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Nitric oxide (NO) is an important antimicrobial effector but also prevents unnecessary tissue damage by shutting down the recruitment of monocyte-derived phagocytes. Intracellular pathogens such as Leishmania major can hijack these cells as a niche for replication. Thus, NO might exert containment by restricting the availability of the cellular niche required for efficient pathogen proliferation. However, such indirect modes of action remain to be established. By combining mathematical modeling with intravital 2-photon biosensors of pathogen viability and proliferation, we show that low L. major proliferation results not from direct NO impact on the pathogen but from reduced availability of proliferation-permissive host cells. Although inhibiting NO production increases recruitment of these cells, and thus pathogen proliferation, blocking cell recruitment uncouples the NO effect from pathogen proliferation. Therefore, NO fulfills two distinct functions for L. major containment: permitting direct killing and restricting the supply of proliferation-permissive host cells.
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Leishmania major/fisiología , Leishmaniasis/inmunología , Macrófagos/inmunología , Óxido Nítrico/metabolismo , Animales , Procesos de Crecimiento Celular , Movimiento Celular , Proliferación Celular , Modelos Animales de Enfermedad , Interacciones Huésped-Patógeno , Humanos , Microscopía Intravital , Ratones , Ratones Endogámicos C57BL , Modelos TeóricosRESUMEN
Cells continuously adjust their behavior in response to changing environmental conditions. Both intensity and duration of external signals are critical factors in determining what response is initiated. To understand how intracellular signaling networks process such multidimensional information, we studied the AtRGS1-mediated glucose response system of Arabidopsis. By combining experiments with mathematical modeling, we discovered a reciprocal dose and duration response relying on the orchestrated action of three kinases (AtWNK1, AtWNK8, and AtWNK10) acting on distinct timescales and activation thresholds. Specifically, we find that high concentrations of D-glucose rapidly signal through AtWNK8 and AtWNK10, whereas low, sustained sugar concentration slowly activate the pathway through AtWNK1, allowing the cells to respond similarly to transient, high-intensity signals and sustained, low-intensity signals. This "dose-duration reciprocity" allows encoding of both the intensity and persistence of glucose as an important energy resource and signaling molecule.
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Arabidopsis/metabolismo , Glucosa/metabolismo , Células Vegetales/metabolismo , Arabidopsis/citología , Proteínas de Arabidopsis/metabolismo , Endocitosis , Cinética , Modelos Biológicos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas RGS/metabolismo , Factores de Tiempo , Proteína Quinasa Deficiente en Lisina WNK 1RESUMEN
Most clinically applied cancer immunotherapies rely on the ability of CD8+ cytolytic T cells to directly recognize and kill tumour cells1-3. These strategies are limited by the emergence of major histocompatibility complex (MHC)-deficient tumour cells and the formation of an immunosuppressive tumour microenvironment4-6. The ability of CD4+ effector cells to contribute to antitumour immunity independently of CD8+ T cells is increasingly recognized, but strategies to unleash their full potential remain to be identified7-10. Here, we describe a mechanism whereby a small number of CD4+ T cells is sufficient to eradicate MHC-deficient tumours that escape direct CD8+ T cell targeting. The CD4+ effector T cells preferentially cluster at tumour invasive margins where they interact with MHC-II+CD11c+ antigen-presenting cells. We show that T helper type 1 cell-directed CD4+ T cells and innate immune stimulation reprogramme the tumour-associated myeloid cell network towards interferon-activated antigen-presenting and iNOS-expressing tumouricidal effector phenotypes. Together, CD4+ T cells and tumouricidal myeloid cells orchestrate the induction of remote inflammatory cell death that indirectly eradicates interferon-unresponsive and MHC-deficient tumours. These results warrant the clinical exploitation of this ability of CD4+ T cells and innate immune stimulators in a strategy to complement the direct cytolytic activity of CD8+ T cells and natural killer cells and advance cancer immunotherapies.
