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1.
Water Res ; 228(Pt A): 119359, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36423548

RESUMO

Antibiotic resistance genes (ARGs) in drinking water sources suggest the possible presence of resistant microorganisms that jeopardize human health. However, explanations for the presence of specific ARGs in situ are largely unknown, especially how their prevalence is affected by local microbial ecology, taxa assembly and community-wide gene transfer. Here, we characterized resistomes and bacterial communities in the Taipu River catchment, which feeds a key drinking water reservoir to a global megacity, Shanghai. Overall, ARG abundances decreased significantly as the river flowed downstream towards the reservoir (P < 0.01), whereas the waterborne bacteria assembled deterministically (|ßNRI| > 2.0) as a function of temperature and dissolved oxygen conditions with the assembly-dominant taxa (e.g. Ilumatobacteraceae and Cyanobiaceae) defining local resistomes (P < 0.01, Cohen's D = 4.22). Bacterial hosts of intragenomic ARGs stayed at the same level across the catchment (60 ∼ 70 genome copies per million reads). Among them, the putative resistant pathogens (e.g. Burkholderiaceae) carried mixtures of ARGs that exhibited high transmission probability (transfer counts = 126, P < 0.001), especially with the microbial assembly-dominant taxa. These putative resistant pathogens had densities ranging form 3.0 to 4.0 × 106 cell/L, which was more pronouncedly affected by resistome and microbial assembly structures than environmental factors (SEM, std-coeff ß = 0.62 vs. 0.12). This work shows that microbial assembly and resistant pathogens play predominant roles in prevelance and dissemination of resistomes in receiving water, which deserves greater attention in devisng control strategies for reducing in-situ ARGs and resistant strains in a catchment.

2.
J Colloid Interface Sci ; 631(Pt B): 135-146, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36399806

RESUMO

The zinc (Zn) dendrite accumulation leads to poor Coulombic efficiency, continuously failing life and severe safety risks, which seriously impede the commercial application of Zn ion capacitors (ZICs). Herein, an interface engineering is proposed for the Zn metal anode to restrain the dendrite by using porous flame reduced graphene oxide (FRGO) as the ex-situ protective and regulated layer to induce the Zn crystal growth and restricts the side reactions. The FRGO possesses extensive nanoscale pores and zincophilic oxygen-containing functional groups, which can absorb Zn2+ and nucleate preferentially on the surface of FRGO, then induce the growth of Zn parallel to the graphene sheet by matching the basal (002) plane of metallic Zn to minimize lattice strain. As a result, it eliminates the tip effect and achieves the deposited Zn with a uniform and flat surface. Therefore, The FRGO on the Zn (FRGO@Zn) anode significantly reduces the nucleation overpotential and improves the cycling life during the plating/stripping process. Notably, FRGO@Zn based ZIC can achieve 91.0% capacity retention after more than 20,000 cycles at 5 A g-1, and its capacity and maximum energy density are 150.6 mAh g-1 and 118.8 Wh kg-1, respectively. This interface engineering of FRGO for the Zn metal anode has excellent application potential and theoretical guidance in the ZICs field.

3.
Front Endocrinol (Lausanne) ; 13: 993253, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36452325

RESUMO

Osteoporosis (OP) is a systemic disease characterized by bone metabolism imbalance and bone microstructure destruction, which causes serious social and economic burden. At present, the diagnosis and treatment of OP mainly rely on imaging combined with drugs. However, the existing pathogenic mechanisms, diagnosis and treatment strategies for OP are not clear and effective enough, and the disease progression that cannot reflect OP further restricts its effective treatment. The application of metabolomics has facilitated the study of OP, further exploring the mechanism and behavior of bone cells, prevention, and treatment of the disease from various metabolic perspectives, finally realizing the possibility of a holistic approach. In this review, we focus on the application of metabolomics in OP research, especially the newer systematic application of metabolomics and treatment with herbal medicine and their extracts. In addition, the prospects of clinical transformation in related fields are also discussed. The aim of this study is to highlight the use of metabolomics in OP research, especially in exploring the pathogenesis of OP and the therapeutic mechanisms of natural herbal medicine, for the benefit of interdisciplinary researchers including clinicians, biologists, and materials engineers.


