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1.
BMC Med Genomics ; 17(1): 199, 2024 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-39113023

RESUMEN

BACKGROUND: Studies have shown that m6A modification is related to the occurrence and development of papillary thyroid carcinoma (PTC). The disorder of succinic acid metabolism is associated with the occurrence and development of various tumors. However, there are few studies based on m6A and succinate metabolism-related genes (SMRGs) in PTC. METHODS: The TCGA-Thyroid carcinoma (THCA), GSE33630, 1159 SMRGs, and 23 m6A regulatory factors were collected from the online databases. Subsequently, the differentially expressed genes (DEGs) were selected between PTC (Tumor) and Normal samples. The overlapping genes among the DEGs, m6A, and SMRGs were applied to screen the biomarkers. Using the 3 machine-learning algorithms, the biomarkers were determined based on the overlapping genes. Next, the biomarkers were evaluated by the ROC curve and expression analysis in TCGA-THCA and GSE33630. Then, the overall survival (OS) differences were compared between the high-and low-expression biomarkers. Finally, immune infiltration analysis, molecular regulatory network, and drug prediction were performed based on the biomarkers. RESULTS: In TCGA-THCA, there were 2800 DEGs between and Normal samples, and then 7 overlapping genes were obtained. Importantly, ADK, TNFRSF10B, CYP7B1, FGFR2, and CPQ were determined as biomarkers with excellent diagnostic efficiency (AUC > 0.7). In PTC samples, ADK and TNFRSF10B were high-expressed while CYP7B1, FGFR2, and CPQ were low-expressed. Especially, the high-expression groups of ADK had a better prognosis, while the high-expression groups of CYP7B1, FGFR2, and CPQ had a worse prognosis. Afterward, immune infiltration analysis found that 16 immune cells had infiltration differences between the Tumor and Normal samples. Finally, transcription factor SP1 could regulate CYP7B1 and TNFRSF10B. Moreover, Navitoclax was a potential drug for PTC patients. CONCLUSION: Overall, we described 5 biomarkers associated with adverse prognosis of PTC, including ADK, TNFRSF10B, CYP7B1, FGFR2, and CPQ. All these biomarkers were involved in succinate metabolism and m6A modification of RNA. This set of biomarkers should be explored further for their diagnostic value in PTC. Investigations into the mechanistic role of alteration of succinate metabolism and m6A modification of RNA pathways in the pathophysiology of PTC are warranted.


Asunto(s)
Biomarcadores de Tumor , Ácido Succínico , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides , Humanos , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/metabolismo , Cáncer Papilar Tiroideo/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Ácido Succínico/metabolismo , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/patología , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Pronóstico , Perfilación de la Expresión Génica , Adenosina/análogos & derivados
2.
Cereb Cortex ; 34(8)2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-39098820

RESUMEN

Drug addiction is a chronic and relapse brain disorder. Psychostimulants such as cocaine and amphetamine are highly addictive drugs. Abuse drugs target various brain areas in the nervous system. Recent studies have shown that the prefrontal cortex (PFC) plays a key role in regulating addictive behaviors. The PFC is made up of excitatory glutamatergic cells and gamma-aminobutyric acid (GABAergic) interneurons. Recently, studies showed that GABA level was related with psychostimulant addiction. In this review, we will introduce the role and mechanism of GABA and γ-aminobutyric acid receptors (GABARs) of the PFC in regulating drug addiction, especially in psychostimulant addiction.


Asunto(s)
Estimulantes del Sistema Nervioso Central , Corteza Prefrontal , Trastornos Relacionados con Sustancias , Ácido gamma-Aminobutírico , Corteza Prefrontal/metabolismo , Corteza Prefrontal/efectos de los fármacos , Humanos , Ácido gamma-Aminobutírico/metabolismo , Animales , Trastornos Relacionados con Sustancias/metabolismo , Estimulantes del Sistema Nervioso Central/farmacología , Receptores de GABA/metabolismo
3.
Gynecol Endocrinol ; 40(1): 2390848, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-39135447