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Linfocitos T CD4-Positivos , Muerte Celular , Inmunoterapia , Inflamación , Neoplasias , Microambiente Tumoral , Humanos , Células Presentadoras de Antígenos/inmunología , Antígeno CD11c/inmunología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Muerte Celular/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Inmunidad Innata , Inflamación/inmunología , Interferones/inmunología , Complejo Mayor de Histocompatibilidad/inmunología , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/terapia , Microambiente Tumoral/inmunología , Inmunoterapia/métodos , Células Asesinas Naturales/inmunología , Células Mieloides/inmunología , Células TH1/citología , Células TH1/inmunologíaRESUMEN
Uncovering the genetic architectures of brain morphology offers valuable insights into brain development and disease. Genetic association studies of brain morphological phenotypes have discovered thousands of loci. However, interpretation of these loci presents a significant challenge. One potential solution is exploring the genetic overlap between brain morphology and disorders, which can improve our understanding of their complex relationships, ultimately aiding in clinical applications. In this review, we examine current evidence on the genetic associations between brain morphology and neuropsychiatric traits. We discuss the impact of these associations on the diagnosis, prediction, and treatment of neuropsychiatric diseases, along with suggestions for future research directions.
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Encéfalo , Trastornos Mentales , Humanos , Encéfalo/diagnóstico por imagen , Encéfalo/crecimiento & desarrollo , Encéfalo/anatomía & histología , Trastornos Mentales/genética , Trastornos Mentales/patología , Fenotipo , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Estudios de Asociación GenéticaRESUMEN
BACKGROUND: Varicose veins (VV) are one of the common human diseases, but the role of genetics in its development is not fully understood. METHODS: We conducted an exome-wide association study of VV using whole-exome sequencing data from the UK Biobank, and focused on common and rare variants using single-variant association analysis and gene-level collapsing analysis. FINDINGS: A total of 13,823,269 autosomal genetic variants were obtained after quality control. We identified 36 VV-related independent common variants mapping to 34 genes by single-variant analysis and three rare variant genes (PIEZO1, ECE1, FBLN7) by collapsing analysis, and most associations between genes and VV were replicated in FinnGen. PIEZO1 was the closest gene associated with VV (P = 5.05 × 10-31), and it was found to reach exome-wide significance in both single-variant and collapsing analyses. Two novel rare variant genes (ECE1 and METTL21A) associated with VV were identified, of which METTL21A was associated only with females. The pleiotropic effects of VV-related genes suggested that body size, inflammation, and pulmonary function are strongly associated with the development of VV. CONCLUSIONS: Our findings highlight the importance of causal genes for VV and provide new directions for treatment.
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Secuenciación del Exoma , Exoma , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Várices , Humanos , Várices/genética , Femenino , Masculino , Exoma/genética , Polimorfismo de Nucleótido Simple , Enzimas Convertidoras de Endotelina/genética , Persona de Mediana Edad , Variación Genética , Adulto , Canales IónicosRESUMEN
Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic tick-borne virus, prevalent in more than 30 countries worldwide. Human infection by this virus leads to severe illness, with an average case fatality of 40%. There is currently no approved vaccine or drug to treat the disease. Neutralizing antibodies are a promising approach to treat virus infectious diseases. This study generated 37 mouse-derived specific monoclonal antibodies against CCHFV Gc subunit. Neutralization assays using pseudotyped virus and authentic CCHFV identified Gc8, Gc13, and Gc35 as neutralizing antibodies. Among them, Gc13 had the highest neutralizing activity and binding affinity with CCHFV Gc. Consistently, Gc13, but not Gc8 or Gc35, showed in vivo protective efficacy (62.5% survival rate) against CCHFV infection in a lethal mouse infection model. Further characterization studies suggested that Gc8 and Gc13 may recognize a similar, linear epitope in domain II of CCHFV Gc, while Gc35 may recognize a different epitope in Gc. Cryo-electron microscopy of Gc-Fab complexes indicated that both Gc8 and Gc13 bind to the conserved fusion loop region and Gc13 had stronger interactions with sGc-trimers. This was supported by the ability of Gc13 to block CCHFV GP-mediated membrane fusion. Overall, this study provides new therapeutic strategies to treat CCHF and new insights into the interaction between antibodies with CCHFV Gc proteins.