Assuntos
Metabolômica , Osteoporose , Humanos , Osteoporose/diagnóstico , Osteoporose/tratamento farmacológico , Osteócitos , Fitoterapia , Progressão da Doença
4.
Adv Healthc Mater ; : e2201708, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36455286

RESUMO

The intricate biochemical functionalities of cellular membranes have inspired numerous strategies for deriving and anchoring cell-surface components onto solid substrates for biological studies, biosensor applications, and tissue engineering. However, introducing conformal and right-side-out cell membrane coverage onto planar substrates requires cumbersome multi-step protocols that can be limited by significant device-to-device variability. Here, we demonstrate a facile approach for biomembrane functionalization of planar substrates by subjecting confluent cellular monolayer to intracellular hydrogel polymerization. The resulting cell-gel hybrid, herein termed GELL, exhibits extraordinary stability and retains the structural integrity, membrane fluidity, membrane protein mobility, and topology of living cells. In assessing the utility of GELL layers as a tissue engineering feeder substrate for stem cell maintenance, GELL feeder prepared from primary mouse embryonic fibroblasts (MEFs) not only preserves stemness of murine stem cells but also exhibits advantages over live feeder cells owing to the GELL's inanimate, non-metabolizing nature. Leveraging the versatility of the intracellular gelation approach, we further show the preparation of xeno-free feeder substrate devoid of non-human components with HeLa cells. With the hydrogelation process eliminating the safety and contamination concerns of the immortalized cells, the inanimate HeLa GELL feeder layer effectively sustains the growth and stemness of both murine and human induced pluripotent stem cells (iPSCs). The study highlights a novel bio-functionalization strategy that introduces new opportunities for tissue engineering and other biomedical applications. This article is protected by copyright. All rights reserved.

5.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 40(6): 619-628, 2022 Dec 01.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-36416313

RESUMO

Immune checkpoint inhibitors (ICIs) present significant efficacy in the treatment of malignant tumors, and they have been approved as the first-line of treatment for various cancers. Pembrolizumab monotherapy or combined with chemotherapy has been recommended by domestic and foreign guidelines for the first-line treatment of recurrent/metastatic head and neck squamous cell carcinoma. Although ICIs represent a milestone in the treatment of head and neck squamous cell carcinoma, potential problems still need to be addressed, such as the selection of the efficacy predictors for ICIs, the evaluation of the tumor response to ICIs, and the treatment of immune hyperprogression and immune-related adverse events. Therefore, to form a relatively unified understanding of ICIs treatment for head and neck squamous cell carcinoma, we integrated the clinical experience of multi-disciplinary experts of head and neck cancers on the basis of current clinical hot issues and finally developed this consensus.


Assuntos
Neoplasias de Cabeça e Pescoço , Inibidores de Checkpoint Imunológico , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Consenso , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico
7.
Front Genet ; 13: 951311, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36406130

RESUMO

Background: Cellular senescence has recently been considered a new cancer hallmark. However, the factors regulating cellular senescence have not been well characterized. The aim of this study is to identify long non-coding RNAs (lncRNAs) associated with senescence and prognosis in patients with lung adenocarcinoma (LUAD). Methods: Using RNA sequence data from the Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) and senescence genes from the CellAge database, a subset of senescence-related lncRNAs was first identified. Then, using univariate and multivariate Cox regression analyses, a senescence lncRNA signature (LUADSenLncSig) associated with LUAD prognosis was developed. Based on the median LUADSenLncSig risk score, LUAD patients were divided into high-risk and low-risk groups. Kaplan-Meier analysis was used to compare the overall survival (OS) in the high- and low-risk score subgroups. Differences in Gene Set Enrichment Analysis (GSEA), immune infiltration, tumor mutation burden (TMB), tumor immune dysfunction and exclusion (TIDE) module score, chemotherapy, and targeted therapy selection were also compared between the high-risk and low-risk groups. Results: A prognostic risk model was obtained consisting of the following nine senescence-related lncRNAs: LINC01116, AC005838.2, SH3PXD2A-AS1, VIMS-AS1, SH3BP5-AS1, AC092279.1, AC026355.1, AC027020.2, and LINC00996. The LUADSenLncSig high-risk group was associated with poor OS (hazard ratio = 1.17, 95% confidence interval = 1.102-1.242; p < 0.001). The accuracy of the model was further supported based on receiver operating characteristic (ROC), principal component analysis (PCA), and internal validation cohorts. In addition, a nomogram was developed consisting of LUADSenLncSig for LUAD prognosis, which is consistent with the actual probability of OS. Furthermore, immune infiltration analysis showed the low-risk group had a stronger anti-tumor immune response in the tumor microenvironment. Notably, the levels of immune checkpoint genes such as CTLA-4, PDCD-1, and CD274, and the TIDE scores were significantly higher in the low-risk subgroups than in high-risk subgroups (p < 0.001). This finding indicates the LUADSenLncSig can potentially predict immunotherapy efficacy. Conclusion: In this study, a lncRNA signature, LUADSenLncSig, that has dual functions of senescence phenotype identification and prognostic prediction as well as the potential to predict the LUAD response to immunotherapy was developed.

