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1.
Cell ; 155(1): 200-214, 2013 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-24074869

RESUMO

Macrophage-mediated inflammation is a major contributor to obesity-associated insulin resistance. The corepressor NCoR interacts with inflammatory pathway genes in macrophages, suggesting that its removal would result in increased activity of inflammatory responses. Surprisingly, we find that macrophage-specific deletion of NCoR instead results in an anti-inflammatory phenotype along with robust systemic insulin sensitization in obese mice. We present evidence that derepression of LXRs contributes to this paradoxical anti-inflammatory phenotype by causing increased expression of genes that direct biosynthesis of palmitoleic acid and ω3 fatty acids. Remarkably, the increased ω3 fatty acid levels primarily inhibit NF-κB-dependent inflammatory responses by uncoupling NF-κB binding and enhancer/promoter histone acetylation from subsequent steps required for proinflammatory gene activation. This provides a mechanism for the in vivo anti-inflammatory insulin-sensitive phenotype observed in mice with macrophage-specific deletion of NCoR. Therapeutic methods to harness this mechanism could lead to a new approach to insulin-sensitizing therapies.


Assuntos
Ácidos Graxos Ômega-3/metabolismo , Resistência à Insulina , Macrófagos/metabolismo , Correpressor 1 de Receptor Nuclear/metabolismo , Receptores Nucleares Órfãos/genética , Animais , Receptores X do Fígado , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Correpressor 1 de Receptor Nuclear/genética
2.
Cell ; 147(4): 815-26, 2011 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-22078880

RESUMO

Insulin resistance, tissue inflammation, and adipose tissue dysfunction are features of obesity and Type 2 diabetes. We generated adipocyte-specific Nuclear Receptor Corepressor (NCoR) knockout (AKO) mice to investigate the function of NCoR in adipocyte biology, glucose and insulin homeostasis. Despite increased obesity, glucose tolerance was improved in AKO mice, and clamp studies demonstrated enhanced insulin sensitivity in liver, muscle, and fat. Adipose tissue macrophage infiltration and inflammation were also decreased. PPARγ response genes were upregulated in adipose tissue from AKO mice and CDK5-mediated PPARγ ser-273 phosphorylation was reduced, creating a constitutively active PPARγ state. This identifies NCoR as an adaptor protein that enhances the ability of CDK5 to associate with and phosphorylate PPARγ. The dominant function of adipocyte NCoR is to transrepress PPARγ and promote PPARγ ser-273 phosphorylation, such that NCoR deletion leads to adipogenesis, reduced inflammation, and enhanced systemic insulin sensitivity, phenocopying the TZD-treated state.


Assuntos
Adipócitos/metabolismo , Proteínas Correpressoras/genética , Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina , Correpressor 1 de Receptor Nuclear/metabolismo , PPAR gama/metabolismo , Animais , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , PPAR gama/antagonistas & inibidores , Fosforilação , Tiazolidinedionas
3.
Nature ; 582(7810): 60-66, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32494078

RESUMO

The nature of the first genetic polymer is the subject of major debate1. Although the 'RNA world' theory suggests that RNA was the first replicable information carrier of the prebiotic era-that is, prior to the dawn of life2,3-other evidence implies that life may have started with a heterogeneous nucleic acid genetic system that included both RNA and DNA4. Such a theory streamlines the eventual 'genetic takeover' of homogeneous DNA from RNA as the principal information-storage molecule, but requires a selective abiotic synthesis of both RNA and DNA building blocks in the same local primordial geochemical scenario. Here we demonstrate a high-yielding, completely stereo-, regio- and furanosyl-selective prebiotic synthesis of the purine deoxyribonucleosides: deoxyadenosine and deoxyinosine. Our synthesis uses key intermediates in the prebiotic synthesis of the canonical pyrimidine ribonucleosides (cytidine and uridine), and we show that, once generated, the pyrimidines persist throughout the synthesis of the purine deoxyribonucleosides, leading to a mixture of deoxyadenosine, deoxyinosine, cytidine and uridine. These results support the notion that purine deoxyribonucleosides and pyrimidine ribonucleosides may have coexisted before the emergence of life5.


