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1.
JGH Open ; 8(5): e13058, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38737501

RESUMO

Background and Aim: Small rectosigmoid colorectal polyps (<10 mm) are prevalent, with a low prevalence of advanced neoplastic lesions. The "diagnose-and-leave" strategy, employing narrow band imaging (NBI), is gaining popularity for its safety and cost-effectiveness by reducing polypectomy complications and minimizing histopathology expenses. This study assessed the diagnostic efficacy of NBI with dual focus (DF) magnification for real-time neoplastic prediction of rectosigmoid polyps and explored the feasibility of implementing this strategy in Vietnam. Methods: In a prospective single-center study, 307 rectosigmoid polyps from 245 patients were analyzed using three consecutive endoscopic modes: white light endoscopy (WLE), NBI, and NBI-DF. Endoscopists assessed polyps for size, location, macroscopic shape, optical diagnosis, and confidence levels before histopathological evaluation. High confidence was assigned when the polyp exhibited all features of a single histology type. Predictions were compared with final histopathology results. Results: Of the total, 237 (77.2%) were diminutive (≤5 mm) polyps, and 18 (5.8%) were advanced neoplastic lesions. WLE + NBI and WLE + NBI + NBI-DF exhibited significantly higher accuracy compared to WLE (88.6% and 90.2% vs 74.2%, P < 0.01). For diminutive polyps, the DF mode significantly increased the rate of high-confidence optical diagnoses (89.1% vs 94.9%, P < 0.001). WLE + NBI + NBI-DF demonstrated high sensitivity (90.1%), specificity (95.5%), and negative predictive value (93.4%) in high-confidence predictions, enabling the implementation of the "diagnose-and-leave" strategy. This approach would have reduced 58.2% of unnecessary polypectomies without missing any advanced neoplastic lesions. Conclusion: NBI and DF modes provide accurate neoplastic predictions for rectosigmoid polyps. For diminutive polyps, DF magnification improves the confidence level of the optical diagnosis, allowing the safe implementation of the "diagnose-and-leave" strategy.

2.
Planta Med ; 90(5): 388-396, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38490239

RESUMO

Diabetes mellitus, linked with insulin resistance and hyperglycaemia, is a leading cause of mortality. Glucose uptake through glucose transporter type 4, especially in skeletal muscle, is crucial for maintaining euglycaemia and is a key pathway targeted by antidiabetic medication. Abrus precatorius is a medicinal plant with demonstrated antihyperglycaemic activity in animal models, but its mechanisms are unclear.This study evaluated the effect of a 50% ethanolic (v/v) A. precatorius leaf extract on (1) insulin-stimulated glucose uptake and (2) related gene expression in differentiated C2C12 myotubes using rosiglitazone as a positive control, and (3) generated a comprehensive phytochemical profile of A. precatorius leaf extract using liquid chromatography-high resolution mass spectrometry to elucidate its antidiabetic compounds. A. precatorius leaf extract significantly increased insulin-stimulated glucose uptake, and insulin receptor substrate 1 and Akt substrate of 160 kDa gene expression; however, it had no effect on glucose transporter type 4 gene expression. At 250 µg/mL A. precatorius leaf extract, the increase in glucose uptake was significantly higher than 1 µM rosiglitazone. Fifty-five phytochemicals (primarily polyphenols, triterpenoids, saponins, and alkaloids) were putatively identified, including 24 that have not previously been reported from A. precatorius leaves. Abrusin, precatorin I, glycyrrhizin, hemiphloin, isohemiphloin, hispidulin 4'-O-ß-D-glucopyranoside, homoplantaginin, and cirsimaritin were putatively identified as known major compounds previously reported from A. precatorius leaf extract. A. precatorius leaves contain antidiabetic phytochemicals and enhance insulin-stimulated glucose uptake in myotubes via the protein kinase B/phosphoinositide 3-kinase pathway by regulating insulin receptor substrate 1 and Akt substrate of 160 kDa gene expression. Therefore, A. precatorius leaves may improve skeletal muscle insulin sensitivity and hyperglycaemia. Additionally, it is a valuable source of bioactive phytochemicals with potential therapeutic use for diabetes.


