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Nearly all prostate cancer deaths are from metastatic castration-resistant prostate cancer (mCRPC), but there have been few whole-genome sequencing (WGS) studies of this disease state. We performed linked-read WGS on 23 mCRPC biopsy specimens and analyzed cell-free DNA sequencing data from 86 patients with mCRPC. In addition to frequent rearrangements affecting known prostate cancer genes, we observed complex rearrangements of the AR locus in most cases. Unexpectedly, these rearrangements include highly recurrent tandem duplications involving an upstream enhancer of AR in 70%-87% of cases compared with <2% of primary prostate cancers. A subset of cases displayed AR or MYC enhancer duplication in the context of a genome-wide tandem duplicator phenotype associated with CDK12 inactivation. Our findings highlight the complex genomic structure of mCRPC, nominate alterations that may inform prostate cancer treatment, and suggest that additional recurrent events in the non-coding mCRPC genome remain to be discovered.
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Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/genética , Sequenciamento Completo do Genoma , Idoso , Anilidas/uso terapêutico , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Elementos Facilitadores Genéticos/genética , Duplicação Gênica , Rearranjo Gênico , Genes myc , Loci Gênicos , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , PTEN Fosfo-Hidrolase/genética , Fenótipo , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêuticoRESUMO
Early spliceosome assembly can occur through an intron-defined pathway, whereby U1 and U2 small nuclear ribonucleoprotein particles (snRNPs) assemble across the intron1. Alternatively, it can occur through an exon-defined pathway2-5, whereby U2 binds the branch site located upstream of the defined exon and U1 snRNP interacts with the 5' splice site located directly downstream of it. The U4/U6.U5 tri-snRNP subsequently binds to produce a cross-intron (CI) or cross-exon (CE) pre-B complex, which is then converted to the spliceosomal B complex6,7. Exon definition promotes the splicing of upstream introns2,8,9 and plays a key part in alternative splicing regulation10-16. However, the three-dimensional structure of exon-defined spliceosomal complexes and the molecular mechanism of the conversion from a CE-organized to a CI-organized spliceosome, a pre-requisite for splicing catalysis, remain poorly understood. Here cryo-electron microscopy analyses of human CE pre-B complex and B-like complexes reveal extensive structural similarities with their CI counterparts. The results indicate that the CE and CI spliceosome assembly pathways converge already at the pre-B stage. Add-back experiments using purified CE pre-B complexes, coupled with cryo-electron microscopy, elucidate the order of the extensive remodelling events that accompany the formation of B complexes and B-like complexes. The molecular triggers and roles of B-specific proteins in these rearrangements are also identified. We show that CE pre-B complexes can productively bind in trans to a U1 snRNP-bound 5' splice site. Together, our studies provide new mechanistic insights into the CE to CI switch during spliceosome assembly and its effect on pre-mRNA splice site pairing at this stage.
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Éxons , Íntrons , Splicing de RNA , Spliceossomos , Humanos , Processamento Alternativo , Microscopia Crioeletrônica , Éxons/genética , Íntrons/genética , Modelos Moleculares , Sítios de Splice de RNA/genética , Splicing de RNA/genética , Spliceossomos/metabolismo , Spliceossomos/química , Spliceossomos/ultraestrutura , Ribonucleoproteínas Nucleares Pequenas/química , Ribonucleoproteínas Nucleares Pequenas/metabolismo , Ribonucleoproteínas Nucleares Pequenas/ultraestruturaRESUMO
The B complex is a key intermediate stage of spliceosome assembly. To improve the structural resolution of monomeric, human spliceosomal B (hB) complexes and thereby generate a more comprehensive hB molecular model, we determined the cryo-EM structure of B complex dimers formed in the presence of ATP γ S. The enhanced resolution of these complexes allows a finer molecular dissection of how the 5' splice site (5'ss) is recognized in hB, and new insights into molecular interactions of FBP21, SNU23 and PRP38 with the U6/5'ss helix and with each other. It also reveals that SMU1 and RED are present as a heterotetrameric complex and are located at the interface of the B dimer protomers. We further show that MFAP1 and UBL5 form a 5' exon binding channel in hB, and elucidate the molecular contacts stabilizing the 5' exon at this stage. Our studies thus yield more accurate models of protein and RNA components of hB complexes. They further allow the localization of additional proteins and protein domains (such as SF3B6, BUD31 and TCERG1) whose position was not previously known, thereby uncovering new functions for B-specific and other hB proteins during pre-mRNA splicing.