8.
Artigo em Inglês | MEDLINE | ID: mdl-36403928

RESUMO

OBJECTIVE: Alar retraction is considered a challenge in rhinoplasty. The classification of alar retraction remains poorly defined, especially in Asia. Patients with alar retraction are associated with excessive exposure to the nostrils in Asia. This study aimed to introduce a classification method of alar retraction based on nostril exposure. MATERIALS AND METHODS: Medical records of patients who had undergone rhinoplasty with alar retraction based on nostril exposure between January 2015 and December 2020 were retrospectively reviewed. The corrections of alar retraction were categorized into three groups according to a classification method of alar retraction based on nostril exposure: mild alar retraction, moderate alar retraction, and severe alar retraction. The visual analog scale (VAS) and rhinoplasty outcomes evaluation (ROE) were used to evaluate the satisfaction rate. RESULTS: Within a median period of 13.3 months, 45 patients (51.14%) with mild alar retraction were corrected by alar contour graft. 23 patients (26.14%) with moderate alar retraction were treated with the alar contour graft(n=10), the lateral crural strut graft (n = 6), and the alar projection graft (n = 7). 20 patients (22.73%) with severe alar retraction were corrected by lateral crural strut graft combined with composite graft (n = 6), lateral crural strut graft (n = 10), and composite graft (n = 4). The severe alar retraction group had a higher satisfaction rate in ROE(P<0.05) and VAS (P<0.05) than moderate alar retraction and mild alar retraction at a follow-up of 12 months after surgery. CONCLUSIONS: The classification of alar retraction based on nostril exposure is more practical for rhinoplasty in Asia.

9.
BMC Vet Res ; 18(1): 407, 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36397114

RESUMO

BACKGROUND: Compared with the stomach of ruminant cattle, the stomach of horse is small and mainly for chemical digestion, but the microorganisms in the stomach play an important role in maintaining the homeostasis of the internal environment. Due to the complexity of the microbes in the stomach, little is known about the diversity and structure of bacteria in the equine stomach. Grains are the main energy source for plant-eating livestock and energy is derived through enzymatic hydrolysis of grains into glucose or their microbial fermentation into Volatile fatty acids (VFA). However, the mechanism through which these ingested grains are chemically digested as well as the effect of these grains on the stomach remains elusive. This study explored the effects of feeding different grains (corn, oats, and barley) on bacterial diversity, structure, and composition in the foal's stomach content. Furthermore, the effects of different grains on the vitality of starch digestion-related stomach enzymes were investigated. RESULTS: No significant differences were observed (P > 0.05) in the bacterial rarefaction curves of Operational Taxonomic Units (OTUs) and diversity of the stomach microbiota in all foals. This study also revealed the statistical differences for Firmicutes, Cyanobacteria, Actinobacteria, Fibrobacteres, Lactobacillaceae, Streptococcaceae, Unidentified_Clostridiales, Prevotellaceae, Lactobacillus, Streptococcus, Unidentified_Cyanobacteria, Unidentified_Clostridiales, Lactococcus, Sphingomonas, Lactobacillus_hayakitensis, Lactobacillus_equigenerosi, and Clostridium_perfringens. The linear discriminant analysis effect size analysis revealed 9 bacteria at each classification level. The functional analysis of species information by using FAPROTAX software was able to predict 35 functions, and the top 5 functions were chemoheterotrophy, fermentation, animal_parasites_or_symbionts, nitrate_reduction, and aerobic_chemoheterotrophy. The study also revealed statistical differences for pH, glucose concentration, ß-amylase, maltase, and amylase. CONCLUSIONS: The different grains had no significant effect on the microbial diversity of the stomach content of the foal. However, the relative bacterial abundances differed significantly in response to different diets. Particularly, oats fed to the foals significantly increased the relative abundance of Firmicutes, Lactobacillaceae, Lactobacillus, and Lactobacillus_hayakitensis. The grain had no significant effect on the pH of the stomach content, glucose concentration, and enzyme viability in the foal.