Assuntos
Abrus , Diabetes Mellitus , Hiperglicemia , Resistência à Insulina , Animais , Insulina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Abrus/química , Proteínas Substratos do Receptor de Insulina/metabolismo , Rosiglitazona/metabolismo , Rosiglitazona/farmacologia , Transportador de Glucose Tipo 4 , Fosfatidilinositol 3-Quinases , Músculo Esquelético/metabolismo , Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/farmacologia , Extratos Vegetais/química , Glucose/farmacologia
3.
Cureus ; 16(2): e53545, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38445134

RESUMO

Background and objectives Achieving accurate real-time optical diagnoses of colorectal polyps with high-confidence predictions is crucial for appropriate decision-making in daily practice. The dual-focus (DF) magnification mode helps endoscopists scrutinize subtle features of polyp surfaces and vessel patterns. This prospective study aimed to evaluate the impact of DF imaging on enhancing the rate of high-confidence narrow-band imaging (NBI)-based optical diagnosis. Methods Consecutive adult patients who underwent colonoscopy and had small colorectal polyps (<10 mm) were enrolled between September 2022 and May 2023. The optical diagnosis of each polyp was evaluated during colonoscopy in two stages by the same endoscopist, utilizing NBI with DF magnification (NDB-DF). A confidence level was assigned to each prediction. High confidence was indicated by clinical judgment when a polyp exhibited distinctive features associated solely with one histological subtype and lacked characteristics of any other subtype. All procedures were carried out with a prototype 190 series Exera III NBI system (Olympus Corporation, Tokyo, Japan) with DF magnification. Results The study included 413 patients with 623 polyps, comprising 483 ≤ 5 mm and 140 measuring 6-9 mm. The majority were low-grade adenomas (343 lesions), with 17 identified as high-grade adenomas, and none characterized as deep submucosal invasive carcinomas. NBI-DF significantly improved the rate of high-confidence optical diagnoses compared to NBI for both ≤ 5 mm polyps (93.1% vs. 87.5%, p < 0.0001) and 6-9 mm polyps (97.9% vs. 94.2%, p = 0.03). Furthermore, DF significantly facilitated the assessment of microvessel and surface pattern criteria (p < 0.01). Conclusion DF magnification markedly enhanced the rate of high-confidence NBI-based optical predictions for small colorectal polyps. This technique demonstrates the potential for improving the diagnostic yield in real-time optical diagnosis of colorectal polyps in the Vietnamese setting.

4.
MicroPubl Biol ; 20232023.
Artigo em Inglês | MEDLINE | ID: mdl-37822685

RESUMO

Entomopathogenic nematodes are commonly used to control insect pest populations in the field. They also contribute substantially to understanding the molecular basis of nematode pathogenicity and insect anti-nematode immunity. Here, we tested the effect of the entomopathogenic nematode Steinernema hermaphroditum on the survival and immune signaling regulation of Drosophila melanogaster wild type larvae. Our results indicate that S. hermaphroditum infective juveniles are pathogenic toward D. melanogaster larvae, but they fail to activate certain immune pathway readout genes. These findings imply that S. hermaphroditum employs mechanisms that allow these parasitic nematodes to interfere with the D. melanogaster immune system.

5.
Sci Rep ; 13(1): 17812, 2023 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-37857694

RESUMO

Although bioderived flame retardants are environmentally sustainable and less toxic, their impact on the thermal stability and flammability of polymers remains poorly understood. In this study, we assessed the influence of mycelium on the thermal stability and flame spread characteristics of epoxy through thermogravimetric analysis, Fourier transform infrared spectroscopy, the UL94 flammability test, and scanning electron microscopy. We observed a decrease in the maximum mass loss rate temperature when mycelium was incorporated into epoxy, indicating an earlier onset of thermal degradation. The inclusion of mycelium increased char yields above 418 °C due to mycelium's inherent char-forming ability. However, mycelium did not alter the thermal degradation pathway of epoxy. Furthermore, according to the UL94 test results, the incorporation of mycelium reduced the flame spread rate compared to that of neat epoxy. These findings contribute to our understanding of the interaction between bioderived flame retardants and polymers paving the way for the development of more sustainable fireproofing materials.

