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1.
Fetal Pediatr Pathol ; : 1-10, 2024 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-39105619

RESUMEN

OBJECTIVE: NeoBase 2 Non-derivatized MSMS assay kit (NeoBase 2 kit) was used for newborn screening, the performance of the NeoBase 2 kit should be validated before its implementation in clinical diagnostic laboratories. METHODS: Leftover dried blood spot samples, quality control materials in the NeoBase 2 kit, and proficiency testing materials received from the NSQAP were used. Precision, accuracy, LOD, LLOQ, recovery, and stability were carried out to verify the performance of the Waters ACQUITY TQD MS/MS system with the NeoBase 2 kit for newborn screening. Cutoffs were determined and analytes requiring different cutoffs in preterm neonates were investigated. RESULTS: Within-run and between-run precisions ranged from 3.95% to 14.41%. The accuracy and stability were within 15%. All analytes demonstrated acceptable LOD, LLOQ, and recoveries. Cutoffs for term and preterm neonates were established. CONCLUSIONS: The performance of the NeoBase 2 kit is acceptable and can be implemented in clinical diagnostic laboratories.

2.
Int Orthop ; 2024 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-39012414

RESUMEN

PURPOSE: Robot-assisted total hip arthroplasty (RA-THA) helps with precise orientation of the prosthesis, but some RA-THA procedures are aborted intraoperatively and are converted to manual total hip arthroplasty (THA). This study aimed to analyse why RA-THA is sometimes aborted intraoperatively and to make recommendations accordingly. METHODS: A total of 429 consecutive Mako THA cases in our prospective database from August 2018 to June 2021 were included in our study. All robotic procedures aborted intraoperatively for any reason were recorded. The patients' demographics, diagnoses, and surgeons' information were included in the statistical analysis to pinpoint the risk factors for intraoperative robot to manual conversion. RESULTS: Intraoperative RA-THA abortions occurred in 17 cases (3.96%) and the patients had to be converted to manual THA. The adverse events leading to intraoperative abortions included pelvic array loosening or malposition (5, 1.17%), inaccurate bone mapping or construction (6, 1.40%), inaccurate initial registration (4, 0.93%), and other reasons (2, 0.47%). CONCLUSION: Robot-related adverse events could be found in all perioperative steps of RA-THA, and some of these events might result in intraoperative abortion. Complex hip disease was a statistically significant factor for an increased risk of intraoperative abortion of RA-THA. Standardized surgical procedures and preoperative assessments can be helpful in reducing the rate of RA-THA abortions.

3.
Brief Bioinform ; 25(4)2024 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-38960407

RESUMEN

The optimization of therapeutic antibodies through traditional techniques, such as candidate screening via hybridoma or phage display, is resource-intensive and time-consuming. In recent years, computational and artificial intelligence-based methods have been actively developed to accelerate and improve the development of therapeutic antibodies. In this study, we developed an end-to-end sequence-based deep learning model, termed AttABseq, for the predictions of the antigen-antibody binding affinity changes connected with antibody mutations. AttABseq is a highly efficient and generic attention-based model by utilizing diverse antigen-antibody complex sequences as the input to predict the binding affinity changes of residue mutations. The assessment on the three benchmark datasets illustrates that AttABseq is 120% more accurate than other sequence-based models in terms of the Pearson correlation coefficient between the predicted and experimental binding affinity changes. Moreover, AttABseq also either outperforms or competes favorably with the structure-based approaches. Furthermore, AttABseq consistently demonstrates robust predictive capabilities across a diverse array of conditions, underscoring its remarkable capacity for generalization across a wide spectrum of antigen-antibody complexes. It imposes no constraints on the quantity of altered residues, rendering it particularly applicable in scenarios where crystallographic structures remain unavailable. The attention-based interpretability analysis indicates that the causal effects of point mutations on antibody-antigen binding affinity changes can be visualized at the residue level, which might assist automated antibody sequence optimization. We believe that AttABseq provides a fiercely competitive answer to therapeutic antibody optimization.