RESUMEN

OBJECTIVE: Anthropometric measurement provides a simple, noninvasive approach to evaluate obesity in pregnant women. We aimed to develop a predictive model utilizing anthropometric index for gestational diabetes mellitus (GDM), the most common obesity-related complications during pregnancy. METHODS: A prospective cohort of 4709 women was enrolled in Qingdao, China. Logistic regression model was constructed to determine the association of body mass index (BMI), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) in the first trimester (<14 weeks' gestation) with GDM. The discrimination ability for GDM was assessed using areas under the receiver operating characteristic (ROC) curve (AUC). Delong tests were performed to compare AUC values between different measures. RESULTS: The GDM incidence was 19.50%. GDM risk increased with VAT during early pregnancy, and the risk increased by 117% (OR = 2.17, 95% CI: 1.23-2.83) to 326% (OR = 4.26, 95% CI: 2.29-7.91) in pregnant women with the second quartile or above after adjusting for confounders (all p<.05). Combined index using VAT and BMI demonstrated superior predictive power for GDM compared with BMI alone (p<.05), but didn't differ from VAT (p>.05). Overall, VAT was positively correlated with GDM occurrence, outperforming BMI, WHR, WHtR and SAT in the predicative model. A first-trimester VAT cutoff of 27.05 mm might be promising for GDM risk stratification. CONCLUSIONS: First-trimester routine ultrasound screening may facilitate earlier identification and intervention of GDM. Pregnant women with VAT above the optimal threshold (27.05 mm) might benefit from targeted GDM monitoring.


Asunto(s)
Índice de Masa Corporal , Diabetes Gestacional , Obesidad , Humanos , Femenino , Diabetes Gestacional/epidemiología , Embarazo , Adulto , Estudios Prospectivos , China/epidemiología , Obesidad/epidemiología , Obesidad/complicaciones , Relación Cintura-Cadera , Factores de Riesgo , Grasa Intraabdominal/diagnóstico por imagen , Relación Cintura-Estatura , Primer Trimestre del Embarazo , Antropometría/métodos , Estudios de Cohortes , Pueblos del Este de Asia
4.
Asian J Surg ; 2024 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-39054140

RESUMEN

BACKGROUND & AIMS: With the rising prevalence of non-alcoholic fatty liver disease (NAFLD) as a significant etiology for hepatocellular carcinoma (HCC), lean NAFLD-HCC has emerged as a specific distinct subtype. This study sought to investigate long-term outcomes following curative-intent hepatectomy for early-stage NAFLD-HCC among lean patients compared with overweight and obese individuals. METHODS: A multicenter retrospective analysis was used to assess early-stage NAFLD-HCC patients undergoing curative-intent hepatectomy between 2009 and 2022. Patients were stratified by preoperative body mass index (BMI) into the lean (<23.0 kg/m2), overweight (23.0-27.4 kg/m2) and obese (≥27.5 kg/m2) groups. Study endpoints were overall survival (OS) and recurrence-free survival (RFS), which were compared among groups. RESULTS: Among 309 patients with NAFLD-HCC, 66 (21.3 %), 176 (57.0 %), and 67 (21.7 %) were lean, overweight, and obese, respectively. The three groups were similar relative to most liver, tumor, and surgery-related variables. Compared with overweight patients (71.3 % and 55.6 %), the lean individuals had a worse 5-year OS and RFS (55.4 % and 35.1 %, P = 0.017 and 0.002, respectively), which were comparable to obese patients (48.5 % and 38.2 %, P = 0.939 and 0.442, respectively). After adjustment for confounding factors, multivariable Cox-regression analysis identified that lean bodyweight was independently associated with decreased OS (hazard ratio: 1.69; 95 % confidence interval: 1.06-2.71; P = 0.029) and RFS (hazard ratio: 1.72; 95 % confidence interval: 1.17-2.52; P = 0.006) following curative-intent hepatectomy for early-stage NAFLD-HCC. CONCLUSIONS: Compared with overweight patients, individuals with lean NAFLD-HCC had inferior long-term oncological survival after hepatectomy for early-stage NAFLD-HCC. These data highlight the need for examination of the distinct carcinogenic pathways of lean NAFLD-HCC and its potential consequences in HCC recurrence.