Assuntos
Ração Animal , Bactérias , Digestão , Amido , Estômago , Animais , Bactérias/classificação , Grão Comestível , Glucose , Cavalos , Amido/metabolismo , Estômago/metabolismo , Estômago/microbiologia
10.
Front Bioeng Biotechnol ; 10: 988436, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36394012

RESUMO

Background: Due to the increasing need for suitable alternatives to bone grafts, artificial bones made of biphasic calcium phosphate (BCP) are currently being extensively researched. These porous bone substitutes have also demonstrated considerable incorporation with the host bone, and new bone is able to grow within the porous structure. They therefore offer a potential therapeutic approach for bone defects. Methods: Vancomycin-loaded Bicera™, a BCP bone substitute, was investigated in order to prevent implant-associated osteomyelitis and postoperative infection after orthopedic surgery. The loading capacity of Bicera™ was measured to understand its potential antibiotic adsorption volume. An antibiotic susceptibility test was also carried out to analyze the effect of Bicera™ loaded with different concentrations of vancomycin on the growth inhibition of methicillin-resistant Staphylococcus aureus (MRSA). Vancomycin-loaded Bicera™ was implanted into rabbits with bone defects, and general gross, radiographic, and histological evaluation was undertaken at 4, 12, and 24 weeks after implantation. Results: The maximum loading capacity of vancomycin-loaded Bicera™ was 0.9 ml of liquid regardless of the vancomycin concentration. Antibiotic susceptibility tests showed that vancomycin-loaded Bicera™ inhibited the growth of MRSA for 6 weeks. In addition, animal studies revealed that new bone grew into the vancomycin-loaded Bicera™. The percentage of new bone formation from 4 to 24 weeks after implantation increased from 17% to 36%. Conclusion: Vancomycin-loaded Bicera™ could effectively inhibit the growth of MRSA in vitro. It was found to incorporate into the host bone well, and new bone was able to grow within the bone substitute. The results of this study indicate that vancomycin-loaded Bicera™ is a potential bone substitute that can prevent implant-associated osteomyelitis and postoperative infection.

11.
Front Genet ; 13: 996444, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36437960

RESUMO

Pyroptosis has been proved to significantly influence the development of lung squamous cell carcinoma (LUSC). To better predict overall survival (OS) and provide guidance on the selection of therapy for LUSC patients, we constructed a novel prognostic biomarker based on pyroptosis-related genes. The dataset for model construction were obtained from The Cancer Genome Atlas and the validation dataset were obtained from Gene Expression Omnibus. Differential expression genes between different pyroptosis expression patterns were identified. These genes were then used to construct pyroptosis expression pattern score (PEPScore) through weighted gene co-expression network analysis, univariate and multivariate cox regression analysis. Afterward, the differences in molecule and immune characteristics and the effect of different therapies were explored between the subgroups divided by the model. The PEPScore was constructed based on six pyroptosis-related genes (CSF2, FGA, AKAP12, CYP2C18, IRS4, TSLP). Compared with the high-PEPScore subgroup, the low-PEPScore subgroup had significantly better OS, higher TP53 and TTN mutation rate, higher infiltration of T follicular helper cells and CD8 T cells, and may benefit more from chemotherapeutic drugs, immunotherapy and radiotherapy. PEPScore is a prospective prognostic model to differentiate prognosis, molecular and immune microenvironmental features, as well as provide significant guidance for selecting clinical therapies.