Asunto(s)
Complejo Antígeno-Anticuerpo , Aprendizaje Profundo , Complejo Antígeno-Anticuerpo/química , Antígenos/química , Antígenos/genética , Antígenos/metabolismo , Antígenos/inmunología , Afinidad de Anticuerpos , Secuencia de Aminoácidos , Biología Computacional/métodos , Humanos , Mutación , Anticuerpos/química , Anticuerpos/inmunología , Anticuerpos/genética , Anticuerpos/metabolismo
4.
Angew Chem Int Ed Engl ; : e202411236, 2024 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-39045910

RESUMEN

Visible light-driven photocatalytic deracemization is highly esteemed as an ideal tool for organic synthesis due to its exceptional atom economy and synthetic efficiency. Consequently, successful instances of deracemization of allenes have been established, where the activated energy of photosensitizer should surpass that of the substrates, representing an intrinsic requirement. Accordingly, this method is not applicable for axially chiral molecules with significantly high triplet energies. In this study, we present a photoredox catalytic deracemization approach that enables the efficient synthesis of valuable yet challenging-to-access axially chiral 2-azaarene-functionalized quinazolinones. The substrate scope is extensive, allowing for both 3-axis and unmet 1-axis assembly through facile oxidation of diverse central chiral 2,3-dihydroquinazolin-4(1H)-ones that can be easily prepared and achieve enantiomer enrichment via deracemization. Mechanistic studies reveal the importance of photosensitizer selection in attaining excellent chemoselectivity and highlight the indispensability of a chiral Brønsted acid in enabling highly enantioselective protonation to accomplish efficient deracemization.

5.
J Control Release ; 373: 216-223, 2024 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-39002797

RESUMEN

Platinum(II)-based drugs (PtII), which hinder DNA replication, are the most widely used chemotherapeutics. However, current PtII drugs often miss their DNA targets, leading to severe side effects and drug resistance. To overcome this challenge, we developed a oxaliplatin-based platinum(IV) (PtIV) prodrug amphiphile (C16-OPtIV-R8K), integrating a long-chain hydrophobic lipid and a nucleus-targeting hydrophilic peptide (R8K). This design allows the prodrug to self-assemble into highly uniform lipid nanoparticles (NTPtIV) for enhanced targeting chemotherapy and immunotherapy. Subsequently, NTPtIV's bioactivity and effects were examined at diverse levels, encompassing cancer cells, 3D tumor spheres, and in vivo. Our in vitro studies show a 74% cancer cell nucleus localization of platinum drugs-3.6 times higher than that of oxaliplatin, achieving more than a ten-fold increase in eliminating drug-resistant cancer cells. In vivo, NTPtIV shows efficient tumor accumulation, leading to suppressed tumor growth of murine breast cancer. Moreover, NTPtIV recruited more CD4+ and CD8+ T cells and reduced CD4+ Foxp3+ Tregs to synergistically enhance targeted chemotherapy and immunotherapy. Overall, this strategy presents a promising advancement in nucleus-targeted cancer therapy, synergistically boosting the efficacy of chemotherapy and immunotherapy.

6.
Adv Sci (Weinh) ; : e2404545, 2024 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-39041942

RESUMEN

Microbial tryptophan (Trp) metabolites acting as aryl hydrocarbon receptor (AhR) ligands are shown to effectively improve metabolic diseases via regulating microbial community. However, the underlying mechanisms by which Trp metabolites ameliorate bone loss via gut-bone crosstalk are largely unknown. In this study, supplementation with Trp metabolites, indole acetic acid (IAA), and indole-3-propionic acid (IPA), markedly ameliorate bone loss by repairing intestinal barrier integrity in ovariectomy (OVX)-induced postmenopausal osteoporosis mice in an AhR-dependent manner. Mechanistically, intestinal AhR activation by Trp metabolites, especially IAA, effectively repairs intestinal barrier function by stimulating Wnt/ß-catenin signaling pathway. Consequently, enhanced M2 macrophage by supplementation with IAA and IPA secrete large amount of IL-10 that expands from intestinal lamina propria to bone marrow, thereby simultaneously promoting osteoblastogenesis and inhibiting osteoclastogenesis in vivo and in vitro. Interestingly, supplementation with Trp metabolites exhibit negligible ameliorative effects on both gut homeostasis and bone loss of OVX mice with intestinal AhR knockout (VillinCreAhrfl/fl). These findings suggest that microbial Trp metabolites may be potential therapeutic candidates against osteoporosis via regulating AhR-mediated gut-bone axis.