5.
J Intensive Med ; 4(2): 240-246, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38681793

RESUMEN

Background: Prolonged length of stay (LOS) of sepsis can drain a hospital's material and human resources. This study investigated the correlations between T helper type 17 (Th17) and regulatory T (Treg) balance with LOS in sepsis. Methods: A prospective clinical observational study was designed in Changhai Hospital affiliated to Naval Medical University in Shanghai, China, from January to October 2020. The patients diagnosed with sepsis and who met the inclusion and exclusion criteria were recruited and whether the levels of cytokines, procalcitonin, subtypes, and biomarkers of T cells in the peripheral blood were detected. We analyzed the correlation between these and LOS. Results: Sixty septic patients were classified into two groups according to whether their intensive care unit (ICU) stay exceeded 14 days. The patients with LOS ≥14 days were older ([72.6±7.5] years vs. [63.3±10.4] years, P=0.015) and had higher Sequential Organ Failure Assessment (SOFA) (median [interquartile range]: 6.5 [5.0-11.0] vs. 4.0 [3.0-6.0], P=0.001) and higher Acute Physiology and Chronic Health Evaluation (APACHE) II scores (16.0 [13.0-21.0] vs. 8.5 [7.0-14.0], P=0.001). There was no difference in other demographic characteristics and cytokines, interleukin-6, tumor necrosis factor-α, and interleukin-10 between the two groups. The Th17/Treg ratio of sepsis with LOS <14 days was considerably lower (0.48 [0.38-0.56] vs. 0.69 [0.51-0.98], P=0.001). For patients with LOS ≥14 days, the area under the receiver operating characteristic curve for the Th17/Treg ratio was 0.766. It improved to 0.840 and 0.850 when combined with the SOFA and APACHE II scores, respectively. Conclusions: The Th17/Treg ratio was proportional to septic severity and can be used as a potential predictor of ICU stay in sepsis, presenting a new option for ICU practitioners to better care for patients with sepsis.

6.
Adv Sci (Weinh) ; 11(9): e2305508, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-38145957

RESUMEN

Hepatocellular carcinoma (HCC) is acknowledged as an immunosuppressive neoplasm, whereby the inactive microenvironment facilitates immune tolerance and evasion of HCC. Post-surgical resected liver cancer exhibits a proclivity for relapse, rendering prevention of recurrence challenging as it may transpire at any point subsequent to surgery. Among the various anti-recurrence interventions, the primary clinical approach involving the administration of regimens atezolizumab and bevacizumab (A+T) is deemed the most efficacious in reversing the tumor microenvironment, albeit still lacking in complete satisfaction. Therefore, the objective is to utilize a recently developed block copolymer as a protective carrier for two specific monoclonal antibody drugs. Subsequently, a modified hemostatic hydrogel will be synthesized for application during hepatic surgery. The immunotherapy impact of this approach is significantly prolonged and intensified due to the combined hemostasis properties and controlled release of the constituents within the synthesized nanocomposite hydrogel. Furthermore, these nanocomposite hydrogels exhibit remarkable efficacy in preventing postoperative wound bleeding and substantially enhancing the safety of liver cancer resection. This research on the anti-recurrence hydrogel system presents a novel therapeutic approach for addressing local recurrence of liver cancer, potentially offering a substantial contribution to the field of surgical treatment for liver cancer in the future.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Humanos , Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/cirugía , Pérdida de Sangre Quirúrgica , Hidrogeles/uso terapéutico , Recurrencia Local de Neoplasia/prevención & control , Recurrencia Local de Neoplasia/patología , Nanopartículas/uso terapéutico , Microambiente Tumoral
7.
J Food Prot ; 86(12): 100158, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37699510

RESUMEN

Fungal spoilage of food is a worldwide concern prompting the development of many antimicrobial agents and applications. In this study, the cell-free supernatant (CFS) of Lacticaseibacillus paracasei ALAC-4 had a significant inhibition effect on fungi. The CFS with antifungal activities were combined with chitosan (CS) matrix to prepare an active packaging CS-CFS films by using a solvent casting method and used for the packaging of Mongolian cheese for 15 days during storage at 4 ± 1℃. The optimized formulation of the film were 1.25% (w/v) chitosan, 1.75% (w/v) gelatin, 0.3% (v/v) glycerol, and 9.6% (w/v) CFS. It was found that CS-CFS films exhibited strong antifungal activities against molds and yeasts, especially Candida albicans, and also had excellent mechanical properties. Additionally, FTIR spectroscopy indicated that hydrogen bonds between the CFS and CS formed, and there was a smooth surface, compact cross-section observed in SEM morphologies of CS-CFS films. Furthermore, CS-CFS film also displayed a strong antifungal effect against molds and yeasts on cheese surface. These results suggest that the chitosan-based CS-CFS film has a promising application for Mongolian cheese and food preservation.