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Virus de la Fiebre Hemorrágica de Crimea-Congo , Fiebre Hemorrágica de Crimea , Animales , Ratones , Humanos , Virus de la Fiebre Hemorrágica de Crimea-Congo/genética , Anticuerpos Monoclonales , Microscopía por Crioelectrón , Anticuerpos Neutralizantes , EpítoposRESUMEN
Plant cells employ intricate defense mechanisms, including mRNA decay pathways, to counter viral infections. Among the RNA quality control (RQC) mechanisms, nonsense-mediated decay (NMD), no-go decay (NGD), and nonstop decay (NSD) pathways play critical roles in recognizing and cleaving aberrant mRNA molecules. Turnip crinkle virus (TCV) is a plant virus that triggers mRNA decay pathways, but it has also evolved strategies to evade this antiviral defense. In this study, we investigated the activation of mRNA decay during TCV infection and its impact on TCV RNA accumulation. We found that TCV infection induced the upregulation of essential mRNA decay factors, indicating their involvement in antiviral defense and the capsid protein (CP) of TCV, a well-characterized viral suppressor of RNA silencing (VSR), also compromised the mRNA decay-based antiviral defense by targeting AtXRN4. This interference with mRNA decay was supported by the observation that TCV CP stabilized a reporter transcript with a long 3' untranslated region (UTR). Moreover, TCV CP suppressed the decay of known NMD target transcripts, further emphasizing its ability to modulate host RNA control mechanisms. Importantly, TCV CP physically interacted with AtXRN4, providing insight into the mechanism of viral interference with mRNA decay. Overall, our findings reveal an alternative strategy employed by TCV, wherein the viral coat protein suppresses the mRNA decay pathway to facilitate viral infection.
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Arabidopsis , Carmovirus , Arabidopsis/genética , Interferencia de ARN , Carmovirus/genética , Degradación de ARNm Mediada por Codón sin Sentido/genética , ARN , Antivirales , ARN Viral/genéticaRESUMEN
The relationship between liver dysfunction and dementia has been researched extensively but remains poorly understood. In this study, we investigate the longitudinal and cross-sectional associations between liver function and liver diseases and risk of incident dementia, impaired cognition, and brain structure abnormalities using Cox proportion hazard model and linear regression model. 431 699 participants with a mean of 8.65 (standard deviation [SD] 2.61) years of follow-up were included from the UK Biobank; 5542 all-cause dementia (ACD), 2427 Alzheimer's disease (AD), and 1282 vascular dementia (VaD) cases were documented. We observed that per SD decreases in alanine transaminase (ALT; hazard ratio [HR], 0.917; PFDR <0.001) and per SD increases in aspartate aminotransferase (AST; HR, 1.048; PFDR = 0.010), AST to ALT ratio (HR, 1.195; PFDR <0.001), gamma-glutamyl transpeptidase (GGT; HR, 1.066; PFDR <0.001), alcoholic liver disease (ALD; HR, 2.872; PFDR <0.001), and fibrosis and cirrhosis of liver (HR, 2.285; PFDR = 0.002), being significantly associated with a higher risk of incident ACD. Restricted cubic spline models identified a strong U-shaped association between Alb and AST and incident ACD (Pnonlinear <0.05). Worse cognition was positively correlated with AST, AST to ALT ratio, direct bilirubin (DBil), and GGT; negatively correlated with ALT, Alb, and total bilirubin (TBil); and ALD and fibrosis and cirrhosis of liver (PFDR <0.05). Moreover, changes in ALT, GGT, AST to ALT ratio, and ALD were significantly associated with altered cortical and subcortical regions, including hippocampus, amygdala, thalamus, pallidum, and fusiform (PFDR <0.05). In sensitivity analysis, metabolic dysfunction-associated steatotic liver disease (MASLD) was associated with the risk of ACD and brain subcortical changes. Our findings provide substantial evidence that liver dysfunction may be an important factor for incident dementia. Early intervention in the unhealthy liver may help prevent cognitive impairment and dementia incidence.