Assuntos
DNA/química , Evolução Química , Origem da Vida , Nucleosídeos de Purina/síntese química , Nucleosídeos de Pirimidina/síntese química , RNA/química , Adenosina/análogos & derivados , Adenosina/química , Citidina/química , DNA/genética , Oxirredução/efeitos da radiação , Nucleosídeos de Purina/química , Nucleosídeos de Purina/genética , Nucleosídeos de Pirimidina/química , Nucleosídeos de Pirimidina/genética , RNA/genética , Uridina/química
4.
Proc Natl Acad Sci U S A ; 119(15): e2120913119, 2022 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-35324337

RESUMO

SignificanceThe coronavirus main protease (Mpro) is required for viral replication. Here, we obtained the extended conformation of the native monomer of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Mpro by trapping it with nanobodies and found that the catalytic domain and the helix domain dissociate, revealing allosteric targets. Another monomeric state is termed compact conformation and is similar to one protomer of the dimeric form. We designed a Nanoluc Binary Techonology (NanoBiT)-based high-throughput allosteric inhibitor assay based on structural conformational change. Our results provide insight into the maturation, dimerization, and catalysis of the coronavirus Mpro and pave a way to develop an anticoronaviral drug through targeting the maturation process to inhibit the autocleavage of Mpro.


Assuntos
Antivirais , COVID-19 , Proteases 3C de Coronavírus , Inibidores de Proteases , SARS-CoV-2 , Regulação Alostérica/efeitos dos fármacos , Antivirais/química , Antivirais/farmacologia , COVID-19/enzimologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , Humanos , Luciferases , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Conformação Proteica , Multimerização Proteica
5.
Anal Chem ; 2024 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-39149969

RESUMO

The distribution of small biomolecules, particularly amino acids (AAs), differs between normal cells and cancer cells. Imaging this distribution is crucial for gaining a deeper understanding of their physiological and pathological significance. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) provides accurate in situ visualization information. However, the analysis of AAs remains challenging due to the background interference by conventional MALDI matrices. On tissue chemical derivatization (OTCD) MSI serves as an important approach to resolve this issue. We designed, synthesized, and tested a series of pyridinium salt probes and screened out the 1-(4-(((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)phenyl)-2,4,6-triphenylpyridin-1-ium (DCT) probe with the highest reaction efficiency and the most effective detection. Moreover, a quantum chemistry calculation was executed to address mechanistic insight into the chemical nature of the novel probes. DCT was found to map 20 common AAs in normal mouse tissues for the first time, which allowed differentiation of AA distribution in normal, normal interstitium, tumor, and tumor interstitium regions and provided potential mechanistic insights for cancer research and other biomedical studies.

6.
Opt Express ; 32(1): 482-498, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38175077

RESUMO

Polycrystalline zinc selenide is widely used in advanced optical systems due to its superior optical properties. However, the soft and brittle properties bring a challenge for high-quality surface processing. In recent years, elliptical vibration cutting has been proven as a promising method for machining brittle materials. In the present research, a series of grooving and planning experiments were carried out to investigate the machinability of zinc selenide with elliptical vibration cutting. The removal mechanism was analyzed from fracture characteristics, chip morphology, and phase transformation. The results show that elliptical vibration cutting is effective in suppressing cleavage-induced craters. Reducing the nominal cutting speed is beneficial to inhibit the spring back-induced tearing of grains. A 94-time increase in the critical depth of cut was achieved by vibration trajectory optimization compared to ordinary cutting. Moreover, the influence mechanism of feed on the evolution of surface morphology was revealed. Finally, a zinc selenide microlens array was successfully fabricated. The performance was evaluated by geometric parameter measurements and a multiple imaging test. The findings provide a prospective method for ductile regime machining of zinc selenide.