7.
Adv Mater ; : e2406815, 2024 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-39081102

RESUMEN

Dinuclear iridium(III) complexes activated by light-inducible spatiotemporal control are emerging as promising candidates for cancer therapy. However, broader applications of current light-activated dinuclear iridium(III) complexes are limited by the ineffective tissue penetration and undesirable feedback on guidance activation. Here, an ultrasound (US) triggered near infrared-fluorescent dinuclear iridium(III) nanoparticle, NanoIr, is first reported to precisely and spatiotemporally inhibit tumor growth. It is demonstrated that reactive oxygen species can be generated by NanoIr upon exposure to US irradiation (NanoIr + US), thereby inducing immunogenic cell death. When combined with cisplatin, NanoIr + US elicits synergistic effects in patient-derived tumor xenograft mice models of ovarian cancer. This work first provides a design of dinuclear iridium(III) nanoparticles for immunogenic sonodynamic therapy.

8.
Front Neurosci ; 18: 1378844, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39071180

RESUMEN

Acute large hemispheric infarction (ALHI) is an overwhelming emergency with a great challenge of gastrointestinal dysfunction clinically. Here, we initially proposed delayed bowel movements as the clinical phenotype of strike to gut-brain axis (GBA) in ALHI patients by epidemiological analysis of 499 acute ischemic stroke (AIS) patients. 1H NMR-based metabolomics revealed that AIS markedly altered plasma global metabolic profiling of patients compared with healthy controls. Risk factors of strike on GBA were the National Institutes of Health Stroke Scale (NIHSS) score ≥ 5 and stroke onset time ≤ 24 h. As a result, first defecating time after admission to the hospital ≥2 days could be considered as a potential risk factor for strike on GBA. Subsequently, the ALHI Bama miniature (BM) pig model with acute symptomatic seizure was successfully established by ligation of the left ascending pharyngeal artery combined with local air injection. Clinical phenotypes of brain necrosis such as hemiplegia were examined with brain diffusion-weighted imaging (DWI) and pathological diagnosis. In addition to global brain injury and inflammation, we also found that ALHI induced marked alterations of intestinal barrier integrity, the gut microbial community, and microbiota-derived metabolites including serotonin and neurotransmitters in both plasma and multiple brain tissues of BM pigs. These findings revealed that microbiota-gut-brain axis highly contributed to the occurrence and development of ALHI.

9.
J Hazard Mater ; 476: 135091, 2024 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-38959828

RESUMEN

The relative severity between chromium (Cr)-mediated ecotoxicity and its bioaccumulation has rarely been compared and evaluated. This study employed pot incubation experiments to simulate the soil environment with increased Cr pollution and study their effects on the growth of crops, including pepper, lettuce, wheat, and rice. Results showed that increasing total Cr presented ascendant ecotoxicity in upland soils when pH > 7.5, and significantly reduced the yield of pepper, lettuce and wheat grain by 0.3-100 %, whereas, this effect was weakened even reversed as the pH decreased. Surprisingly, a series of soils with Cr concentration of 22.7-623.5 mg kg-1 did not cause Cr accumulation in four crops over the Chinese permissible limit. The toxicity of Cr was highly associated with extractable Cr, where Cr (VI) made the greater contributions than Cr (III). Conclusively, the ecotoxicity of Cr poses a greater environmental issue as compared to the bioaccumulation of Cr in crops in upland soils, while extractable Cr (VI) makes the predominant contributions to the ecotoxicity of Cr as the total Cr increased. Our study proposes a synchronous consideration involving total Cr and Cr (VI) as the theoretical basis to establish a more reliable soil quality standard for safe production in China.


