furthermore, patients with CC genotype showed a reduced risk of major cerebrovascular events in antihypertensive group (HR = 0.36, 95% CI 0.15-0.86, P = 0.021). For RASGRP1 rs56254815, compared with the AA genotype carriers, the systolic blood pressure of AG/GG carriers in the antihypertensive group decreased by 1.5mmhg on average (P = 0.04). In the placebo group, the blood pressure of AG/GG carriers was 1.7mmHg higher than that of AA carriers (P = 0.02). CONCLUSION: We found that patients with G allele of RASGRP1 (rs56254815) showed a better antihypertensive therapy efficacy in T2DM patients. The rs7403531 T allele could reduce the risk of major microvascular events and major eye diseases in T2DM patients receiving either hypoglycemic or antihypertensive therapy. Our findings suggest that RASGRP1 genetic polymorphism might predict the cardiovascular complications in T2DM patients.
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Antihipertensivos , Glucemia , Presión Sanguínea , Diabetes Mellitus Tipo 2 , Predisposición Genética a la Enfermedad , Control Glucémico , Factores de Intercambio de Guanina Nucleótido , Polimorfismo de Nucleótido Simple , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antihipertensivos/uso terapéutico , Antihipertensivos/efectos adversos , Pueblo Asiatico/genética , Biomarcadores/sangre , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/genética , China/epidemiología , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/sangre , Angiopatías Diabéticas/genética , Angiopatías Diabéticas/diagnóstico , Proteínas de Unión al ADN/genética , Pueblos del Este de Asia , Estudios de Asociación Genética , Control Glucémico/efectos adversos , Factores de Intercambio de Guanina Nucleótido/genética , Hipertensión/genética , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Hipertensión/diagnóstico , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/efectos adversos , Fenotipo , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Identifying patients who can benefit from immune checkpoint inhibitors (ICIs) is a critical challenge in immunotherapy. This study aimed to investigate the association between fat mass and obesity-associated protein (FTO) polymorphisms and ICIs treatment outcomes. METHOD: This retrospective study was conducted on 371 patients with malignant tumors who received ICIs treatment and were followed-up for a minimum duration of 12 months. Seven variants in FTO gene were genotyped using the Sequenome MassARRAY platform, and their associations with ICIs treatment outcomes were analyzed. RESULTS: Pharmacogenomic research revealed that individuals carrying the rs11075995AT/TT genotype were more likely to benefit from ICIs treatment compare to TT genotype. Cox regression analysis showed that rs1125338TT carriers exhibited a shorter progression-free survival (PFS, hazard ratio (HR) = 1.72, 95 % confidence interval (CI) = 1.12-2.46), while rs12596638GG carriers experienced extended PFS (HR = 0.71, 95 % CI = 0.50-0.99). Multiple Cox regression analysis indicated that rs12596638GG (HR = 6.81, 95 %CI = 1.20-38.56) and rs1125338CC (HR = 1.78, 95 %CI = 0.07-0.45), rs12600192CC (HR = 0.13, 95 %CI = 0.037-0.44) genotypes were independently associated with overall survival (OS) after adjusting clinical characteristics. Furthermore, patients with rs12600192CC genotype had a lower risk of severe irAEs compared to those with GG/GC genotypes (P < 0.01). CONCLUSION: We identified FTO gene polymorphisms associated with treatment outcomes of ICI treatment in patients with multiple solid cancers, which might serve as potential predictive biomarkers.
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Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Inhibidores de Puntos de Control Inmunológico , Neoplasias , Polimorfismo de Nucleótido Simple , Humanos , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Femenino , Estudios Retrospectivos , Masculino , Persona de Mediana Edad , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/genética , Neoplasias/tratamiento farmacológico , Neoplasias/mortalidad , Anciano , Adulto , Genotipo , Resultado del TratamientoRESUMEN
Survival of the immobile embryo in response to rising temperature is important to determine a species' vulnerability to climate change. However, the collective effects of 2 key thermal characteristics associated with climate change (i.e., rising average temperature and acute heat events) on embryonic survival remain largely unexplored. We used empirical measurements and niche modeling to investigate how chronic and acute heat stress independently and collectively influence the embryonic survival of lizards across latitudes. We collected and bred lizards from 5 latitudes and incubated their eggs across a range of temperatures to quantify population-specific responses to chronic and acute heat stress. Using an embryonic development model parameterized with measured embryonic heat tolerances, we further identified a collective impact of embryonic chronic and acute heat tolerances on embryonic survival. We also incorporated embryonic chronic and acute heat tolerance in hybrid species distribution models to determine species' range shifts under climate change. Embryos' tolerance of chronic heat (T-chronic) remained consistent across latitudes, whereas their tolerance of acute heat (T-acute) was higher at high latitudes than at low latitudes. Tolerance of acute heat exerted a more pronounced influence than tolerance of chronic heat. In species distribution models, climate change led to the most significant habitat loss for each population and species in its low-latitude distribution. Consequently, habitat for populations across all latitudes will shift toward high latitudes. Our study also highlights the importance of considering embryonic survival under chronic and acute heat stresses to predict species' vulnerability to climate change.