6.
Clin Endosc ; 56(4): 479-489, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37501625

RESUMO

BACKGROUND/AIMS: Accurate neoplastic prediction can significantly decrease costs associated with pathology and unnecessary colorectal polypectomies. Narrow band imaging (NBI) and dual-focus (DF) mode are promising emerging optical technologies for recognizing neoplastic features of colorectal polyps digitally. This study aimed to clarify the clinical usefulness of NBI with and without DF assistance in the neoplastic prediction of small colorectal polyps (<10 mm). METHODS: This cross-sectional study included 530 small colorectal polyps from 343 consecutive patients who underwent colonoscopy at the University Medical Center from September 2020 to May 2021. Each polyp was endoscopically diagnosed in three successive steps using white-light endoscopy (WLE), NBI, and NBI-DF and retrieved for histopathological assessment. The diagnostic accuracy of each modality was evaluated with reference to histopathology. RESULTS: There were 295 neoplastic polyps and 235 non-neoplastic polyps. The overall accuracies of WLE, WLE+NBI, and WLE+NBI+NBI-DF in the neoplastic prediction of colorectal polyps were 70.8%, 87.4%, and 90.8%, respectively (p<0.001). The accuracy of WLE+NBI+NBI-DF was significantly higher than that of WLE+NBI in the polyp size ≤5 mm subgroup (87.3% vs. 90.1%, p<0.001). CONCLUSION: NBI improved the real-time neoplastic prediction of small colorectal polyps. The DF mode was especially useful in polyps ≤5 mm in size.

7.
Nat Commun ; 14(1): 2929, 2023 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-37217466

RESUMO

Cytotoxic-T-lymphocyte (CTL) mediated control of HIV-1 is enhanced by targeting highly networked epitopes in complex with human-leukocyte-antigen-class-I (HLA-I). However, the extent to which the presenting HLA allele contributes to this process is unknown. Here we examine the CTL response to QW9, a highly networked epitope presented by the disease-protective HLA-B57 and disease-neutral HLA-B53. Despite robust targeting of QW9 in persons expressing either allele, T cell receptor (TCR) cross-recognition of the naturally occurring variant QW9_S3T is consistently reduced when presented by HLA-B53 but not by HLA-B57. Crystal structures show substantial conformational changes from QW9-HLA to QW9_S3T-HLA by both alleles. The TCR-QW9-B53 ternary complex structure manifests how the QW9-B53 can elicit effective CTLs and suggests sterically hindered cross-recognition by QW9_S3T-B53. We observe populations of cross-reactive TCRs for B57, but not B53 and also find greater peptide-HLA stability for B57 in comparison to B53. These data demonstrate differential impacts of HLAs on TCR cross-recognition and antigen presentation of a naturally arising variant, with important implications for vaccine design.


Assuntos
Infecções por HIV , Humanos , Antígenos HLA-B/genética , Linfócitos T Citotóxicos , Peptídeos , Epitopos de Linfócito T , Receptores de Antígenos de Linfócitos T
9.
Pharmaceuticals (Basel) ; 16(1)2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36678596

RESUMO

Momordica cochinchinensis is a herbal medicine used throughout Asia and this study investigated the antimelanoma potentials and molecular mechanisms of M. cochinchinensis seed with emphasis on extraction to optimise bioactivity. Overall, the aqueous extract was superior, with a wider diversity and higher concentration of proteins and peptides that was more cytotoxic to the melanoma cells than other extraction solvents. The IC50 of the aqueous extract on melanoma cells were similar to treatment with current anticancer drugs, vemurafenib and cisplatin. This cytotoxicity was cancer-specific with lower cytotoxic effects on HaCaT epidermal keratinocytes. Cytotoxicity correlated with MAPK signalling pathways leading to apoptosis and necrosis induced by triggering tumour necrosis factor receptor-1 (TNFR1), reducing the expression of nuclear factor kappa B (NF-kB), and suppression of BRAF/MEK. This efficacy of M. cochinchinensis seed extracts on melanoma cells provides a platform for future clinical trials as potent adjunctive therapy for metastatic melanoma.