Asunto(s)
Cromo , Productos Agrícolas , Contaminantes del Suelo , Cromo/toxicidad , Contaminantes del Suelo/toxicidad , Productos Agrícolas/crecimiento & desarrollo , Productos Agrícolas/efectos de los fármacos , Productos Agrícolas/metabolismo , Agricultura , Suelo/química , China
10.
Cell Signal ; 121: 111287, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38969191

RESUMEN

The progression of osteoarthritis (OA) includes the initial inflammation, subsequent degradation of the extracellular matrix (ECM), and chondrocyte apoptosis. Down syndrome candidate region 1 (DSCR1) is a stress-responsive gene and expresses in varied types of cells, including chondrocytes. Bioinformatics analysis of GSE103416 and GSE104739 datasets showed higher DSCR1 expression in the inflamed cartilage tissues and chondrocytes of OA. DSCR1 had two major isoforms, isoform 1 (DSCR1-1) and isoform 4 (DSCR1-4). We found that DSCR1-1 had a faster (in vitro) and higher expression (in vivo) response to OA compared to DSCR1-4. IL-1ß-induced apoptosis, inflammation, and ECM degradation in chondrocytes were attenuated by DSCR1-1 overexpression. DSCR1-1 triggered the phosphorylation of cAMP response element-binding 1 (CREB1) at 133 serine sites by decreasing calcineurin activity. Moreover, activated CREB1 moved into the cell nucleus and combined in the promoter regions of aldehyde dehydrogenase 2 (ALDH2), thus enhancing its gene transcription. ALDH2 could recover Wnt/ß-catenin signaling transduction by enhancing phosphorylation of ß-catenin at 33/37 serine sites and inhibiting the migration of ß-catenin protein from the cellular matrix to the nucleus. In vivo, adenoviruses (1 × 108 PFU) overexpressing DSCR1-1 were injected into the articular cavity of C57BL/6 mice with medial meniscus surgery-induced OA, and it showed that DSCR1-1 overexpression ameliorated cartilage injury. Collectively, our study demonstrates that DSCR1-1 may be a potential therapeutic target of OA.


Asunto(s)
Condrocitos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Osteoartritis , Vía de Señalización Wnt , Condrocitos/metabolismo , Animales , Osteoartritis/metabolismo , Osteoartritis/patología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Humanos , Ratones , Aldehído Deshidrogenasa Mitocondrial/metabolismo , Aldehído Deshidrogenasa Mitocondrial/genética , beta Catenina/metabolismo , Masculino , Ratones Endogámicos C57BL , Apoptosis/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética
11.
Front Cardiovasc Med ; 11: 1374241, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38841257

RESUMEN

Hereditary transthyretin amyloid (ATTRv) cardiomyopathy (CM) is caused by mutations in the TTR gene. TTR mutations contribute to TTR tetramer destabilization and dissociation, leading to excessive deposition of insoluble amyloid fibrils in the myocardium and finally resulting in cardiac dysfunction. In this article, we report a case of a Chinese patient with transthyretin mutation p.D58Y and provide detailed information on cardiac amyloidosis, including transthoracic echocardiography, cardiac magnetic resonance, and SPECT imaging for the first time. Our report aims to provide a better understanding of ATTR genotypes and phenotypes.