12.
Respir Res ; 23(1): 314, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36376948

RESUMO

BACKGROUND: Pregnant women with pulmonary hypertension (PH) have higher mortality rates and poor foetal/neonatal outcomes. Tools to assess these risk factors are not well established. METHODS: Predictive and prognostic nomograms were constructed using data from a "Development" cohort of 420 pregnant patients with PH, recorded between January 2009 and December 2018. Logistic regression analysis established models to predict the probability of adverse maternal and foetal/neonatal events and overall survival by Cox analysis. An independent "Validation" cohort comprised data of 273 consecutive patients assessed from January 2019 until May 2022. Nomogram performance was evaluated internally and implemented with online software to increase the ease of use. RESULTS: Type I respiratory failure, New York Heart Association functional class, N-terminal pro-brain natriuretic peptide [Formula: see text] 1400 ng/L, arrhythmia, and eclampsia with pre-existing hypertension were independent risk factors for maternal mortality or heart failure. Type I respiratory failure, arrhythmia, general anaesthesia for caesarean section, New York Heart Association functional class, and N-terminal pro-brain natriuretic peptide [Formula: see text] 1400 ng/L were independent predictors of pulmonary hypertension survival during pregnancy. For foetal/neonatal adverse clinical events, type I respiratory failure, arrhythmia, general anaesthesia for caesarean section, parity, platelet count, fibrinogen, and left ventricular systolic diameter were important predictors. Nomogram application for the Development and Validation cohorts showed good discrimination and calibration; decision curve analysis demonstrated their clinical utility. CONCLUSIONS: The nomogram and its online software can be used to analyse individual mortality, heart failure risk, overall survival prediction, and adverse foetal/neonatal clinical events, which may be useful to facilitate early intervention and better survival rates.


Assuntos
Insuficiência Cardíaca , Hipertensão Pulmonar , Insuficiência Respiratória , Humanos , Recém-Nascido , Feminino , Gravidez , Nomogramas , Hipertensão Pulmonar/diagnóstico , Cesárea , Prognóstico , Estudos Retrospectivos
13.
Angew Chem Int Ed Engl ; : e202213686, 2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36342432

RESUMO

The aldehydes installation by radical formylation constitutes an attractive synthetic strategy. However, the generation of formyl radicals for organic synthesis applications remains unknown. Herein we report the first formyl radical generation from α-chloro N-methoxyphthalimides, which selectively synthesize aldehydes by alkene hydroformylation under mild photoredox conditions. The aldehydes can be installed on acrylates, acrylamides, vinyl sulfones, vinyl ketones, and complex steroids by radical hydroformylation in excellent chemoselectivity and regioselectivity. The concerted hydrochloride elimination for the formyl radical generation from α-chloro methoxy radicals is established by experimental and computational approaches.

14.
Pharmaceutics ; 14(11)2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36432662

RESUMO

Extensive effort has been devoted to developing new clinical therapies based on membrane-active peptides (MAPs). Previous models on the membrane action mechanisms of these peptides mostly focused on the MAP-membrane interactions in a local region, while the influence of the spatial heterogeneity of the MAP distribution on the membrane was much ignored. Herein, three types of natural peptide variants, AS4-1, AS4-5, and AS4-9, with similar amphiphilic α-helical structures but distinct hydrophobic degrees (AS4-1 < AS4-5 < AS4-9) and net charges (+9 vs. +7 vs. +5), were used to interact with a mixed phosphatidylcholine (PC) and phosphatidylglycerol (PG) membrane. A combination of giant unilamellar vesicle (GUV) leakage assays, atomic force microscopy (AFM) characterizations, and molecular dynamics (MD) simulations demonstrated the coexistence of multiple action mechanisms of peptides on a membrane, probably due to the spatially heterogeneous distribution of peptides on the membrane surface. Specifically, the most hydrophobic peptide (i.e., AS4-9) had the strongest membrane binding, perturbation, and permeabilization effects, leading to the formation of large peptide-lipid aggregates (10 ± 5 nm in height and 150 ± 50 nm in size), as well as continuous fragments and ridges on the supported membrane surface. The AS4-5 peptides, with a half-hydrophilic and half-hydrophobic structure, induced membrane lysis in addition to reconstruction. The most hydrophilic peptide AS4-1 only exhibited unstable binding on the supported membrane surface. These results demonstrate the heterogeneous structural disturbance of model cell membranes by amphiphilic α-helical peptides, which could be significantly strengthened by increasing the degree of hydrophobicity and/or local number density of peptides. This work provides support for the modulation of the membrane activity of MAPs by adjusting their hydrophobicity and local concentration.