Asunto(s)
Queso , Quitosano , Antifúngicos/farmacología , Embalaje de Alimentos/métodos , Quitosano/farmacología , Lacticaseibacillus , Queso/microbiología , Candida albicans
9.
Int Immunopharmacol ; 117: 109947, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37012892

RESUMEN

Therapeutic intervention to block IL-17A signaling has proven to be an effective treatment for numerous autoimmune diseases, including psoriasis, psoriatic arthritis, and axial spondylarthritis. Among the IL-17 family members, IL-17F, which shares 55% sequence homology with IL-17A, has been reported to functionally overlap with IL-17A in many inflammatory diseases. In this study, we describe the generation and characterization of QLS22001, a humanized monoclonal IgG1 antibody with an extended half-life and high affinity for both IL-17A and IL-17F. QLS22001 effectively blocks IL-17A and IL-17F mediated signaling pathways both in vitro and in vivo. Briefly, the YTE (M225Y/S254T/T256E) modification was introduced into the Fc fragment of QLS22001 WT Fc to prolong its half-life, and the resulting construct was named QLS22001. Functionally, it significantly inhibits IL-17A- and IL-17F-stimulated signaling in cell-based IL-6 release and reporter assays. The dual neutralization of the endogenous IL-17A and IL-17F produced by Th17 cells, as opposed to the selective blockade of IL-17A alone, results in a greater suppression of inflammatory cytokine secretion, according to in vitro blockade assays. Furthermore, in an in vivo mouse pharmacodynamic study, QLS22001 blocked human IL-17A-induced mouse keratinocyte chemoattractant (KC) release. In cynomolgus monkey pharmacokinetics evaluation, QLS22001 showed linear pharmacokinetic characteristics with a mean half-life of 31.2 days, while its parent antibody, QLS22001 WT Fc, had a mean half-life of 17.2 days. In addition, QLS22001 does not induce cytokine release in a human whole-blood assay. Collectively, these data provide a comprehensive preclinical characterization of QLS22001 and support its clinical development.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Interleucina-17 , Humanos , Animales , Ratones , Interleucina-17/metabolismo , Macaca fascicularis/metabolismo , Semivida , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Citocinas/metabolismo
10.
BMC Pregnancy Childbirth ; 23(1): 202, 2023 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-36959594

RESUMEN

BACKGROUND: The joint effect of folic acid (FA) supplements and maternal pre-pregnancy body mass index (BMI) on gestational diabetes mellitus (GDM) has not been fully addressed. This study aimed to examine the joint effect of FA supplements and pre-pregnancy BMI on GDM. METHODS: Pregnant women at 4 to 14 weeks of gestation (n = 3186) were recruited during their first prenatal visit in Qingdao from May 1, 2019, to June 27, 2021. The main outcome was GDM at 24-28 weeks' gestation. Screening was based on 75 g 2-hour oral glucose tolerance (OGTT), a fasting glucose ≥ 5.1 mmol/L, or a 1-hour result ≥ 10.0 mmol/L, or a 2-hour result ≥ 8.5 mmol/L. The interactive effect of FA supplements and pre-pregnancy BMI on GDM was examined using logistic regression analysis and ratio of odds ratios (ROR) was used to compare subgroup differences. RESULTS: Overall, 2,095 pregnant women were included in the analysis, and GDM incidence was 17.76%. Compared with women with pre-pregnancy BMI lower than 25.0 kg/m2 and FA-Sufficient supplements ≥ 400 µg/day (FA-S) population, the adjusted odds ratios (aORs) of FA-S and FA-Deficiency supplements < 400 µg/d (FA-D) were 3.57 (95% confidence interval [CI]: 2.02-6.34) and 10.82 (95% CI: 1.69-69.45) for the obese women (BMI ≥ 30.0 kg/m2), and the aORs of FA-S and FA-D were 2.17 (95% CI: 1.60-2.95) and 3.27 (95% CI: 1.55-6.92) for overweight women (25.0 kg/m2 ≤ BMI < 30.0 kg/m2). However, the risk of GDM did not differ significantly between the FA-D and the FA-S group in pre-pregnancy obese women (ROR = 2.70, 95%CI: 0.47-2.30), or overweight women (ROR = 0.66, 95%CI: 0.30-1.49). After further stratification of FA supplementation time, F-D and FA-S in obese women showed an interaction when FA supplement intake time < 3 months. However, there was no significant difference between subgroups (ROR = 1.63, 95% CI: 0.37-7.04). CONCLUSION: Maternal pre-pregnancy BMI was associated with the incidence of GDM, the dose of FA supplementation from pre-pregnancy to early pregnancy was not found to be related to the incidence of GDM. The dosage of FA supplement was not associated with GDM irrespective of maternal pre-pregnancy BMI.