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Demencia , Hepatopatías , Adulto , Humanos , Estudios Prospectivos , Estudios Transversales , Hepatopatías/epidemiología , Hígado , Cognición , Bilirrubina , Encéfalo , Cirrosis Hepática , Demencia/epidemiología , Aspartato AminotransferasasRESUMEN
Liver function has been suggested as a possible factor in the progression of Alzheimer's disease (AD) development. However, the association between liver function and cerebrospinal fluid (CSF) levels of AD biomarkers remains unclear. In this study, we analyzed the data from 1687 adults without dementia from the Chinese Alzheimer's Biomarker and LifestylE study to investigate differences in liver function between pathological and clinical AD groups, as defined by the 2018 National Institute on Aging-Alzheimer's Association Research Framework. We also examined the linear relationship between liver function, CSF AD biomarkers, and cognition using linear regression models. Furthermore, mediation analyses were applied to explore the potential mediation effects of AD pathological biomarkers on cognition. Our findings indicated that, with AD pathological and clinical progression, the concentrations of total protein (TP), globulin (GLO), and aspartate aminotransferase/alanine transaminase (ALT) increased, while albumin/globulin (A/G), adenosine deaminase, alpha-L-fucosidase, albumin, prealbumin, ALT, and glutamate dehydrogenase (GLDH) concentrations decreased. Furthermore, we also identified significant relationships between TP (ß = -0.115, pFDR < 0.001), GLO (ß = -0.184, pFDR < 0.001), and A/G (ß = 0.182, pFDR < 0.001) and CSF ß-amyloid1-42 (Aß1-42 ) (and its related CSF AD biomarkers). Moreover, after 10 000 bootstrapped iterations, we identified a potential mechanism by which TP and GLDH may affect cognition by mediating CSF AD biomarkers, with mediation effect sizes ranging from 3.91% to 16.44%. Overall, our results suggested that abnormal liver function might be involved in the clinical and pathological progression of AD. Amyloid and tau pathologies also might partially mediate the relationship between liver function and cognition. Future research is needed to fully understand the underlying mechanisms and causality to develop an approach to AD prevention and treatment approach.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Globulinas , Humanos , Enfermedad de Alzheimer/patología , Proteínas tau/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Albúminas , Hígado , Fragmentos de Péptidos/líquido cefalorraquídeoRESUMEN
Though previous studies revealed the potential associations of elevated levels of plasma fibrinogen with dementia, there is still limited understanding regarding the influence of Alzheimer's disease (AD) biomarkers on these associations. We sought to investigate the interrelationships among fibrinogen, cerebrospinal fluid (CSF) AD biomarkers, and cognition in non-demented adults. We included 1996 non-demented adults from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study and 337 from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The associations of fibrinogen with AD biomarkers and cognition were explored using multiple linear regression models. The mediation analyses with 10 000 bootstrapped iterations were conducted to explore the mediating effects of AD biomarkers on cognition. In addition, interaction analyses and subgroup analyses were conducted to assess the influence of covariates on the relationships between fibrinogen and AD biomarkers. Participants exhibiting low Aß42 were designated as A+, while those demonstrating high phosphorylated tau (P-tau) and total tau (Tau) were labeled as T+ and N+, respectively. Individuals with normal measures of Aß42 and P-tau were categorized as the A-T- group, and those with abnormal levels of both Aß42 and P-tau were grouped under A+T+. Fibrinogen was higher in the A+ subgroup compared to that in the A- subgroup (p = 0.026). Fibrinogen was higher in the A+T+ subgroup compared to that in the A-T- subgroup (p = 0.011). Higher fibrinogen was associated with worse cognition and Aß pathology (all p < 0.05). Additionally, the associations between fibrinogen and cognition were partially mediated by Aß pathology (mediation proportion range 8%-28%). Interaction analyses and subgroup analyses showed that age and ApoE ε4 affect the relationships between fibrinogen and Aß pathology. Fibrinogen was associated with both cognition and Aß pathology. Aß pathology may be a critical mediator for impacts of fibrinogen on cognition.
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IMPORTANCE: Intra-arterial therapies(IATs) are promising options for unresectable hepatocellular carcinoma(HCC). Stratifying the prognostic risk before administering IAT is important for clinical decision-making and for designing future clinical trials. OBJECTIVE: To develop and validate a machine learning(ML)-based decision support model(MLDSM) for recommending IAT modalities for unresectable HCC. DESIGN, SETTING, AND PARTICIPANTS: Between October 2014 and October 2022, a total of 2,959 patients with HCC who underwent initial IATs were enroled retrospectively from 13 tertiary hospitals. These patients were divided into the training cohort (n = 1700), validation cohort (n = 428), and test cohort (n = 200). MAIN OUTCOMES AND MEASURES: Thirty-two clinical variables were input, and five supervised ML algorithms, including eXtreme Gradient Boosting (XGBoost), Categorical Gradient Boosting (CatBoost), Gradient Boosting Decision Tree (GBDT), Light Gradient Boosting Machine (LGBM) and Random Forest (RF), were compared using the areas under the receiver operating characteristic curve (AUC) with the DeLong test. RESULTS: A total of 1856 patients were assigned to the IAT alone Group(I-A), and 1103 patients were assigned to the IAT combination Group(I-C). The 12-month death rates were 31.9% (352/1103) in the I-A group and 50.4% (936/1856) in the I-C group. For the test cohort, in the I-C group, the CatBoost model achieved the best discrimination when 30 variables were input, with an AUC of 0.776 (95% confidence intervals [CI], 0.833-0.868). In the I-A group, the LGBM model achieved the best discrimination when 24 variables were input, with an AUC of 0.776 (95% CI, 0.833-0.868). According to the decision trees, BCLC grade, local therapy, and diameter as top three variables were used to guide clinical decisions between IAT modalities. CONCLUSIONS AND RELEVANCE: The MLDSM can accurately stratify prognostic risk for HCC patients who received IATs, thus helping physicians to make decisions about IAT and providing guidance for surveillance strategies in clinical practice.