7.
Diabetes Obes Metab ; 2024 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-39495140

RESUMO

AIMS: GLP-1 receptor agonists (GLP-1 RAs) are proven therapies for type 2 diabetes mellitus (T2DM) and overweight or obesity. We performed non-clinical and first-in-human (FIH) evaluation of ECC5004/AZD5004, an oral small-molecule GLP-1 RA. MATERIALS AND METHODS: ECC5004 was profiled in cell lines overexpressing human GLP-1R, in glucose-stimulated insulin secretion (GSIS) assays in a human ß-cell line and non-human primates (NHPs). To evaluate safety, ECC5004 was orally administered to NHPs for 9 months and a phase I, double-blind, placebo-controlled FIH study was conducted. This study evaluated single doses of ECC5004 (1-300 mg) in healthy volunteers, and multiple daily doses (5, 10, 30 and 50 mg) in patients with T2DM for 28 days. RESULTS: ECC5004 bound to the hGLP-1R (IC50 = 2.4 nM) augmented cAMP signalling without ß-arrestin-2 recruitment or receptor internalization. ECC5004 potentiated GSIS in both EndoC-ßH5 cells (EC50 = 5.9 nM) and in vivo in NHPs (EC50 = 0.022 nM). Dose-dependent body weight changes compared to control were seen in the 9-month NHP toxicity study. In the first-in-human study, ECC5004 was well tolerated with no serious adverse events. Dose-dependent reductions in glucose and body weight were observed with a dose-proportional exposure at doses ≥25 mg. CONCLUSION: ECC5004 engaged the GLP-1R across the therapeutic dose range tested and had a safety and tolerability profile consistent with other GLP-1 RAs, along with a pharmacokinetic profile compatible with once-daily oral dosing. These data support continued development of ECC5004 as a potential therapy for T2DM and overweight or obesity. CLINICAL TRIAL REGISTRATION: NCT05654831.

8.
BMC Gastroenterol ; 24(1): 348, 2024 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-39363268

RESUMO

BACKGROUND: The objectives were to assess the safety and efficacy of drug-eluting bead transarterial chemoembolization (DEB-TACE) as locoregional therapy (LRT) in hepatocellular carcinoma (HCC) before liver transplantation (LT) beyond Hangzhou criteria (HC) and to analyze the prognostic factors. METHODS: Forty patients with HCC beyond HC who received DEB-TACE only before LT were retrospectively analyzed between January 2017 and December 2022. Data on patient demographics, disease characteristics, treatment response, and adverse events (AE) were collected. Overall survival (OS) and recurrence-free survival (RFS) were evaluated with Kaplan-Meier curves. Univariate and multivariate Cox regression analyses were performed to identify factors independently associated with RFS and OS. RESULTS: All patients successfully underwent LT following DEB-TACE with a mean interval of 2.3 months. The objective response rates (ORRs) for these patients following DEB-TACE was 82.5%. The primary AE was post-embolization syndrome (PES), with affected patients experiencing grades I and II. The median RFS and OS were 12.0 months (95%CI: 0.0-30.1) and 52.0 months (95%CI: 11.8-92.2) over the follow-up period until December 2022. The 2-year RFS and OS rates were 42.5%, and 67.5%. Multivariate analyses revealed Child-Pugh classification (HR = 6.24; 95%CI,1.83-21.24; P = 0.01) and macrovascular invasion (MAV) (HR = 3.89; 95%CI,1.07-14.15; P = 0.04) were both significant independent predictors of OS. CONCLUSIONS: DEB-TACE can serve as a safe and effective LRT in HCC patients beyond HC before LT, and can improve the prognosis of patients, especially without MAV. The higher Child-Pugh classification and MAV are independent prognostic factors after LT.


Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Transplante de Fígado , Humanos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Quimioembolização Terapêutica/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto , Idoso , Prognóstico , Estimativa de Kaplan-Meier , Recidiva Local de Neoplasia
9.
Headache ; 64(1): 68-92, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38071464