Asunto(s)
Diabetes Gestacional , Embarazo , Femenino , Humanos , Diabetes Gestacional/epidemiología , Diabetes Gestacional/diagnóstico , Sobrepeso/epidemiología , Ácido Fólico , Índice de Masa Corporal , Estudios Prospectivos , Obesidad/complicaciones , Obesidad/epidemiología , Suplementos Dietéticos , Factores de Riesgo
11.
Diabetes Res Clin Pract ; 199: 110628, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-36965710

RESUMEN

AIMS: To investigate whether recurrent gestational diabetes mellitus (GDM) is associated with an increased risk of preterm birth. METHODS: We conducted a prospective population-based cohort study covering all live singleton births born to nulliparous and multiparous mothers aged 20 years and older in Qingdao, from 2018 to 2020 (n = 105,528). Preterm birth (<37 gestational weeks) was classified into moderate preterm birth (32-36 weeks of gestation) and very preterm birth (<32 weeks). Logistic regression analysis was performed to estimate the risk and severity of prematurity in relation to parity among mothers with previous GDM, current GDM, and recurrent GDM (previous and current GDM), using mothers without GDM as the reference group. Z-test and ratio of odds ratios (ROR) were used to determine subgroup differences. RESULTS: Maternal GDM increased the risk of preterm birth in both nullipara (ORadj = 1.28, 95 %CI: 1.14-1.45) and multipara (ORadj = 1.26, 95 %CI: 1.14-1.40). However, the risk of premature delivery in multiparous mothers with recurrent GDM and those with current GDM did not differ significantly, with a ROR of 0.89 (95 %CI: 0.71-1.12). The risk of recurrent GDM on preterm birth was most pronounced among multiparous mothers with pre-pregnancy BMI above 30 kg/m2 (ORadj = 2.18, 95 %CI: 1.25-3.82) as compared with those with current GDM alone (ROR = 2.20, 95 %CI: 1.07-4.52). The risk of GDM for moderate preterm birth was similar to that of overall preterm birth. In contrast, GDM was not associated with very preterm birth irrespective of parity (all P values > 0.05). CONCLUSIONS: Maternal GDM increased the risk of preterm birth in nullipara and multipara, whereas recurrent GDM was not associated with a further increase in the risk of prematurity in multiparous mothers. Maternal GDM did not contribute to very preterm birth irrespective of parity. Our findings can be useful for facilitating more targeted preventive strategies for adverse pregnancy outcomes.


Asunto(s)
Diabetes Gestacional , Enfermedades del Recién Nacido , Nacimiento Prematuro , Embarazo , Femenino , Recién Nacido , Humanos , Diabetes Gestacional/epidemiología , Diabetes Gestacional/etiología , Nacimiento Prematuro/epidemiología , Nacimiento Prematuro/etiología , Estudios de Cohortes , Estudios Prospectivos , Resultado del Embarazo
13.
Virol J ; 19(1): 177, 2022 11 05.
Artículo en Inglés | MEDLINE | ID: mdl-36335385