12.
Adv Sci (Weinh) ; : e2404375, 2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38889339

RESUMEN

In the treatment of uveal melanoma (UVM), histone deacetylase inhibitors (HDACi) have emerged as a promising epigenetic therapy. However, their clinical efficacy is hindered by the suboptimal pharmacokinetics and the strong self-rescue of tumor cells. To overcome these limitations, reactive oxygen species (ROS)-responsive nanoparticles (NPs) are designed that encapsulate HDACi MS-275 and the glutamine metabolism inhibitor V-9302. Upon reaching the tumor microenvironment, these NPs can disintegrate, thereby releasing MS-275 to increase the level of ROS and V-9302 to reduce the production of glutathione (GSH) related to self-rescue. These synergistic effects lead to a lethal ROS storm and induce cell pyroptosis. When combined with programmed cell death protein 1 monoclonal antibodies (α-PD-1), these NPs facilitate immune cell infiltration, improving anti-tumor immunity, converting "immune-cold" tumors into "immune-hot" tumors, and enhancing immune memory in mice. The findings present a nano-delivery strategy for the co-delivery of epigenetic therapeutics and metabolic inhibitors, which induces pyroptosis in tumors cells and improves the effectiveness of chemotherapy and immunotherapy.

13.
Adv Mater ; : e2403116, 2024 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-38819929

RESUMEN

Protein therapeutics offer high therapeutic potency and specificity; the broader adoptions and development of protein therapeutics, however, have been constricted by their intrinsic limitations such as inadequate stability, immunogenicity, suboptimal pharmacokinetics and biodistribution, and off-target effects. This review describes a platform technology that formulates individual protein molecules with a thin formulation layer of crosslinked polymers, which confers the protein therapeutics with high activity, enhanced stability, controlled release capability, reduced immunogenicity, improved pharmacokinetics and biodistribution, and ability to cross the blood brain barriers. Based on currently approved protein therapeutics, this formulating platform affords the development of a vast family of superior protein therapeutics with improved efficacy and broadened indications at significantly reduced cost.

14.
Kaohsiung J Med Sci ; 40(7): 660-670, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38801488

RESUMEN

Bladder cancer (BC) poses high morbidity and mortality, with urinary exosomal microRNA (miR)-21 showing potential value in its diagnosis and prognosis, and we probed its specific role. We prospectively selected 116 BC patients and 116 healthy volunteers as the BC and control groups, respectively. BC urinary exosomal miR-146a-5p, miR-93-5p, miR-663b, miR-21, and miR-4454 relative expression levels were assessed. The correlations between clinical indexes and urinary exosomal miR-21, prognostic value of miR-21, and diagnostic value of the five candidate miRNAs, urine cytology, and miRNA joint diagnostic panel for BC and urinary exosomal miR-21, miR-4454, and urine cytology for Ta-T1 and T2-T4 stage BC were analyzed. Urinary exosomal miR-146a-5p, miR-93-5p, miR-663b, miR-21, and miR-4454 were highly expressed in BC patients. miR-146a-5p, miR-93-5p, miR-663b, miR-21, miR-4454, miRNA combined diagnostic panel, and urine cytology had certain diagnostic value for BC, with miR-21, miR-4454, and miRNA co-diagnostic panel showing the highest diagnostic value. Collectively, urinary exosomal miR-21 was closely related to Tumor-Node-Metastasis staging and grading in BC patients. Urinary exosomal miR-21 had high diagnostic value for BC and Ta-T1 and T2-T4 stage BC, and had high predictive value for BC poor prognosis, providing an effective indicator for the occurrence, development, and prognostic assessment of BC.


Asunto(s)
Exosomas , MicroARNs , Neoplasias de la Vejiga Urinaria , Humanos , MicroARNs/orina , MicroARNs/genética , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/orina , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Femenino , Exosomas/genética , Exosomas/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Anciano , Biomarcadores de Tumor/orina , Biomarcadores de Tumor/genética , Detección Precoz del Cáncer , Regulación Neoplásica de la Expresión Génica , Estudios de Casos y Controles , Estadificación de Neoplasias
15.
J Clin Nurs ; 2024 May 26.
Artículo en Inglés | MEDLINE | ID: mdl-38797951