RESUMO

OBJECTIVE: To evaluate response to anti-calcitonin gene-related peptide (CGRP) migraine preventives in a real-world community cohort of persons living with migraine and to identify clinical and genetic characteristics associated with efficacious response. BACKGROUND: Erenumab-aooeb, fremanezumab-vrfm, and galcanezumab-gnlm target CGRP or its receptor; however, many patients are non-responsive. METHODS: In this retrospective clinical and genetic study, we identified 1077 adult patients who satisfied the International Classification of Headache Disorders, 3rd edition, criteria for migraine without aura, migraine with aura, or chronic migraine and who were prescribed an anti-CGRP migraine preventive between May 2018 and May 2021. Screening of 558 patients identified 289 with data at baseline and first follow-up visits; data were available for 161 patients at a second follow-up visit. The primary outcome was migraine days per month (MDM). In 198 genotyped patients, we evaluated associations between responders (i.e., patients with ≥50% reduction in MDM at follow-up) and genes involved in CGRP signaling or pharmacological response, and genetic and polygenic risk scores. RESULTS: The median time to first follow-up was 4.4 (0.9-22) months after preventive start. At the second follow-up, 5.7 (0.9-13) months later, 145 patients had continued on the same preventive. Preventives had strong, persistent effects in reducing MDM in responders (follow-up 1: η2 = 0.26, follow-up 2: η2 = 0.22). At the first but not second follow-up: galcanezumab had a larger effect than erenumab, while no difference was seen at either follow-up between galcanezumab and fremanezumab or fremanezumab and erenumab. The decrease in MDM at follow-up was generally proportional to baseline MDM, larger in females, and increased with months on medication. At the first follow-up only, patients with prior hospitalization for migraine or who had not responded to more preventive regimens had a smaller decrease in MDM. Reasons for stopping or switching a preventive varied between medications and were often related to cost and insurance coverage. At both follow-ups, patient tolerance (1: 92.2% [262/284]; 2: 95.2% [141/145]) and continued use (1: 77.5% [224/289]; 2: 80.6% [116/145]) were high and similar across preventives. Response consistency (always non-responders: 31.7% [46/145]; always responders: 56.5% [82/145], and one-time only responders: 11.7% [17/145]) was also similar across preventives. Non-responder status had nominally significant associations with rs12615320-G in RAMP1 (odds ratio [95% confidence interval]: 4.7 [1.5, 14.7]), and rs4680-A in COMT (0.6[0.4, 0.9]). Non-responders had a lower mean genetic risk score than responders (1.0 vs. 1.1; t(df) = -1.75(174.84), p = 0.041), and the fraction of responders increased with genetic and polygenic risk score percentile. CONCLUSIONS: In this real-world setting, anti-CGRP preventives reduced MDM persistently and had similar and large effect sizes on MDM reduction; however, clinical and genetic factors influenced response.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina , Transtornos de Enxaqueca , Adulto , Feminino , Humanos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/genética , Transtornos de Enxaqueca/prevenção & controle , Estudos Retrospectivos , Resultado do Tratamento , Masculino
10.
Plant Cell Rep ; 43(8): 202, 2024 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-39073636

RESUMO

KEY MESSAGE: E1 holoenzyme was extensively Hyp-O-glycosylated at the proline rich linker region in plants, which substantially increased the molecular size and improved the enzymatic digestibility of the biomass of transgenic plants. Thermophilic E1 endo-1,4-ß-glucanase derived from Acidothermus cellulolyticus has been frequently expressed in planta to reconstruct the plant cell wall to overcome biomass recalcitrance. However, the expressed holoenzyme exhibited a larger molecular size (~ 100 kDa) than the theoretical one (57 kDa), possibly due to posttranslational modifications in the recombinant enzyme within plant cells. This study investigates the glycosylation of the E1 holoenzyme expressed in tobacco plants and determines its impact on enzyme activity and biomass digestibility. The E1 holoenzyme, E1 catalytic domain (E1cd) and E1 linker (E1Lk) were each expressed in tobacco plants and suspension cells. The accumulation of holoenzyme was 2.0- to 2.3- times higher than that of E1cd. The proline-rich E1Lk region was extensively hydroxyproline-O-glycosylated with arabinogalactan polysaccharides. Compared with E1cd, the holoenzyme displayed a broader optimal temperature range (70 to 85 ºC). When grown in greenhouse, the expression of E1 holoenzyme induced notable phenotypic changes in plants, including delayed flowering and leaf variegation post-flowering. However, the final yield of plant biomass was not significantly affected. Finally, plant biomass engineering with E1 holoenzyme showed 1.7- to 1.8-fold higher saccharification efficiency than the E1cd lines and 2.4- to 2.7-fold higher than the wild-type lines, which was ascribed to the synergetic action of the E1Lk and cellulose binding module in reducing cell wall recalcitrance.


Assuntos
Biomassa , Celulase , Hidroxiprolina , Nicotiana , Plantas Geneticamente Modificadas , Glicosilação , Celulase/metabolismo , Celulase/genética , Nicotiana/genética , Nicotiana/metabolismo , Hidroxiprolina/metabolismo , Parede Celular/metabolismo , Celulose/metabolismo , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/genética , Caldicellulosiruptor/genética , Caldicellulosiruptor/metabolismo
11.
J Endocrinol Invest ; 47(9): 2261-2268, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38383878