Efectos colectivos del aumento de las temperaturas promedio y los eventos de calor en embriones ovíparos Resumen La supervivencia de los embriones inmóviles en respuesta al incremento de temperatura es importante para determinar la vulnerabilidad de las especies al cambio climático. Sin embargo, los efectos colectivos de dos características térmicas claves asociadas con el cambio climático (i. e., aumento de temperatura promedio y eventos de calor agudo) sobre la supervivencia embrionaria permanecen en gran parte inexplorados. Utilizamos mediciones empíricas y modelos de nicho para investigar cómo el estrés térmico crónico y agudo influye de forma independiente y colectiva en la supervivencia embrionaria de los lagartos en todas las latitudes. Recolectamos y criamos lagartos de cinco latitudes e incubamos sus huevos en un rango de temperaturas para cuantificar las respuestas específicas de la población al estrés por calor crónico y agudo. Posteriormente, mediante un modelo de desarrollo embrionario parametrizado con mediciones de tolerancia embrionaria al calor, identificamos un impacto colectivo de las tolerancias embrionarias al calor agudo y crónico en la supervivencia embrionaria. También incorporamos la tolerancia embrionaria crónica y aguda al calor en modelos de distribución de especies híbridas para determinar los cambios de distribución de las especies bajo el cambio climático. La tolerancia embrionaria al calor crónico (Tcrónico) permaneció constante, mientras que la tolerancia al calor agudo (Tagudo) fue mayor en latitudes altas que en latitudes bajas. La tolerancia al calor agudo ejerció una influencia más pronunciada que la tolerancia al calor crónico. En los modelos de distribución de especies, el cambio climático provocó la pérdida de hábitat más significativa para cada población y especie en su distribución de latitudes bajas. En consecuencia, el hábitat para poblaciones en todas las latitudes se desplazará a latitudes altas. Nuestro estudio también resalta la importancia de considerar la supervivencia embrionaria bajo estrés térmico crónico y agudo para predecir la vulnerabilidad de las especies al cambio climático.
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Cambio Climático , Embrión no Mamífero , Calor , Lagartos , Animales , Lagartos/fisiología , Lagartos/embriología , Embrión no Mamífero/fisiología , Oviparidad , Femenino , Modelos Biológicos , Desarrollo Embrionario , TermotoleranciaRESUMEN
BACKGROUND: Aberrant expressions of desmoglein 2 (Dsg2) and desmocollin 2(Dsc2), the two most widely distributed desmosomal cadherins, have been found to play various roles in cancer in a context-dependent manner. Their specific roles on breast cancer (BC) and the potential mechanisms remain unclear. METHODS: The expressions of Dsg2 and Dsc2 in human BC tissues and cell lines were assessed by using bioinformatics analysis, immunohistochemistry and western blotting assays. Wound-healing and Transwell assays were performed to evaluate the cells' migration and invasion abilities. Plate colony-forming and MTT assays were used to examine the cells' capacity of proliferation. Mechanically, Dsg2 and Dsc2 knockdown-induced malignant behaviors were elucidated using western blotting assay as well as three inhibitors including MK2206 for AKT, PD98059 for ERK, and XAV-939 for ß-catenin. RESULTS: We found reduced expressions of Dsg2 and Dsc2 in human BC tissues and cell lines compared to normal counterparts. Furthermore, shRNA-mediated downregulation of Dsg2 and Dsc2 could significantly enhance cell proliferation, migration and invasion in triple-negative MDA-MB-231 and luminal MCF-7 BC cells. Mechanistically, EGFR activity was decreased but downstream AKT and ERK pathways were both activated maybe through other activated protein tyrosine kinases in shDsg2 and shDsc2 MDA-MB-231 cells since protein tyrosine kinases are key drivers of triple-negative BC survival. Additionally, AKT inhibitor treatment displayed much stronger capacity to abolish shDsg2 and shDsc2 induced progression compared to ERK inhibition, which was due to feedback activation of AKT pathway induced by ERK inhibition. In contrast, all of EGFR, AKT and ERK activities were attenuated, whereas ß-catenin was accumulated in shDsg2 and shDsc2 MCF-7 cells. These results indicate that EGFR-targeted therapy is not a good choice for BC patients with low Dsg2 or Dsc2 expression. Comparatively, AKT inhibitors may be more helpful to triple-negative BC patients with low Dsg2 or Dsc2 expression, while therapies targeting ß-catenin can be considered for luminal BC patients with low Dsg2 or Dsc2 expression. CONCLUSION: Our finding demonstrate that single knockdown of Dsg2 or Dsc2 could promote proliferation, motility and invasion in triple-negative MDA-MB-231 and luminal MCF-7 cells. Nevertheless, the underlying mechanisms were cellular context-specific and distinct.