15.
Viruses ; 14(11)2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36366525

RESUMO

The outcomes for patients with NASH-related HCC after curative resection have not been clarified. This study compared the overall survival (OS), time-to-tumor recurrence (TTR), and recurrence-free survival (RFS) associated with NASH-related HCC and virus-related HCC after resection. Methods: Patients with HCC who underwent curative resection were retrospectively enrolled. Baseline characteristics, including disease etiologies and clinical and tumor features, were reviewed. The primary outcomes were OS, TTR, and RFS. Results: Two hundred and six patients were enrolled (HBV: n = 121, HCV: n = 54, NASH: n = 31). Of those with virus-related HCC, 84.0% achieved viral suppression. In both the overall and propensity-score-matched cohorts, those with NASH-related HCC experienced recurrence significantly earlier than those with virus-related HCC (median TTR: 1108 days vs. non-reached; p = 0.03). Through multivariate analysis, NASH-related HCC (hazard ratio (HR), 2.27; 95% confidence interval (CI), 1.25-4.12) was independently associated with early recurrence. The unadjusted RFS rate of the NASH-related HCC group was lower than the virus-related HCC group. There was no difference in the OS between the two groups. Conclusions: NASH-related HCC was associated with earlier tumor recurrence following curative resection compared to virus-related HCC. Post-surgical surveillance is crucial for detecting early recurrence in patients with NASH-related HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/cirurgia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/cirurgia , Estudos Retrospectivos , Recidiva Local de Neoplasia
16.
Protein Sci ; 31(12): e4512, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36382882

RESUMO

Phage-assisted, active site-directed ligand evolution (PADLE) is a recently developed technique that uses an amber codon-encoded noncanonical amino acid (ncAA) as an anchor to direct phage-displayed peptides to a target for an enhanced ligand identification process. 2-Amino-8-oxodecanoic acid (Aoda) is a ketone-containing ncAA residue in the macrocyclic peptide natural product apicidin that is a pan-inhibitor of Zn2+ -dependent histone deacetylases (HDACs). Its ketone serves as an anchoring point to coordinate the catalytic zinc ion in HDACs. Using a previously evolved N𝜀 -acetyl-lysyl-tRNA synthetase in combination with tRNAPyl , we showed that Aoda was efficiently incorporated into proteins in Escherichia coli by amber suppression. By propagating an amber codon-obligate phagemid library in E. coli encoding Aoda, we generated an Aoda-containing phage-displayed peptide library. Using this library to conduct PADLE against HDAC8 revealed a 7-mer peptide GH8P01F1 with Aoda-flanking amino acid residues that matched existing peptide sequences in identified HDAC8 substrates. Switching Aoda in GH8P01F1 to a more Zn2+ -chelating ncAA S-2-amino-8-hydroxyamino-8-oxooctanoic acid (Asuha) led to an extremely potent compound GH8HA01, which has an HDAC8-inhibition Ki value of 0.67 nM. GH8HA01 and its 5-mer truncation analogue Ac-GH8HA01Δ1Δ7 that has an HDAC8-inhibition Ki value of 0.31 nM are two of the most potent HDAC8 inhibitors that have been developed. Furthermore, both are highly selective against HDAC8 compared with other HDACs tested, demonstrating the great potential of using PADLE to identify highly potent and selective ligands for targets with conserved active sites among homologues.


Assuntos
Bacteriófagos , Inibidores de Histona Desacetilases , Aminoácidos/genética , Bacteriófagos/genética , Bacteriófagos/metabolismo , Domínio Catalítico , Códon de Terminação , Escherichia coli/genética , Escherichia coli/metabolismo , Histona Desacetilases/química , Cetonas , Ligantes , Peptídeos/química
17.
Ann Transl Med ; 10(19): 1050, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36330395