RESUMO

PURPOSE: To better understand the effects of aging, metabolic syndrome, diurnal variation, and seasonal variation on serum testosterone levels in the context of current guideline statements on testosterone deficiency. METHODS: This cross-sectional study utilized the United Kingdom Biobank. Physical examination, anthropomorphic measurements, and laboratory evaluation were performed at the time of enrollment from 2006 to 2010. The primary outcomes were the effect of age, the presence of metabolic syndrome, the time of day, and the month of the year on serum testosterone levels. RESULTS: Among 197,883 included men, the 5th, 25th, 50th, 75th and 95th percentile testosterone levels in men without metabolic syndrome were significantly higher than those in men with metabolic syndrome at every decade of life (p < 0.001). The average testosterone level within each group (men without metabolic syndrome vs. men with) was clinically similar across decade of life (12.43 in 40's 12.29 in 50's 12.24 in 60's vs. 10.69 in 40's 10.56 in 50's 10.63 in 60's respectively). Average testosterone levels decreased with blood draws later in the day ranging from 10.91 to 12.74 nmol/L (p < 0.01). Similarly, there was seasonal variation in serum testosterone ranging from 11.86 to 12.18 nmol/L (p < 0.01). CONCLUSIONS: We found significant variation in serum testosterone according to the presence of metabolic syndrome and time of laboratory draw, but not according to age. These data challenge the prior dogma of age-related hypogonadism and favor an individualized approach towards serum testosterone measurement and interpretation. However, further studies are needed to correlate these population-based data with individuals' hypogonadal symptoms.


Assuntos
Síndrome Metabólica , Testosterona , Humanos , Testosterona/sangue , Masculino , Estudos Transversais , Pessoa de Meia-Idade , Adulto , Síndrome Metabólica/sangue , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/epidemiologia , Valores de Referência , Idoso , Reino Unido/epidemiologia , Estações do Ano , Envelhecimento/sangue
12.
Ann Vasc Surg ; 109: 316-325, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39067852

RESUMO

BACKGROUND: Abdominal aortic aneurysm (AAA) is a complex disease with environmental and genetic risk factors. Polygenic risk scores (PRSs) based on disease-specific risk-associated single nucleotide variants (SNVs) have demonstrated effectiveness in stratifying individual-level disease risk for cardiovascular diseases. This prospective cohort study assessed associations of PRS of AAA (PRSAAA) with risk of incident AAA, analyzed the effectiveness of a combined clinical-genetic risk model, and explored the clinical utility of the model in identifying high-risk individuals for AAA screening. METHODS: PRSAAA was calculated using 911,440 SNVs and PRS of coronary artery disease was calculated using 2,324,683 SNVs derived from mixed ancestry genome-wide association studies. The UK Biobank was used as the study cohort. All individuals with complete genetic data available and no diagnosis of AAA at the time of recruitment were included in the analysis and followed prospectively to assess for incident AAA. A PRS-informed clinical model, Prob-AAA, was developed using clinically significant variables and PRSAAA. RESULTS: Four hundred eighty-one thousand one hundred 5 individuals were included in the analysis with 2,668 incident AAA cases. Incident AAA increased from 0.30 to 0.93% between the lowest and highest decile of PRSAAA; similarly, severe AAA, requiring surgery and/or presenting with rupture, increased from 23 to 39% of incident AAA cases across deciles. PRSAAA was a predictor of incident AAA diagnosis (hazard ratio 2.06 [1.70-2.48]) independent of other clinical risk factors including male sex, older age, and smoking history. Prob-AAA was an independent predictor of incident AAA (hazard ratio 1.92 [1.69-2.20]), and identified 9.6% of cases of incident AAA compared to only 4.2% by PRSAAA. Current screening guidelines captured 5.7% of the overall cohort, with an incident AAA rate of approximately 3.2%. Among males not included by current guidelines, Prob-AAA identified an additional cohort, approximately 2% of the overall cohort, with a similar rate of incident AAA. CONCLUSIONS: Prob-AAA, a PRS-informed clinical model for AAA, improved upon the predictive power of current, clinical risk factor-informed, screening guidelines for AAA.