RESUMEN

BACKGROUND: Human papilloma virus (HPV) DNA test was applied in cervical cancer screening as an effective cancer prevention strategy. The viral load of HPV generated by different assays attracted increasing attention on its potential value in disease diagnosis and progression discovery. METHODS: In this study, three HPV testing datasets were assessed and compared, including Hybrid Capture 2 (n = 31,954), Aptima HPV E6E7 (n = 3269) and HPV Cobas 4800 (n = 13,342). Logistic regression models for diagnosing early cervical lesions of the three datasets were established and compared. The best variable factor combination (VL + BV) and dataset (HC2) were used for the establishment of six machine learning models. Models were evaluated and compared, and the best-performed model was validated. RESULTS: Our results show that viral load value was significantly correlated with cervical lesion stages in all three data sets. Viral Load and Bacterial Vaginosis were the best variable factor combination for logistic regression model establishment, and models based on the HC2 dataset performed best compared with the other two datasets. Machine learning method Xgboost generated the highest AUC value of models, which were 0.915, 0.9529, 0.9557, 0.9614 for diagnosing ASCUS higher, ASC-H higher, LSIL higher, and HSIL higher staged cervical lesions, indicating the acceptable accuracy of the selected diagnostic model. CONCLUSIONS: Our study demonstrates that HPV viral load and BV status were significantly associated with the early stages of cervical lesions. The best-performed models can serve as a useful tool to help diagnose cervical lesions early.


Asunto(s)
Infecciones por Papillomavirus , Lesiones Precancerosas , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Femenino , Humanos , Detección Precoz del Cáncer/métodos , Infecciones por Papillomavirus/diagnóstico , Papillomaviridae/genética , Lesiones Precancerosas/diagnóstico , ADN Viral/genética
14.
J Chem Inf Model ; 62(17): 4222-4231, 2022 09 12.
Artículo en Inglés | MEDLINE | ID: mdl-35994329

RESUMEN

K-Ras4B, the most frequently mutated Ras isoform in human tumors, plays a vital part in cell growth, differentiation, and survival. Its tail, the C-terminal hypervariable region (HVR), is involved in anchoring K-Ras4B at the cellular plasma membrane and in isoform-specific protein-protein interactions and signaling. In the inactive guanosine diphosphate-bound state, the intrinsically disordered HVR interacts with the catalytic domain at the effector-binding region, rendering K-Ras4B in its autoinhibited state. Activation releases the HVR from the catalytic domain, with its ensemble favoring an ordered α-helical structure. The large-scale conformational transition of the HVR from the intrinsically disordered to the ordered conformation remains poorly understood. Here, we deploy a computational scheme that integrates a transition path-generation algorithm, extensive molecular dynamics simulation, and Markov state model analysis to investigate the conformational landscape of the HVR transition pathway. Our findings reveal a stepwise pathway for the HVR transition and uncover several key conformational substates along the transition pathway. Importantly, key interactions between the HVR and the catalytic domain are unraveled, highlighting the pathogenesis of K-Ras4B mild mutations in several congenital developmental anomaly syndromes. Together, these findings provide a deeper understanding of the HVR transition mechanism and the regulation of K-Ras4B activity at an atomic level.


Asunto(s)
Simulación de Dinámica Molecular , Proteínas Proto-Oncogénicas p21(ras) , Dominio Catalítico , Membrana Celular/metabolismo , Guanosina Difosfato/química , Guanosina Difosfato/metabolismo , Humanos , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética
15.
J Mol Biol ; 434(17): 167730, 2022 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-35872068