10.
Brief Bioinform ; 25(1)2023 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-38233090

RESUMO

Immunologic recognition of peptide antigens bound to class I major histocompatibility complex (MHC) molecules is essential to both novel immunotherapeutic development and human health at large. Current methods for predicting antigen peptide immunogenicity rely primarily on simple sequence representations, which allow for some understanding of immunogenic features but provide inadequate consideration of the full scale of molecular mechanisms tied to peptide recognition. We here characterize contributions that unsupervised and supervised artificial intelligence (AI) methods can make toward understanding and predicting MHC(HLA-A2)-peptide complex immunogenicity when applied to large ensembles of molecular dynamics simulations. We first show that an unsupervised AI method allows us to identify subtle features that drive immunogenicity differences between a cancer neoantigen and its wild-type peptide counterpart. Next, we demonstrate that a supervised AI method for class I MHC(HLA-A2)-peptide complex classification significantly outperforms a sequence model on small datasets corrected for trivial sequence correlations. Furthermore, we show that both unsupervised and supervised approaches reveal determinants of immunogenicity based on time-dependent molecular fluctuations and anchor position dynamics outside the MHC binding groove. We discuss implications of these structural and dynamic immunogenicity correlates for the induction of T cell responses and therapeutic T cell receptor design.


Assuntos
Antígeno HLA-A2 , Simulação de Dinâmica Molecular , Humanos , Antígeno HLA-A2/metabolismo , Inteligência Artificial , Peptídeos/química , Antígenos de Histocompatibilidade Classe I/metabolismo , Ligação Proteica
11.
J Chem Inf Model ; 62(18): 4295-4299, 2022 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-36098536

RESUMO

Recent work showed that active site rather than full-protein-sequence information improves predictive performance in kinase-ligand binding affinity prediction. To refine the notion of an "active site", we here propose and compare multiple definitions. We report significant evidence that our novel definition is superior to previous definitions and better models of ATP-noncompetitive inhibitors. Moreover, we leverage the discontiguity of the active site sequence to motivate novel protein-sequence augmentation strategies and find that combining them further improves performance.


Assuntos
Trifosfato de Adenosina , Trifosfato de Adenosina/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Ligantes , Ligação Proteica
12.
Sci Rep ; 12(1): 15105, 2022 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-36068256

RESUMO

Mycelium fungal species exhibit fire retardant characteristics. The influence of the growth media on the fungal growth rates, biochemical composition, and microstructural characteristics and their relationship to thermal properties is poorly understood. In this paper, we demonstrate that molasses can support the growth of non-pathogenic Basidiomycota phylum fungal species producing bio-derived materials with potential fire retardation characteristics. Scanning electron microscopy and Fourier transform infrared (FTIR) spectrometry were used to interrogate the microstructural and biochemical properties of the molasses-grown mycelia species. Thermal decomposition of molasses-fed mycelia was evaluated via thermogravimetric analysis interfaced with FTIR for real-time evolved gas analysis. The morphological and microstructural characteristics of the residual char post-thermal exposure were also evaluated. The material characterization enabled the establishment of a relationship between the microstructural, biochemical properties, and thermal properties of molasses-fed mycelia. This paper presents a comprehensive exploration of the mechanisms governing the thermal degradation of three mycelial species grown in molasses. These research findings advance the knowledge of critical parameters controlling fungal growth rates and yields as well as how the microstructural and biochemical properties influence the thermal response of mycelia.