Assuntos
Aneurisma da Aorta Abdominal , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Herança Multifatorial , Fenótipo , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/epidemiologia , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Humanos , Masculino , Fatores de Risco , Medição de Risco , Feminino , Idoso , Estudos Prospectivos , Incidência , Pessoa de Meia-Idade , Técnicas de Apoio para a Decisão , Testes Genéticos , Reino Unido/epidemiologia , Programas de Rastreamento , Prognóstico , Estratificação de Risco Genético
13.
Immunopharmacol Immunotoxicol ; : 1-9, 2024 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-39353867

RESUMO

OBJECTIVE: This study examines the therapeutic potential of monotropein (Mon) in a rat model of acute pulmonary embolism (APE), aiming to elucidate its mechanistic role and provide new insights for APE treatment. METHODS: Thirty Sprague Dawley (SD) rats were randomly assigned to five groups (n = 6 per group): sham, Mon (40 mg/kg), APE, APE + 20 mg/kg Mon, and APE + 40 mg/kg Mon. APE was induced via autologous thrombus infusion in all groups except sham and Mon-only groups. We assessed blood gas parameters, lung wet/dry weight (W/D) ratio, and oxidative stress markers. Additionally, excised lung tissues underwent evaluation for serum inflammatory factors via ELISA, apoptotic cells via TUNEL assay, and protein expression via Western blot. RESULTS: Compared to the sham group, APE-induced rats exhibited significantly elevated blood oxygen levels and increased pro-inflammatory factors, including interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, and IL-8. Mon treatment effectively mitigated these APE-induced changes, reducing blood oxygen concentration and downregulating IL-1ß and TNF-α levels. Furthermore, Mon demonstrated anti-apoptotic effects by decreasing cleaved caspase-3 and Bax protein levels while upregulating Bcl-2 expression. Mon also suppressed nuclear factor-κB (NF-κB) activation by inhibiting the phosphorylation levels of p65/RelA and IκBα proteins, while the total protein level of IκBα was increased with Mon treatment. CONCLUSION: Mon effectively ameliorated lung tissue injury in APE rats by inhibiting apoptosis, attenuating inflammatory responses, and alleviating oxidative stress. These beneficial effects appear to be mediated through modulation of the NF-κB pathway, suggesting Mon as a promising therapeutic candidate for APE treatment.

14.
J Stroke Cerebrovasc Dis ; 33(8): 107788, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38878393

RESUMO

BACKGROUND: Electroacupuncture (EA) could represent a clinically effective treatment strategy for patients with vascular cognitive impairment no dementia (VCIND). This randomized trial aims to explore the underlying mechanism of EA in VCIND patients through cognitive function assessment and neuroimaging assessment. METHODS: 140 eligible patients with VCIND were recruited and randomly divided into EA group (n = 70) and Control group (n = 70). The Montreal Cognitive Assessment (MoCA), and the Auditory Verbal Learning Test (AVLT), the Stroop color-naming task (STROOP), and the resting-state functional magnetic resonance imaging assessment. The EA group received treatment for 30 min/day, 5 times/week, for 8 weeks. RESULTS: EA intervention could increase the MoCA score and improve the neutral and consistency response of the STROOP test in VCIND patients (P < 0.05). fMRI functional connectivity analysis showed that, after EA, the default mode network (DMN) function of the posterior cingulate gyrus, left middle frontal gyrus, left anterior cingulate gyrus, left and right superior temporal gyrus, right insula, left precentral gyrus and other brain regions were significantly higher than that in the control group. The functional connectivity between the posterior cingulate gyrus-left middle frontal gyrus and the posterior cingulate gyrus-right superior temporal gyrus was positively correlated with cognitive function (P < 0.05). Gray Matter Volume increased in VCIND after EA(P < 0.05). CONCLUSIONS: EA can increase the functional connectivity between posterior cingulate gyrus-other gyri in VCIND patients. The functional connectivity is positively correlated with cognitive function.


Assuntos
Cognição , Disfunção Cognitiva , Eletroacupuntura , Imageamento por Ressonância Magnética , Humanos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Resultado do Tratamento , Disfunção Cognitiva/terapia , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/diagnóstico , Fatores de Tempo , Testes de Estado Mental e Demência , Rede de Modo Padrão/fisiopatologia , Rede de Modo Padrão/diagnóstico por imagem , Teste de Stroop , Encéfalo/fisiopatologia , Encéfalo/diagnóstico por imagem
15.
Zhongguo Yi Liao Qi Xie Za Zhi ; 48(1): 44-50, 2024 Jan 30.
Artigo em Zh | MEDLINE | ID: mdl-38384216