RESUMO

Background: Little is known about the impact of prevalent dementia on in-hospital outcomes of patients with incident stroke in China. Using data from the Chinese Stroke Center Alliance (CSCA), we aim to quantify the prevalence of pre-stroke dementia and whether this group is at higher risk of adverse in-hospital outcomes compared to those without pre-stroke dementia. Methods: We used multivariable logistic regression models to assess the associations between pre-stroke dementia and ambulation by day 2, in-hospital mortality, in-hospital complications, and being discharged home. Covariates included age, sex, comorbidities [dyslipidemia, atrial fibrillation, peripheral vascular disease (PVD), smoking, and alcohol use], medication history (antiplatelet drugs or lipid-lowering drugs), stroke severity [measured by the National Institute of Health Stroke Scale (NIHSS)], administration of intravenous tissue plasminogen activator (IV tPA) within 4.5 hours of stroke onset, and receipt of deep vein thrombosis (DVT) prophylaxis if indicated. Results: In the final analytic sample of 559,070 ischemic stroke patients with no prior stroke history enrolled across 1,476 hospitals, those with pre-stroke dementia (n=1,511; 0.3%) were older and more likely to be female. Despite having received similar treatment, patients with pre-stroke dementia had lower odds of ambulating by day 2 [odds ratio (OR) =0.69; 95% confidence interval (CI): 0.62-0.78], higher odds of in-hospital mortality (OR =2.01; 95% CI: 1.35-2.99) or complications (OR =2.17; 95% CI: 1.93-2.44), and lower odds of being discharged home compared to those without pre-stroke dementia (OR =0.71; 95% CI: 0.62-0.83). Conclusions: Worse in-hospital outcomes among patients with pre-stroke dementia may be explained by pre-existing cognitive impairment that limited their ability to advocate for care needs. Further research is needed to determine whether a different care pathway or additional attention from clinicians is necessary for patients with pre-stroke dementia.

18.
RSC Adv ; 12(41): 26704-26711, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36320845

RESUMO

The combined abuse of benzodiazepines and antipsychotics has become a global problem, and to develop a highly sensitive and selective method for monitoring of benzodiazepine hypnotics and antipsychotics is urgently necessary. In this work, we established a rapid method for the simultaneous determination of benzodiazepines (diazepam, alprazolam, triazolam, and estazolam) and antipsychotic drugs (clozapine, and chlorpromazine) based on ultra performance liquid chromatography-mass spectrometry (UPLC-MS). The accuracy, precision, limit of detection (LOD), limit of quantification (LOQ), specificity, matrix effect and carry-over effect were verified in detail. The results of the recovery and repeat experiments proved that the proposed UPLC-MS method possessed very satisfactory accuracy and precision. The LOD and LOQ of the six psychoactive substances were as low as 0.001-0.005 and 0.005-0.01 µg L-1, respectively. The proposed method was employed to analyze urine samples which were pretreated with a protein precipitation process. The potential influences of precipitants on the analysis results were evaluated statistically, and 0.1% formic acid/acetonitrile/water was selected as the optimum precipitation agent. The detection of the targets was free from matrix and carryover effects.

19.
Front Neurosci ; 16: 1010951, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36325479

RESUMO

Recent studies have shown that the recognition and monitoring of different valence emotions can effectively avoid the occurrence of human errors due to the decline in cognitive ability. The quality of features directly affects emotion recognition results, so this manuscript explores the effective electroencephalography (EEG) features for the recognition of different valence emotions. First, 110 EEG features were extracted from the time domain, frequency domain, time-frequency domain, spatial domain, and brain network, including all the current mainly used features. Then, the classification performance, computing time, and important electrodes of each feature were systematically compared and analyzed on the self-built dataset involving 40 subjects and the public dataset DEAP. The experimental results show that the first-order difference, second-order difference, high-frequency power, and high-frequency differential entropy features perform better in the recognition of different valence emotions. Also, the time-domain features, especially the first-order difference features and second-order difference features, have less computing time, so they are suitable for real-time emotion recognition applications. Besides, the features extracted from the frontal, temporal, and occipital lobes are more effective than others for the recognition of different valence emotions. Especially, when the number of electrodes is reduced by 3/4, the classification accuracy of using features from 16 electrodes located in these brain regions is 91.8%, which is only about 2% lower than that of using all electrodes. The study results can provide an important reference for feature extraction and selection in emotion recognition based on EEG.

20.
Exp Ther Med ; 24(6): 727, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36340603

RESUMO

Inherited epidermolysis bullosa (IEB) represents a group of rare genetic dermatoses comprising various phenotypes ranging from severe cutaneous and extracutaneous involvement to mild cutaneous fragility. Pathogenic variants have been identified in at least 20 genes responsible for IEB. In the present study, six cases of epidermolysis bullosa were recruited and subjected to a combination of clinical and genetic analysis. The family history of each case was surveyed. Whole exome sequencing was performed to identify the causative variation. The six patients showed typical EB symptoms. In all cases, WES detected the diagnostic variations of the COL7A1 or DST gene. A total of 10 variants were identified and verified. The findings of the present study further expanded the mutation spectrum of IEB, provided evidence for genetic counseling to the affected families, as well as highlighted the complexity of the pathogenesis of IEB.

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