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Movimiento Celular , Proliferación Celular , Desmocolinas , Desmogleína 2 , Neoplasias de la Mama Triple Negativas , Humanos , Desmocolinas/metabolismo , Desmocolinas/genética , Desmogleína 2/metabolismo , Desmogleína 2/genética , Femenino , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/genética , Línea Celular Tumoral , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Invasividad Neoplásica , Regulación Neoplásica de la Expresión Génica , beta Catenina/metabolismo , Transducción de SeñalRESUMEN
In clinical treatments, reliable flow rate measurements ensure accurate drug delivery during infusions, precise gas delivery during artificial ventilations, etc., thereby reducing patient morbidity and mortality. However, precise flow rate sensors are costly, so medical devices with limited budgets choose cheaper but unsatisfactory flow rate measurement approaches, leading to increased medical risks. Here, a photoelectric flow rate sensor based on a flexible planar curved beam structure (FPCBS) is proposed. The FPCBS ensures low out-of-plane stiffness of the sensitive sheet and allows large deformation in the elastic range, enabling the flow rate sensor to measure the flow rate with high sensitivity over a wide range. Meanwhile, the flow rate sensor can be mass-produced using mature materials and manufacturing technology at less than $5 each. The flow rate sensors are integrated into a commercial infusion pump to measure drug infusion and a home ventilator to monitor respiration. The results are comparable to those measured by a commercial flow rate sensor, demonstrating the applicability of the sensor. Considering its proven outstanding performance at low cost, the flow rate sensor shows great potential in clinical treatment, medical diagnosis, and other medical fields.
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Diseño de Equipo , Humanos , Bombas de Infusión , Sistemas de Liberación de Medicamentos/instrumentación , Sistemas de Liberación de Medicamentos/métodosRESUMEN
BACKGROUND: Baijiu is a well-known alcoholic beverage in China and the quality is determined by various microorganisms during the fermentation process. Yeast is one of the most important microorganisms in the fermentation of baijiu. It has a strong esterification capacity and also affects the aroma. RESULTS: High-throughput sequencing results showed that the fermented grains (jiupei) during baijiu production were mainly composed of eight highly abundant yeast species. The species and abundance of yeasts changed significantly with the fermentation process. The flavor of 30 yeast strains in the jiupei was determined by a sniffing test and gas chromatography-mass spectrometry (GC-MS). The strain with the highest flavor substance content (2.34 mg L-1), named YX3205, was identified as Clavispora lusitaniae. Tolerance results showed that C. lusitaniae YX3205 can tolerate up to 15% (v v-1) ethanol. In a solid-state simulated fermentation experiment, the content of 24 flavor substances was significantly increased in the fortified group, and the total ester content reached 4240.73 µg kg-1, which was 2.8 times higher than that of the control group. CONCLUSION: The present study demonstrated the potential of C. lusitaniae YX3205 to enhance the flavor of baijiu, thereby serving as a valuable strain for the improvement of the flavor quality of baijiu. © 2024 Society of Chemical Industry.