RESUMO

This study summarizes the application of automatic recognition technologies for patient-ventilator asynchrony (PVA) during mechanical ventilation. In the early stages, the method of setting rules and thresholds relied on manual interpretation of ventilator parameters and waveforms. While these methods were intuitive and easy to operate, they were relatively sensitive in threshold setting and rule selection and could not adapt well to minor changes in patient status. Subsequently, machine learning and deep learning technologies began to emerge and develop. These technologies automatically extract and learn data characteristics through algorithms, making PVA detection more robust and universal. Among them, logistic regression, support vector machines, random forest, hidden Markov models, convolutional autoencoders, long short-term memory networks, one-dimensional convolutional neural networks, etc., have all been successfully used for PVA recognition. Despite the significant advancements in feature extraction through deep learning methods, their demand for labelled data is high, potentially consuming significant medical resources. Therefore, the combination of reinforcement learning and self-supervised learning may be a viable solution. In addition, most algorithm validations are based on a single dataset, so the need for cross-dataset validation in the future will be an important and challenging direction for development.


Assuntos
Assincronia Paciente-Ventilador , Respiração Artificial , Humanos , Ventiladores Mecânicos , Algoritmos , Redes Neurais de Computação
16.
J Struct Biol ; 215(3): 107996, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37419228

RESUMO

The evolving SARS-CoV-2 Omicron strain has repeatedly caused widespread disease epidemics, and effective antibody drugs continue to be in short supply. Here, we identified a batch of nanobodies with high affinity for receptor binding domain (RBD) of SARS-CoV-2 spike protein, separated them into three classes using high performance liquid chromatography (HPLC), and then resolved the crystal structure of the ternary complexes of two non-competing nanobodies (NB1C6 and NB1B5) with RBD using X-ray crystallography. The structures showed that NB1B5 and NB1C6 bind to the left and right flank of the RBD, respectively, and that the binding epitopes are highly conserved cryptic sites in all SARS-CoV-2 mutant strains, as well as that NB1B5 can effectively block the ACE2. These two nanobodies were covalently linked into multivalent and bi-paratopic formats, and have a high affinity and neutralization potency for omicron, potentially inhibiting viral escape. The binding sites of these two nanobodies are relatively conserved, which help guide the structural design of antibodies targeting future variants of SARS-CoV-2 to combat COVID-19 epidemics and pandemics.


Assuntos
COVID-19 , Anticorpos de Domínio Único , Humanos , SARS-CoV-2/genética , Anticorpos , Epitopos/genética , Anticorpos Neutralizantes
17.
Mol Cancer ; 22(1): 157, 2023 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-37770864

RESUMO

BACKGROUND: Although colonoscopy is the standard screening test for colorectal cancer (CRC), its use is limited by a poor compliance rate, the need for extensive bowel preparation, and the risk of complications. As an alternative, an FDA-approved stool-based DNA test, Cologuard, has demonstrated satisfactory detection performance for CRC, but its compliance rate remains suboptimal, primarily attributable to individuals' reluctance to provide stool samples. METHODS: We developed a noninvasive blood-based CRC test, ColonSecure, based on cell-free DNA containing cancer-specific CpG island methylation patterns. We initially screened publicly available datasets for differentially methylated CpG sites in CRC with prediction potential. Subsequently, we performed two sequential bisulfite-free methylation sequencing on blood samples obtained from CRC patients and non-cancer controls. Through rigorous evaluation of each marker and machine learning-assisted feature selection, we identified 149 hypermethylated markers from over 193,000 CpG sites. These markers were then utilized to construct the ColonSecure model, enabling accurate CRC detection. RESULTS: We validated the efficacy of our cell-free DNA methylation-based blood test for CRC screening with 3493 high-risk individuals identified from 114,136 urban residents. The ColonSecure test identified 89 out of 103 CRC patients diagnosed by the follow-up colonoscopy, outperforming CEA, CRP, and CA19-9 (with a sensitivity of 86.4% compared to 45.6%, 39.8%, and 25.2% for CEA, CRP, and CA19-9 respectively; an AUROC of 0.956 compared to an AUROC of < 0.77 for other methods). CONCLUSION: Our observations emphasize the potential of our multiple cfDNA methylation marker-based test for CRC screening in high-risk populations.