RESUMEN

OBJECTIVE: The objective of this study was to construct and validate a structural equation model (SEM) to identify factors associated with sleep quality in awake patients in the intensive care unit (ICU) and to assist in the development of clinical intervention strategies. RESEARCH METHODS/SETTING: In this cross-sectional study, 200 awake patients who were cared for in the ICU of a tertiary hospital in China were surveyed via several self-report questionnaires and wearable actigraphy sleep monitoring devices. Based on the collected data, structural equation modelling analysis was performed using SPSS and AMOS statistical analysis software. The study is reported using the STROBE checklist. RESULTS: The fit indices of the SEM were acceptable: χ2/df = 1.676 (p < .001) and RMSEA = .058 (p < 0.080). Anxiety/depression had a direct negative effect on the sleep quality of awake patients cared for in the ICU (ß = -.440, p < .001). In addition, disease-freeness progress had an indirect negative effect on the sleep quality of awake patients cared for in the ICU (ß = -.142, p < .001). Analgesics had an indirect negative effect on the sleep quality of awake patients cared for in the ICU through pain and sedatives (ß = -.082, p < .001). Sedation had a direct positive effect on the sleep quality of conscious patients cared for in the ICU (ß = .493; p < .001). CONCLUSION: The results of the SEM showed that the sleep quality of awake patients cared for in the ICU is mainly affected by psychological and disease-related factors, especially anxiety, depression and pain, so we can improve the sleep quality of patients through psychological intervention and drug intervention.

16.
World J Gastrointest Surg ; 16(5): 1363-1370, 2024 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-38817273

RESUMEN

BACKGROUND: A comprehensive understanding of the extrahepatic bile duct anatomy is vital to guide surgical procedures and perform endoscopic retrograde cholangiography. Anatomical irregularities within the extrahepatic bile duct may increase susceptibility to bile duct stones. AIM: To investigate the anatomical risk factors associated with extrahepatic bile ducts in patients diagnosed with choledocholithiasis, with a specific focus on preventing stone recurrence after surgical intervention and endoscopic lithotomy. METHODS: We retrospectively analyzed the medical records of 124 patients without choledocholithiasis and 108 with confirmed choledocholithiasis who underwent magnetic resonance cholangiopancreatography examinations at our center between January 2022 and October 2022. Logistic regression analyses were conducted to identify the anatomical risk factors influencing the incidence of common bile duct stones. RESULTS: Multivariate logistic regression analysis revealed that several factors independently contributed to choledocholithiasis risk. Significant independent risk factors for choledocholithiasis were diameter of the common hepatic [adjusted odds ratio (aOR) = 1.43, 95% confidence interval (CI): 1.07-1.92, adjusted P value = 0.016] and common bile (aOR = 1.68, 95%CI: 1.27-2.23, adjusted P value < 0.001) ducts, length of the common hepatic duct (aOR = 0.92, 95%CI: 0.84-0.99, adjusted P value = 0.034), and angle of the common bile duct (aOR = 0.92, 95%CI: 0.89-0.95, adjusted P value < 0.001). CONCLUSION: The anatomical features of the extrahepatic bile duct were directly associated with choledocholithiasis risk. Key risk factors include an enlarged diameter of the common hepatic and bile ducts, a shorter length of the common hepatic duct, and a reduced angle of the common bile duct.

18.
Biochim Biophys Acta Biomembr ; 1866(5): 184325, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38653423

RESUMEN

Helical membrane proteins generally have a hydrophobic nature, with apolar side chains comprising the majority of the transmembrane (TM) helices. However, whenever polar side chains are present in the TM domain, they often exert a crucial role in structural interactions with other polar residues, such as TM helix associations and oligomerization. Moreover, polar residues in the TM region also often participate in protein functions, such as the Schiff base bonding between Lys residues and retinal in rhodopsin-like membrane proteins. Although many studies have focused on these functional polar residues, our understanding of stand-alone polar residues that are energetically unfavored in TM helixes is limited. Here, we adopted bacteriorhodopsin (bR) as a model system and systematically mutated 17 of its apolar Leu or Phe residues to polar Asn. Stability measurements of the resulting mutants revealed that all of these polar substitutions reduced bR stability to various extents, and the extent of destabilization of each mutant bR is also correlated to different structural factors, such as the relative accessible surface area and membrane depth of the mutation site. Structural analyses of these Asn residues revealed that they form sidechain-to-backbone hydrogen bonds that alleviate the unfavorable energetics in hydrophobic and apolar surroundings. Our results indicate that membrane proteins are able to accommodate certain stand-alone polar residues in the TM region without disrupting overall structures.