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This study aims to develop an ensemble learning (EL) method based on magnetic resonance (MR) radiomic features to preoperatively differentiate intracranial extraventricular ependymoma (IEE) from glioblastoma (GBM). This retrospective study enrolled patients with histopathologically confirmed IEE and GBM from June 2016 to June 2021. Radiomics features were extracted from T1-weighted imaging (T1WI) and T2-weighted imaging (T2WI) sequence images, and classification models were constructed using EL methods and logistic regression (LR). The efficiency of the models was assessed using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis. The combined EL model, based on clinical parameters and radiomic features from T1WI and T2WI images, demonstrated good discriminative ability, achieving an area under the receiver operating characteristics curve (AUC) of 0.96 (95% CI 0.94-0.98), a specificity of 0.84, an accuracy of 0.92, and a sensitivity of 0.95 in the training set, and an AUC of 0.89 (95% CI 0.83-0.94), a specificity of 0.83, an accuracy of 0.81, and a sensitivity of 0.74 in the validation set. The discriminative efficacy of the EL model was significantly higher than that of the LR model. Favorable calibration performance and clinical applicability for the EL model were observed. The EL model combining preoperative MR-based tumor radiomics and clinical data showed high accuracy and sensitivity in differentiating IEE from GBM preoperatively, which may potentially assist in clinical management of these brain tumors.
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BACKGROUND: The identification of survival predictors is crucial for early intervention to improve outcome in acute myeloid leukemia (AML). This study aim to identify chest computed tomography (CT)-derived features to predict prognosis for acute myeloid leukemia (AML). METHODS: 952 patients with pathologically-confirmed AML were retrospectively enrolled between 2010 and 2020. CT-derived features (including body composition and subcutaneous fat features), were obtained from the initial chest CT images and were used to build models to predict the prognosis. A CT-derived MSF nomogram was constructed using multivariate Cox regression incorporating CT-based features. The performance of the prediction models was assessed with discrimination, calibration, decision curves and improvements. RESULTS: Three CT-derived features, including myosarcopenia, spleen_CTV, and SF_CTV (MSF) were identified as the independent predictors for prognosis in AML (P < 0.01). A CT-MSF nomogram showed a performance with AUCs of 0.717, 0.794, 0.796 and 0.792 for predicting the 1-, 2-, 3-, and 5-year overall survival (OS) probabilities in the validation cohort, which were significantly higher than the ELN risk model. Moreover, a new MSN stratification system (MSF nomogram plus ELN risk model) could stratify patients into new high, intermediate and low risk group. Patients with high MSN risk may benefit from intensive treatment (P = 0.0011). CONCLUSIONS: In summary, the chest CT-MSF nomogram, integrating myosarcopenia, spleen_CTV, and SF_CTV features, could be used to predict prognosis of AML.