Assuntos
Basidiomycota , Incêndios , Meios de Cultura/metabolismo , Melaço , Micélio
13.
J Parasitol ; 108(4): 403-407, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-36027574

RESUMO

The Baermann filter method is a long-standing, simple technique for recovering nematodes from soil and charcoal coprocultures. Material containing the nematodes is placed on a mesh screen lined with several layers of tissue paper or cheesecloth, and the screen is placed in the mouth of the funnel. Rubber tubing attached to the funnel stem is clamped, and water is added to submerge the material. The filtration material allows the nematodes to swim through while holding back the substrate. Over time the nematodes settle at the clamp in the tubing. After several hours, the clamp is opened and water containing the nematodes is collected. Although recovery of the nematodes is efficient, they are often contaminated with soil or charcoal debris, requiring a secondary cleaning by sedimentation or filtration. Described here is a small, simplified version of the Baermann apparatus that can be used as a secondary cleaning device. The "mini-Baermann" is constructed from materials commonly found in the laboratory. Experiments using infective larvae of 3 nematode species demonstrated that the majority of the larvae applied to the device are collected within 2 hr, and nearly all by 4 hr. Dead larvae fail to pass through the filter and do not significantly impact the passage of living larvae. In addition to removing debris from nematode suspensions, this device can rapidly and efficiently separate living, motile larvae from dead larvae.


Assuntos
Carvão Vegetal , Nematoides , Animais , Larva , Solo , Água
14.
Korean J Gastroenterol ; 80(2): 93-98, 2022 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-36004637

RESUMO

Ischemic colitis (IC) is an underreported chronic disease characterized by the hypoperfusion of the bowel mucosa. The diagnosis and treatment may be challenging because its clinical course resembles other colitis or even colorectal malignancies. This paper reports an untypical case to underline the diversity of IC manifestation. A 68-year-old man with several comorbidities was admitted because of abdominal pain with a 6-month duration and a mass in the left lower quadrant. Colonoscopy revealed erosive pseudomembranous colitis narrowed colon segments with ulcerated mucosa mimicking colorectal cancer and inflammatory bowel disease. The stool cultures and Clostridium difficile toxin tests were negative. After the failure of conservative therapy, the Hartmann procedure with temporary ileostomy was performed uneventfully. The histological results of the surgical specimens revealed IC with focal pseudomembranous areas.


Assuntos
Colite Isquêmica , Colite , Enterocolite Pseudomembranosa , Idoso , Colite/complicações , Colite Isquêmica/complicações , Colite Isquêmica/diagnóstico , Enterocolite Pseudomembranosa/diagnóstico , Enterocolite Pseudomembranosa/tratamento farmacológico , Humanos , Masculino , Vietnã
15.
Cureus ; 14(3): e23323, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35464539

RESUMO

Background Through the coronavirus disease 2019 (COVID-19) pandemic, portable radiography was particularly useful for assessing and monitoring the COVID-19 disease in Vietnamese field hospitals. It provides a convenient and precise picture of the progression of the disease. The purpose of this study was to evaluate the predictive value of chest radiograph reporting systems (Brixia and total severity score (TSS)) and the National Early Warning Score (NEWS) clinical score in a group of hospitalized patients with COVID-19. Methods This retrospective cohort study used routinely collected clinical data from polymerase chain reaction (PCR)-positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients admitted to Field Hospital District 8, Ho Chi Minh City, Vietnam, from August 2021 to September 2021. The initial chest radiographs were scored based on the TSS and Brixia scoring systems to quantify the extent of lung involvement. After the chest radiograph score was reported, two residents calculated the rate of all-cause in-hospital mortality with the consultation of expert radiologists. In this study, NEWS2 scores on hospital admission were calculated. The gradient boosting machines (GBMs) and Shapley additive exPlanations (SHAP) were applied to access the important variable and improve the accuracy of mortality prediction. The adjusted odds ratio for predictor was presented by univariate analysis and multivariate analysis. Results The chest X-rays (CXRs) at the admission of 273 patients (mean age 59 years +/-16, 42.1% were male) were scored. In the univariate analysis, age, vaccination status, previous disease, NEWS2, a saturation of peripheral oxygen (Sp02), the Brixia and TSS scores were significant predictors of mortality (p-value < 0.05). In multivariate analysis, there were statistically significant differences in mortality between age, Sp02, Brixia score, and patients with previous diseases were independent predictors of mortality and hospitalization. A gradient boosting machine was performed in the train data set, which showed that the best hyperparameters for predicting the mortality of patients are the Brixia score (exclude TSS score). In the top five predictors, an increase in Brixia, age, and BMI increased the logarithmic number of probability clarifying as death status. Although the TSS and Brixia scores evaluated chest imaging, the TSS score was not essential as the Brixia score (rank 6/11). It was clear that the BMI and NEWS2 score was positively correlated with the Brixia score, and age did not affect this correlation. Meanwhile, we did not find any trend between the TSS score versus BMI and NEWS2. Conclusion When integrated with the BMI and NEWS2 clinical classification systems, the severity score of COVID-19 chest radiographs, particularly the Brixia score, was an excellent predictor of all-cause in-hospital mortality.