RESUMEN

Allosteric regulation is the most direct and efficient way of regulating protein function, wherein proteins transmit the perturbations at one site to another distinct functional site. Deciphering the mechanism of allosteric regulation is of vital importance for the comprehension of both physiological and pathological events in vivo as well as the rational allosteric drug design. However, it remains challenging to elucidate dominant allosteric signal transduction pathways, especially for large and multi-component protein machineries where long-range allosteric regulation exits. One of the quintessential examples having long-range allosteric regulation is the ternary complex, SPRED1-RAS-neurofibromin type 1 (NF1, a RAS GTPase-activating protein), in which SPRED1 facilitates RAS-GTP hydrolysis by interacting with NF1 at a distal, allosteric site from the RAS binding site. To address the underlying mechanism, we performed extensive Gaussian accelerated molecular dynamics simulations and Markov state model analysis of KRAS-NF1 complex in the presence and absence of SPRED1. Our findings suggested that SPRED1 loading allosterically enhanced KRAS-NF1 binding, but hindered conformational transformation of the NF1 catalytic center for RAS hydrolysis. Moreover, we unveiled the possible allosteric pathways upon SPRED1 binding through difference contact network analysis. This study not only provided an in-depth mechanistic insight into the allosteric regulation of KRAS by SPRED1, but also shed light on the investigation of long-range allosteric regulation among complex macromolecular systems.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Neurofibromina 1 , Proteínas Proto-Oncogénicas p21(ras) , Proteínas Adaptadoras Transductoras de Señales/química , Regulación Alostérica , Humanos , Proteínas de la Membrana/metabolismo , Neurofibromina 1/química , Proteínas Proto-Oncogénicas p21(ras)/química , Proteínas Proto-Oncogénicas p21(ras)/genética
16.
Front Nutr ; 9: 1069911, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36741994

RESUMEN

Background: The risk of maternal gestational diabetes mellitus (GDM) may be influenced by pregnancies conceived through assisted reproductive technology (ART). However, the influence of the dosage of B vitamins (folate, vitamin B6 and vitamin B12) on GDM weren't considered. Thus, we hypothesized that periconceptional B vitamins could modify maternal GDM in singleton pregnancies conceived by ART. Methods: This study is a prospective cohort study using data from 3,252 women with singleton pregnancies and received a 75 g oral glucose tolerance test (OGTT) at 24-28 weeks of gestation. We included an interaction term in the multivariable logistic and linear regression models, respectively, to test our hypothesis. Results: Women who underwent ART were significantly associated with the incidence of GDM compared with spontaneous pregnancy women. The adjusted odds ratio (aOR) was 1.59, and the 95% confidence interval (CI) was 1.08-2.34. ART pregnancies also elevated OGTT (oral glucose tolerance test) 1-h blood glucose levels and OGTT 2-h blood glucose levels (P < 0.05). A positive association between dietary vitamin B6 (aOR = 1.60, 95% CI: 1.13-2.27), dietary vitamin B12 (aOR = 1.88, 95% CI: 1.34-2.64) and dietary folate (aOR = 1.66, 95% CI: 1.19-2.32) with GDM risk comparing the highest to the lowest quartile (all P trend < 0.001). The aORs of GDM for inadequate (< 400 µg/day), adequate (400-800 µg/day), and excessive (> 800 µg/day) supplemental folate intake were 1.00, 0.93, and 1.30, respectively (P trend = 0.033). Since only the supplemental folate illustrates a statistically significant interaction with ART (P for interaction < 0.05), the association between ART and GDM and OGTT blood glucose levels stratifying by supplemental folate were further evaluated. These increased risks of GDM (aOR = 1.62, 95% CI: 1.39-3.39) and the regression coefficients (ß) of 1-h blood glucose (ß = 0.76, 95% CI: 0.39-1.13) and 2-h blood glucose (ß = 0.60, 95% CI: 0.29-0.92) in the multiple linear regression model were significant only in the ART group with excessive supplemental folate (> 800 µg/day). Conclusion: The risk of GDM is significantly elevated, particularly among those women who conceived ART with the intake of excessive supplemental folate (> 800 µg/day).

18.
ACS Omega ; 6(25): 16410-16418, 2021 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-34235312

RESUMEN

Green and environment-friendly high-efficiency flame retardants (FRs) are crucial to polymer FR modification. Here, a green FR 2-((bis(2-hydroxyethyl)amino)methyl)-5,5-dimethyl-1,3,2-dioxaphosphinane 2-oxide (HAMPP) was synthesized. The HAMPP was incorporated with a cyclic phosphorus structure, which will readily carbonize to inhibit or prevent further combustion. Moreover, the HAMPP contains dihydroxy reactive groups that can be used as a monomer in the polymerization reaction to obtain the main chain containing phosphorus polymer. Research studies on FRs were based on flexible polyurethane foam (PU-HAMPPs). The limiting oxygen index value of PU foam with 10% HAMPP could reach 23.7%, passing a UL-94 V-0 rating together. With the addition of HAMPP, the peak heat release rate of PU foam decreased significantly, the decomposition temperature increased, the heat release capacity reduced by 31%, and the char yield increased by 42%. The chemical composition and morphology of the char residual have been studied and analyzed thoroughly. We find that HAMPP forms a molten viscous protective layer uniformly on the material surface and releases some incombustible gases. These indicated that the FR exploited both condensed-phase and gas-phase flame retardancy mechanisms. Besides, the addition of FRs improved the mechanical properties.