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Bebidas Alcohólicas , Fermentación , Aromatizantes , Gusto , Levaduras , Aromatizantes/metabolismo , Aromatizantes/química , Levaduras/metabolismo , Levaduras/clasificación , Levaduras/genética , Bebidas Alcohólicas/análisis , Bebidas Alcohólicas/microbiología , China , Cromatografía de Gases y Espectrometría de Masas , Grano Comestible/química , Grano Comestible/microbiología , Grano Comestible/metabolismo , Etanol/metabolismo , Etanol/análisisRESUMEN
Doxorubicin (DOX) is a clinical chemotherapeutic drug and patients usually suffer from dose-dependent cytotoxic and side effects during chemotherapy process with DOX. Therefore, developing a reliable strategy for DOX analysis in biological samples for dosage guidance during chemotherapy process is of great significance. Herein, a sensitive and selective electrochemical biosensor for DOX detection was designed based on gold nanoparticles (AuNPs) and DNA tetrahedron (TDN) nanoprobe bifunctional glassy carbon electrode that could detect DOX in human serum and cell lysate samples. AuNPs not only could enhance electron transfer efficiency and detection sensitivity, but also could improve the biocompatibility of electrode. TDN nanoprobes were employed as specific DOX bind sites that could bind abundant DOX through intercalative characteristics to contribute to sensitive and selective detection. Under the optimal conditions, the proposed TDN nanoprobes-based DOX biosensor exhibited a wide linear range that ranged from 1.0 nM to 50 µM and a low detection limit that was 0.3 nM. Moreover, the proposed DOX biosensor displayed nice selectivity, reproducibility and stability, and was successfully applied for DOX detection in human serum and cell lysate samples. These promising results maybe pave a way for DOX dosage guidance and therapeutic efficacy optimization in clinic.
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Técnicas Biosensibles , Nanopartículas del Metal , Humanos , Oro , Reproducibilidad de los Resultados , Técnicas Electroquímicas/métodos , Doxorrubicina/análisis , ADN , Técnicas Biosensibles/métodos , Límite de DetecciónRESUMEN
OBJECTIVES: To compare the clinicopathological, molecular, and immune features of conventional and high-grade transformation (HGT) secretory carcinoma (SC) in salivary glands. MATERIALS AND METHODS: The clinicopathological data of 88 cases including 74 conventional SCs and 14 SCs with HGT were reviewed. Targeted next-generation sequencing was performed in 11 SCs with HGT and 7 conventional SCs. The level of PD-L1 and CD8+ TILs was determined by immunohistochemistry. RESULTS: Compared with the conventional group, the rates of nodal metastasis, local recurrence, distant metastasis and mortality were significantly higher in the HGT cohort. Mutations of ARID1A/B, KMT2A, HOXD13, NRG1 and ETV6 genes were identified in HGT SCs. A recurrent E307G mutation in GATA6 gene was also observed in two cases. Two deceased HGT patients with distant metastasis harboured NOTCH3 mutations. ETV6-RET translocation was prone to occur in the HGT SCs. Additionally, PD-L1 expression was low, and CD8+ TILs were sparse in most HGT cases. CONCLUSION: Our findings reveal novel gene alterations involved in the progression of HGT in SCs. Most HGT SCs patients cannot benefit from PD-L1 blocking and may be approached with a distinct treatment strategy including the lymph node dissection and application of molecular target drugs in precision oncology.
RESUMEN
Local adaptation is critical in speciation and evolution, yet comprehensive studies on proximate and ultimate causes of local adaptation are generally scarce. Here, we integrated field ecological experiments, genome sequencing, and genetic verification to demonstrate both driving forces and molecular mechanisms governing local adaptation of body coloration in a lizard from the Qinghai-Tibet Plateau. We found dark lizards from the cold meadow population had lower spectrum reflectance but higher melanin contents than light counterparts from the warm dune population. Additionally, the colorations of both dark and light lizards facilitated the camouflage and thermoregulation in their respective microhabitat simultaneously. More importantly, by genome resequencing analysis, we detected a novel mutation in Tyrp1 that underpinned this color adaptation. The allele frequencies at the site of SNP 459# in the gene of Tyrp1 are 22.22% G/C and 77.78% C/C in dark lizards and 100% G/G in light lizards. Model-predicted structure and catalytic activity showed that this mutation increased structure flexibility and catalytic activity in enzyme TYRP1, and thereby facilitated the generation of eumelanin in dark lizards. The function of the mutation in Tyrp1 was further verified by more melanin contents and darker coloration detected in the zebrafish injected with the genotype of Tyrp1 from dark lizards. Therefore, our study demonstrates that a novel mutation of a major melanin-generating gene underpins skin color variation co-selected by camouflage and thermoregulation in a lizard. The resulting strong selection may reinforce adaptive genetic divergence and enable the persistence of adjacent populations with distinct body coloration.