16.
Gut ; 71(9): 1812-1820, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35017200

RESUMO

OBJECTIVE: The human gut fungal community, known as the mycobiome, plays a fundamental role in the gut ecosystem and health. Here we aimed to investigate the determinants and long-term stability of gut mycobiome among middle-aged and elderly adults. We further explored the interplay between gut fungi and bacteria on metabolic health. DESIGN: The present study included 1244 participants from the Guangzhou Nutrition and Health Study. We characterised the long-term stability and determinants of the human gut mycobiome, especially long-term habitual dietary consumption. The comprehensive multiomics analyses were performed to investigate the ecological links between gut bacteria, fungi and faecal metabolome. Finally, we examined whether the interaction between gut bacteria and fungi could modulate the metabolic risk. RESULTS: The gut fungal composition was temporally stable and mainly determined by age, long-term habitual diet and host physiological states. Specifically, compared with middle-aged individuals, Blastobotrys and Agaricomycetes spp were depleted, while Malassezia was enriched in the elderly. Dairy consumption was positively associated with Saccharomyces but inversely associated with Candida. Notably, Saccharomycetales spp interacted with gut bacterial diversity to influence insulin resistance. Bidirectional mediation analyses indicated that bacterial function or faecal histidine might causally mediate an impact of Pichia on blood cholesterol. CONCLUSION: We depict the sociodemographic and dietary determinants of human gut mycobiome in middle-aged and elderly individuals, and further reveal that the gut mycobiome may be closely associated with the host metabolic health through regulating gut bacterial functions and metabolites.


Assuntos
Microbioma Gastrointestinal , Micobioma , Adulto , Idoso , Bactérias , Ecossistema , Fezes/microbiologia , Fungos , Humanos , Pessoa de Meia-Idade , Micobioma/fisiologia
17.
J Med Chem ; 65(4): 2820-2826, 2022 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33834772

RESUMO

The highly infectious SARS-CoV-2 variant B.1.351 that first emerged in South Africa with triple mutations (N501Y, K417N, and E484K) is globally worrisome. It is known that N501Y and E484K can enhance binding between the coronavirus receptor domain (RBD) and human ACE2. However, the K417N mutation appears to be unfavorable as it removes one interfacial salt bridge. Here, we show that despite the decrease in binding affinity (1.48 kcal/mol) between RBD and ACE2, the K417N mutation abolishes a buried interfacial salt bridge between the RBD and neutralizing antibody CB6. This substantially reduces their binding energy by 9.59 kcal/mol, thus facilitating the process by which the variant efficiently eludes CB6 (including many other antibodies). Our theoretical predictions agree with existing experimental findings. Harnessing the revealed molecular mechanisms makes it possible to redesign therapeutic antibodies, thus making them more efficacious.


Assuntos
Enzima de Conversão de Angiotensina 2/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Enzima de Conversão de Angiotensina 2/genética , Humanos , Modelos Moleculares , Mutação , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética
18.
Proteins ; 90(5): 1081-1089, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34636446

RESUMO

Since the beginning of the COVID-19 pandemic, scientists across the globe are racing to find a cure for the highly contagious infectious disease caused by the SARS-CoV-2 virus. Despite many promising ongoing progress, there are currently no FDA approved drug to treat infected patients. Recently, the crowdsourcing of drug discovery for inhibiting the main protease (Mpro) of SARS-CoV-2 have yielded a plenty of drug fragments resolved inside the active site of Mpro via the crystallography method. Following the principle of fragment-based drug design (FBDD), we are motivated to design a potent drug candidate (named B19) by merging three fragments JFM, U0P, and HWH. Through extensive all-atom molecular dynamics simulation and molecular docking, we found that B19 among all designed ones is most stable inside the Mpro's active site and the binding free energy of B19 is comparable to or even a little better than that of a native protein ligand processed by Mpro. Our promising results suggest that B19 and its derivatives can potentially be efficacious drug candidates for COVID-19.