Asunto(s)
Bacteriorodopsinas , Interacciones Hidrofóbicas e Hidrofílicas , Estabilidad Proteica , Bacteriorodopsinas/química , Bacteriorodopsinas/genética , Bacteriorodopsinas/metabolismo , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Mutación , Estructura Secundaria de Proteína , Halobacterium salinarum/química , Halobacterium salinarum/genética , Halobacterium salinarum/metabolismo , Modelos Moleculares
19.
J Psychiatr Res ; 174: 172-180, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38640796

RESUMEN

Growing evidence suggested that individuals with autism spectrum disorder (ASD) associated with stroke and cardiovascular disease (CVD). However, the causal association between ASD and the risk of stroke and CVD remains unclear. To validate this, we performed two-sample Mendelian randomization (MR) and two-step mediation MR analyses, using relevant genetic variants sourced from the largest genome-wide association studies (GWASs). Two-sample MR evidence indicated causal relationships between ASD and any stroke (OR = 1.1184, 95% CI: 1.0302-1.2142, P < 0.01), ischemic stroke (IS) (OR = 1.1157, 95% CI: 1.0237-1.2160, P = 0.01), large-artery atherosclerotic stroke (LAS) (OR = 1.2902, 95% CI: 1.0395-1.6013, P = 0.02), atrial fibrillation (AF) (OR = 1.0820, 95% CI: 1.0019-1.1684, P = 0.04), and heart failure (HF) (OR = 1.1018, 95% CI: 1.0007-1.2132, P = 0.05). Additionally, two-step mediation MR suggested that type 2 diabetes mellitus (T2DM) partially mediated this effect (OR = 1.14, 95%CI: 1.02-1.28, P = 0.03). The mediated proportion were 10.96% (95% CI: 0.58%-12.10%) for any stroke, 11.77% (95% CI: 10.58%-12.97%) for IS, 10.62% (95% CI: 8.04%-13.20%) for LAS, and 7.57% (95% CI: 6.79%-8.36%) for HF. However, no mediated effect was observed between ASD and AF risk. These findings have implications for the development of prevention strategies and interventions for stroke and CVD in patients with ASD.


Asunto(s)
Trastorno del Espectro Autista , Enfermedades Cardiovasculares , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Accidente Cerebrovascular , Humanos , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/epidemiología , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/epidemiología , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/epidemiología , Predisposición Genética a la Enfermedad
20.
Int J Mol Sci ; 25(7)2024 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-38612682

RESUMEN

Squalene epoxidase (SQLE) is a key enzyme in the mevalonate-cholesterol pathway that plays a critical role in cellular physiological processes. It converts squalene to 2,3-epoxysqualene and catalyzes the first oxygenation step in the pathway. Recently, intensive efforts have been made to extend the current knowledge of SQLE in cancers through functional and mechanistic studies. However, the underlying mechanisms and the role of SQLE in cancers have not been fully elucidated yet. In this review, we retrospected current knowledge of SQLE as a rate-limiting enzyme in the mevalonate-cholesterol pathway, while shedding light on its potential as a diagnostic and prognostic marker, and revealed its therapeutic values in cancers. We showed that SQLE is regulated at different levels and is involved in the crosstalk with iron-dependent cell death. Particularly, we systemically reviewed the research findings on the role of SQLE in different cancers. Finally, we discussed the therapeutic implications of SQLE inhibitors and summarized their potential clinical values. Overall, this review discussed the multifaceted mechanisms that involve SQLE to present a vivid panorama of SQLE in cancers.


Asunto(s)
Neoplasias , Escualeno-Monooxigenasa , Humanos , Muerte Celular , Colesterol , Ácido Mevalónico , Neoplasias/genética , Escualeno-Monooxigenasa/genética
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