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Leucemia Mieloide Aguda , Nomogramas , Humanos , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Área Bajo la Curva , Leucemia Mieloide Aguda/diagnóstico por imagenRESUMEN
Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. The existence of cancer stem cells (CSC) causes tumor relapses, metastasis, and resistance to conventional therapy. Alternative splicing has been shown to affect physiological and pathological processes. Accumulating evidence has confirmed that targeting alternative splicing could be an effective strategy to treat CRC. Currently, the role of alternative splicing in the regulation of CSC properties in CRC has not been elucidated. Here, we show that RBM17 displays oncogenic roles in CRC cells. RBM17 enhances cell proliferation and reduces chemotherapeutic-induced apoptosis in CRC cells. Besides, RBM17 increases CD133 positive and ALDEFLUOR positive populations and promotes sphere formation in CRC cells. In mechanism studies, we found that FOXM1 is critical for RBM17 enhanced CSC properties. Moreover, FOXM1 alternative splicing is essential for RBM17 enhanced CSC properties in CRC cells. Additionally, RBM17 enhances CSC characteristics by controlling FOXM1 expression to promote Sox2 expression. Furthermore, AKT1 works as an upstream kinase to control RBM17-mediated FOXM1 alternative splicing and enhancement of CSC properties in CRC cells. Our study reveals that AKT1-RBM17-FOXM1-Sox2 axis could be a potential target for modulating alternative splicing to reduce CSC properties in CRC cells.
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Neoplasias Colorrectales , Humanos , Empalme Alternativo , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Regulación Neoplásica de la Expresión Génica , Células Madre Neoplásicas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factores de Empalme de ARN/metabolismo , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismoRESUMEN
AIM: Novel long-acting drugs for type 2 diabetes mellitus may optimize patient compliance and glycaemic control. Exendin-4-IgG4-Fc (E4F4) is a long-acting glucagon-like peptide-1 receptor agonist. This first-in-human study investigated the safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of a single subcutaneous injection of E4F4 in healthy subjects. METHODS: This single-centre, randomized, double-blind, placebo-controlled phase 1 clinical trial included 96 subjects in 10 sequential cohorts that were provided successively higher doses of E4F4 (0.45, 0.9, 1.8, 3.15, 4.5, 6.3, 8.1, 10.35, 12.6 and 14.85 mg) or placebo (ChinaDrugTrials.org.cn: ChiCTR2100049732). The primary endpoint was safety and tolerability of E4F4. Secondary endpoints were pharmacokinetic, pharmacodynamic and immunogenicity profiles of E4F4. Safety data to day 15 after the final subject in a cohort had been dosed were reviewed before commencing the next dose level. RESULTS: E4F4 was safe and well tolerated among healthy Chinese participants in this study. There was no obvious dose-dependent relationship between frequency, severity or causality of treatment-emergent adverse events. Cmax and area under the curve of E4F4 were dose proportional over the 0.45-14.85 mg dose range. Median Tmax and t1/2 ranged from 146 to 210 h and 199 to 252 h, respectively, across E4F4 doses, with no dose-dependent trends. For the intravenous glucose tolerance test, area under the curve of glucose in plasma from time 0 to 180 min showed a dose-response relationship in the 1.8-10.35 mg dose range, with an increased response at the higher doses. CONCLUSION: E4F4 exhibited an acceptable safety profile and linear pharmacokinetics in healthy subjects. The recommended phase 2 dose is 4.5-10.35 mg once every 2 weeks.
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Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Exenatida/efectos adversos , Voluntarios Sanos , Área Bajo la Curva , Prueba de Tolerancia a la Glucosa , Método Doble Ciego , Relación Dosis-Respuesta a DrogaRESUMEN
Multiple hypothesis testing has been widely applied to problems dealing with high-dimensional data, for example, the selection of important variables or features from a large number of candidates while controlling the error rate. The most prevailing measure of error rate used in multiple hypothesis testing is the false discovery rate (FDR). In recent years, the local false discovery rate (fdr) has drawn much attention, due to its advantage of accessing the confidence of individual hypotheses. However, most methods estimate fdr through P $$ P $$ -values or statistics with known null distributions, which are sometimes unavailable or unreliable. Adopting the innovative methodology of competition-based procedures, for example, the knockoff filter, this paper proposes a new approach, named TDfdr, to fdr estimation, which is free of P $$ P $$ -values or known null distributions. Extensive simulation studies demonstrate that TDfdr can accurately estimate the fdr with two competition-based procedures. We applied the TDfdr method to two real biomedical tasks. One is to identify significantly differentially expressed proteins related to the COVID-19 disease, and the other is to detect mutations in the genotypes of HIV-1 that are associated with drug resistance. Higher discovery power was observed compared to existing popular methods.