19.
BMC Pregnancy Childbirth ; 21(1): 262, 2021 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-33784999

RESUMEN

BACKGROUND: Gestational diabetes mellitus (GDM) has become alarming public health concern. It is associated with adverse pregnancy outcomes and increased risk of postpartum type 2 diabetes. Pre-pregnant body mass index (BMI), waist circumference and other anthropometric parameters have been proposed to predict GDM. However, visceral fat thickness can better reflect the distribution of body fat, and may more accurately predict the risk of GDM. Visceral fat thickness may lead to insulin resistance by regulating the adipose-derived exosomes miRNA-148 family, which affect the development of GDM. Evidence from prospective cohort studies on visceral fat thickness as a predictor of GDM and the possible mechanisms is still insufficient. METHODS: In this prospective cohort study, we will recruit 3000 women at first antenatal visit between 4 and 12 weeks of gestation. Baseline socio-demographic factors and visceral fat thickness will be assessed by questionnaire form and the ultrasonic measurement, respectively. At 20 weeks of gestation, 10 ml blood samples will be drawn and we will extract adipose-derived exosomes miRNA on the basis of nested case-control study. GDM will be screened at 24-28 weeks' gestation and the expression of miRNA-148 family between pregnant women with GDM and without GDM will be analyzed. Intermediary analysis will be used to investigate whether visceral fat thickness can predict GDM by regulating adipose-derived exosomes miRNA-148 family. DISCUSSION: We hypothesized that visceral fat thickness may predict GDM by regulating the miRNA-148 family of adipose-derived exosomes. The findings of the study will assist in further clarifying the pathophysiological mechanism of GDM, it will also provide technical support for effective screening of high-risk pregnant women with GDM.


Asunto(s)
Adiposidad , Diabetes Gestacional/epidemiología , Grasa Intraabdominal/diagnóstico por imagen , MicroARNs/sangre , Adulto , Glucemia/análisis , Estudios de Casos y Controles , Diabetes Gestacional/sangre , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/genética , Exosomas/metabolismo , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Incidencia , Grasa Intraabdominal/metabolismo , MicroARNs/metabolismo , Estudios Observacionales como Asunto , Embarazo , Segundo Trimestre del Embarazo , Estudios Prospectivos , Medición de Riesgo/métodos , Factores de Riesgo , Ultrasonografía , Circunferencia de la Cintura , Adulto Joven
20.
ACS Appl Mater Interfaces ; 12(52): 58212-58222, 2020 Dec 30.
Artículo en Inglés | MEDLINE | ID: mdl-33319989

RESUMEN

A mechanical disintegration of waste wood biomass and freeze-induced assembly of colloidal nanowood were effectively deployed to explore ion-associated cellular foams (NWFs) with unidirectional channels. Under the assistance of inorganic ions, the as-fabricated foams were significantly enhanced in physical stability, compressive strength, flame retardancy, and thermal barrier, accounting for the tuning effects of pores and channels, surface charges, and microphase interaction by ion effects and freeze orientation. As a result, the vascular-like ion-doped channels benefited from quick capillary liquid transport. Under 1 sun illumination, NWF-V as a 3-D evaporator exhibited a high evaporation rate of 1.50 kg m-2 h-1 and a conversion efficiency of up to 88.9% for seawater desalination. Dramatically, an average of 12.5 kg m-2 of fresh water could be generated on each sunny day by outdoor NWFs for durability beyond 15 days. Under the drive of fuel combustion, an efficient conveying of ethanol or pump oil could be at rates of 0.44 and 0.26 mL min-1, respectively. Moreover, combustion flame with variable color was generated according to the doping cations in NWFs. Therefore, sustainable, green, facile, and multifunctional wood-based cellular foams could be tailored, scaled-up, and applied as color flame burners or desalination evaporators under combustion or solar drive in the energy and environment fields.

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