Assuntos
Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , Antivirais/farmacologia , Antivirais/uso terapêutico , Endopeptidases/metabolismo , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , Peptídeo Hidrolases/metabolismo , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico
19.
J Chem Inf Model ; 62(2): 240-257, 2022 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-34905358

RESUMO

Recent advances in deep learning have enabled the development of large-scale multimodal models for virtual screening and de novo molecular design. The human kinome with its abundant sequence and inhibitor data presents an attractive opportunity to develop proteochemometric models that exploit the size and internal diversity of this family of targets. Here, we challenge a standard practice in sequence-based affinity prediction models: instead of leveraging the full primary structure of proteins, each target is represented by a sequence of 29 discontiguous residues defining the ATP binding site. In kinase-ligand binding affinity prediction, our results show that the reduced active site sequence representation is not only computationally more efficient but consistently yields significantly higher performance than the full primary structure. This trend persists across different models, data sets, and performance metrics and holds true when predicting pIC50 for both unseen ligands and kinases. Our interpretability analysis reveals a potential explanation for the superiority of the active site models: whereas only mild statistical effects about the extraction of three-dimensional (3D) interaction sites take place in the full sequence models, the active site models are equipped with an implicit but strong inductive bias about the 3D structure stemming from the discontiguity of the active sites. Moreover, in direct comparisons, our models perform similarly or better than previous state-of-the-art approaches in affinity prediction. We then investigate a de novo molecular design task and find that the active site provides benefits in the computational efficiency, but otherwise, both kinase representations yield similar optimized affinities (for both SMILES- and SELFIES-based molecular generators). Our work challenges the assumption that the full primary structure is indispensable for modeling human kinases.


Assuntos
Proteínas , Sítios de Ligação , Domínio Catalítico , Humanos , Ligantes , Ligação Proteica , Proteínas/metabolismo
20.
ACS Appl Mater Interfaces ; 13(49): 58309-58318, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34855354

RESUMO

Metal-organic frameworks (MOFs) have recently been shown to be effective antimicrobial agents, particularly if they comprise pathogenicidal metal ions. Nevertheless, the accessibility of these active metal sites to the pathogen, and hence the MOFs' antimicrobial activity itself, is often poor since the metal nodes are usually embedded deep within its three-dimensional (3D) structure. We show that a unique copper-based (copper(II)-benzene-1,3,5-tricarboxylate) MOF, whose quasi-two-dimensional (quasi-2D) swordlike structure facilitates exposure of the metal ions along its surface, exhibits enhanced antimicrobial properties against three representative plant pathogens: a bacterium (Pseudomonas syringae), a fungus (Fusarium solani), and a virus (Odontoglossum ringspot virus (ORSV)). Such superior antimicrobial activity results in low minimum inhibitory concentrations (MICs)─half that of a commercial pesticide and an eighth of its conventional 3D cubic MOF counterpart (HKUST-1)─and hence low phytotoxicity, which can be attributed to the accessibility of the surface copper sites to the pathogen, thereby facilitating their adhesion and physical contact with the MOF. Additionally, we observed that orchids treated with the quasi-2D MOF showed negligible phytotoxicity and 80% decreased viral load. This work constitutes the first study to demonstrate the antimicrobial properties of this novel MOF against bacterial, fungal, and viral plant pathogens, and the first chemical control of ORSV.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antivirais/farmacologia , Estruturas Metalorgânicas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antivirais/síntese química , Antivirais/química , Fusarium/efeitos dos fármacos , Teste de Materiais , Estruturas Metalorgânicas/síntese química , Estruturas Metalorgânicas/química , Testes de Sensibilidade Microbiana , Processos Fotoquímicos , Pseudomonas syringae/efeitos dos fármacos , Tobamovirus/efeitos dos fármacos
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