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Algoritmos , Proyectos de Investigación , Humanos , Simulación por ComputadorRESUMEN
Potassium carbonate-catalyzed (3 + 2) cycloaddition reaction between N-2,2,2-trifluoroethylisatin ketimines and azodicarboxylates has been developed, constructing a series of novel N-heterocycle infused spirooxindoles in good to excellent yields (up to 98%) under milder conditions. The presence of both biologically active oxindole and trifluoromethyl-1,2,4-triazoline moieties in these novel spirocyclic compounds would provide new lead structures in the discovery of heterocyclic compounds with potential pharmaceutical activities.
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Among the HDACs family, histone deacetylase 6 (HDAC6) has attracted extensive attention due to its unique structure and biological functions. Numerous studies have shown that compared with broad-spectrum HDACs inhibitors, selective HDAC6 inhibitors exert ideal efficacy in tumor treatment with insignificant toxic and side effects, demonstrating promising clinical application prospect. Herein, we carried out rational drug design by integrating a deep learning model, molecular docking, and molecular dynamics simulation technology to construct a virtual screening process. The designed derivatives with 5-phenyl-1H-indole fragment as Cap showed desirable cytotoxicity to the various tumor cell lines, all of which were within 15 µM (ranging from 0.35 to 14.87 µM), among which compound 5i had the best antiproliferative activities against HL-60 (IC50 = 0.35 ± 0.07 µM) and arrested HL-60 cells in the G0/G1 phase. In addition, 5i exhibited better isotype selective inhibitory activities due to the potent potency against HDAC6 (IC50 = 5.16 ± 0.25 nM) and the reduced inhibitory activities against HDAC1 (selective index ≈ 124), which was further verified by immunoblotting results. Moreover, the representative binding conformation of 5i on HDAC6 was revealed and the key residues contributing 5i's binding were also identified via decomposition free-energy analysis. The discovery of lead compound 5i also indicates that virtual screening is still a beneficial tool in drug discovery and can provide more molecular skeletons with research potential for drug design, which is worthy of widespread application.
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Diseño de Fármacos , Histona Desacetilasa 6 , Inhibidores de Histona Desacetilasas , Indoles , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos , Histona Desacetilasa 6/antagonistas & inhibidores , Histona Desacetilasa 6/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/química , Indoles/farmacología , Indoles/química , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Interfaz Usuario-ComputadorRESUMEN
Abnormal tryptophan (Trp) metabolism can be used as an important indicator of chronic hepatitis, paranoia, Parkinson's disease and other diseases. Deficiency or excessive accumulation of Cu2+ can cause diseases such as Wilson's disease and Alzheimer's disease. Eu-based metal-organic framework (Eu-MOF) was successfully prepared for fluorescence sensing of Trp and Cu2+ in an aqueous solution (pH = 7.4). Eu-MOF showed high selectivity and sensitivity for Trp and Cu2+ with detection limits of 0.22 µM and 0.09 µM and Ksv of 6.17 × 103 M- 1 and 2.37 × 104 M- 1 respectively. Trp and Cu2+ had overlapped UV absorption spectra with that of Eu-MOF and competed for the excitation light source. Trp also attenuated the antennae effect of organic ligands on Eu-MOF, thus quenching the red fluorescence of Eu-MOF. This study provides insights into the application of MOFs in bioanalysis and diagnostics.
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An accurate, global, full-dimensional potential energy surface (PES) of NaCl + NaCl has been constructed by the fundamental invariant-neural network (FI-NN) fitting based on roughly 13,000 ab initio energies at the level of CCSD(T)-F12a/aug-cc-pVTZ, with the small fitting error of 0.16 meV. Extensive quasiclassical trajectory (QCT) calculations were performed on this PES to investigate the energy transfer process of the NaCl + NaCl collision at four different collision energies. Various quantities were obtained, including the cross-sections, energy transfer probability, average energy transfer, and collision lifetime. The probabilities of energy transfer (P(ΔE)) for prompt trajectories, nonreactive trajectories, and reactive trajectories deviate from a simple exponential decay pattern. Instead, a noteworthy probability is observed in the high-energy transfer region, indicative of supercollisions. The formation of the (NaCl)2 complex, coupled with a comparatively extended collision lifetime, promotes vibrational excitation in NaCl molecules. The reactive trajectories exhibit enhanced energy transfer, attributed to the longer lifetime of the NaCl dimer. This study not only provides an accurate and extensive understanding of the NaCl + NaCl collision dynamics but also reveals intriguing phenomena, such as supercollisions and enhanced energy transfer in reactive trajectories, shedding light on the complex intricacies of molecular interactions.