Assuntos
Ácidos Nucleicos Livres , Neoplasias Colorretais , Humanos , Metilação de DNA , Ácidos Nucleicos Livres/genética , Estudos Prospectivos , Antígeno CA-19-9 , Detecção Precoce de Câncer , Ilhas de CpG , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Biomarcadores Tumorais/genética
18.
Prostate ; 83(5): 454-461, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36567534

RESUMO

BACKGROUND: Although men of African ancestry (AA) have the highest mortality rate from prostate cancer (PCa), relatively little is known about the germline variants that are associated with PCa risk in AA men. The goal of this study is to systematically evaluate rare, recurrent nonsynonymous variants across the exome for their association with PCa in AA men. METHODS: Whole exome sequencing (WES) of germline DNA in two AA PCa patient cohorts of Johns Hopkins Hospital (N = 960) and Wayne State University (N = 747) was performed. All nonsynonymous variants present in both case cohorts, with a carrier rate between 0.5% and 1%, were identified. Their carrier rates were compared with rates from 8128 African/African American (AFR) control subjects from The Genome Aggregation Database (gnomAD) using Fisher's exact test. Significant variants, defined as false discovery rate (FDR) adjusted p-value ≤ 0.05, were further evaluated in AA PCa cases (N = 132) and controls (N = 1184) from the UK Biobank (UKB). RESULTS: Two variants reached a pre-specified statistical significance level. The first was p.R14Q in GPRC5C (found in 0.47% of PCa cases and 0.01% of population controls); odds ratio (OR) for PCa was 37.46 (95% confidence interval CI 4.68-299.72), pexact = 7.01E-06, FDR-adjusted p-value = 0.05. The second was p.R511Q in IGF1R (found in 0.53% of PCa cases and 0.01% of population controls); OR for PCa was 21.54 (95%CI 4.65-99.76), pexact = 5.51E-06, FDR-adjusted p-value = 0.05. The mean percentage of African ancestry was similar between variant carriers and noncarriers of each variant, p > 0.05. In the UKB AA men, GPRC5C R14Q was 0.76% and 0.08% in cases and controls, respectively, OR for PCa was 9.00 (95%CI 0.56-145.23), pexact = 0.19. However, IGF1R R511Q was not found in cases or controls. CONCLUSIONS: This WES study identified two rare, recurrent nonsynonymous PCa risk-associated variants in AA. Confirmation in additional large populations of AA PCa cases and controls is required.


Assuntos
Mutação em Linhagem Germinativa , Neoplasias da Próstata , Humanos , Masculino , Negro ou Afro-Americano , Células Germinativas , Heterozigoto , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/genética , População Negra
19.
Opt Express ; 31(20): 31993-32009, 2023 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-37859012

RESUMO

Infrared micro-lens arrays (MLAs) are widely used in advanced optical systems due to their advantages such as low focusing depth and high sensitivity. Elliptical vibration cutting (EVC) is a promising approach for the fabrication of MLAs on infrared brittle materials. However, the mechanism of ductile machining of MLAs prepared by EVC has not been fully elucidated so far. In this paper, based on the vibration intermittent cutting characteristics and the transient material removal state, a ductile machining model of MLAs on brittle material by EVC was established. This model effectively calculates the subsurface damage of the machined surface and realizes the prediction of the critical depth for ductile machining of MLAs. Furthermore, the concave micro-lenses were prepared on single crystal silicon by EVC and ordinary cutting (OC) to verify this model. The results demonstrated that EVC could significantly enhance the critical depth by approximately 4.3 times compared to OC. Microstructural surface damage predominantly occurs at the exit side of the tool cutting. This proposed model accurately predicts the actual critical depth, with an average error of about 7.5%. Additionally, elevating the amplitude in the depth of cut direction could increase the critical depth, but a larger amplitude would inhibit the increase of the critical depth. This study contributes to a better understanding of ductile machining of microstructure on brittle materials and facilitates the process optimization of MLAs fabrication using EVC.

20.
Protein Expr Purif ; 207: 106267, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37030644

RESUMO

Coronavirus Papain-like protease (PLpro) mediates the cleavage of viral polyproteins and assists the virus escaping from innate immune response. Thus, PLpro is an attractive target for the development of broad-spectrum drugs as it has a conserved structure across different coronaviruses. In this study, we purified SARS-CoV-2 PLpro as an immune antigen, constructed a nanobody phage display library, and identified a set of nanobodies with high affinity for SARS-CoV-2. In addition, enzyme activity experiments demonstrated that two nanobodies had a significant inhibitory effect on the PLpro. These nanobodies should therefore be investigated as candidates for the treatment of coronaviruses.


Assuntos
COVID-19 , Anticorpos de Domínio Único , Humanos , Proteases Semelhantes à Papaína de Coronavírus , SARS-CoV-2 , Peptídeo Hidrolases , Papaína/química
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