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Splicing de RNA , Spliceossomos , Humanos , Spliceossomos/genética , Microscopia Crioeletrônica , Sítios de Splice de RNA , Éxons , Precursores de RNA/genética , Precursores de RNA/metabolismo , Fatores de Elongação da Transcrição/genética , Proteínas Nucleares/metabolismoRESUMO
During the splicing of introns from precursor messenger RNAs (pre-mRNAs), the U2 small nuclear ribonucleoprotein (snRNP) must undergo stable integration into the spliceosomal A complex-a poorly understood, multistep process that is facilitated by the DEAD-box helicase Prp5 (refs. 1-4). During this process, the U2 small nuclear RNA (snRNA) forms an RNA duplex with the pre-mRNA branch site (the U2-BS helix), which is proofread by Prp5 at this stage through an unclear mechanism5. Here, by deleting the branch-site adenosine (BS-A) or mutating the branch-site sequence of an actin pre-mRNA, we stall the assembly of spliceosomes in extracts from the yeast Saccharomyces cerevisiae directly before the A complex is formed. We then determine the three-dimensional structure of this newly identified assembly intermediate by cryo-electron microscopy. Our structure indicates that the U2-BS helix has formed in this pre-A complex, but is not yet clamped by the HEAT domain of the Hsh155 protein (Hsh155HEAT), which exhibits an open conformation. The structure further reveals a large-scale remodelling/repositioning of the U1 and U2 snRNPs during the formation of the A complex that is required to allow subsequent binding of the U4/U6.U5 tri-snRNP, but that this repositioning is blocked in the pre-A complex by the presence of Prp5. Our data suggest that binding of Hsh155HEAT to the bulged BS-A of the U2-BS helix triggers closure of Hsh155HEAT, which in turn destabilizes Prp5 binding. Thus, Prp5 proofreads the branch site indirectly, hindering spliceosome assembly if branch-site mutations prevent the remodelling of Hsh155HEAT. Our data provide structural insights into how a spliceosomal helicase enhances the fidelity of pre-mRNA splicing.
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RNA Helicases DEAD-box/química , RNA Helicases DEAD-box/metabolismo , Precursores de RNA/química , Precursores de RNA/genética , Splicing de RNA , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae , Spliceossomos/enzimologia , Actinas/genética , Adenosina/metabolismo , Sítios de Ligação , Microscopia Crioeletrônica , RNA Helicases DEAD-box/ultraestrutura , Modelos Moleculares , Mutação , Domínios Proteicos , Precursores de RNA/metabolismo , Precursores de RNA/ultraestrutura , Splicing de RNA/genética , Ribonucleoproteína Nuclear Pequena U1/metabolismo , Ribonucleoproteína Nuclear Pequena U2/química , Ribonucleoproteína Nuclear Pequena U2/metabolismo , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/ultraestrutura , Proteínas de Saccharomyces cerevisiae/ultraestrutura , Spliceossomos/química , Spliceossomos/metabolismoRESUMO
The U2 small nuclear ribonucleoprotein (snRNP) has an essential role in the selection of the precursor mRNA branch-site adenosine, the nucleophile for the first step of splicing1. Stable addition of U2 during early spliceosome formation requires the DEAD-box ATPase PRP52-7. Yeast U2 small nuclear RNA (snRNA) nucleotides that form base pairs with the branch site are initially sequestered in a branchpoint-interacting stem-loop (BSL)8, but whether the human U2 snRNA folds in a similar manner is unknown. The U2 SF3B1 protein, a common mutational target in haematopoietic cancers9, contains a HEAT domain (SF3B1HEAT) with an open conformation in isolated SF3b10, but a closed conformation in spliceosomes11, which is required for stable interaction between U2 and the branch site. Here we report a 3D cryo-electron microscopy structure of the human 17S U2 snRNP at a core resolution of 4.1 Å and combine it with protein crosslinking data to determine the molecular architecture of this snRNP. Our structure reveals that SF3B1HEAT interacts with PRP5 and TAT-SF1, and maintains its open conformation in U2 snRNP, and that U2 snRNA forms a BSL that is sandwiched between PRP5, TAT-SF1 and SF3B1HEAT. Thus, substantial remodelling of the BSL and displacement of BSL-interacting proteins must occur to allow formation of the U2-branch-site helix. Our studies provide a structural explanation of why TAT-SF1 must be displaced before the stable addition of U2 to the spliceosome, and identify RNP rearrangements facilitated by PRP5 that are required for stable interaction between U2 and the branch site.
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Microscopia Crioeletrônica , Ribonucleoproteína Nuclear Pequena U2/química , Ribonucleoproteína Nuclear Pequena U2/ultraestrutura , Sequência de Bases , RNA Helicases DEAD-box/química , RNA Helicases DEAD-box/metabolismo , Células HeLa , Humanos , Modelos Moleculares , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Ligação Proteica , Conformação Proteica , Fatores de Processamento de RNA/química , Fatores de Processamento de RNA/metabolismo , Ribonucleoproteína Nuclear Pequena U2/genética , Ribonucleoproteína Nuclear Pequena U2/metabolismo , Transativadores/química , Transativadores/metabolismoRESUMO
α-PD-L1 therapy has shown encouraging results at harnessing the immune system to combat cancer. However, the treatment effect is relatively low due to the dense extracellular matrix (ECM) and tumor immunosuppressive microenvironment (TIME). Therefore, an ultrasound (US)-responsive nanosensitizer (URNS) is engineered to deliver losartan (LST) and polyethylenimine (PEI) to remolde the TME, driving "cold"-"hot" tumor transformation and enhancing the sensitivity of α-PD-L1 therapy. In the tumor site, noninvasive US can make MTNP generate ROS, which cleave ROS-sensitive bonds to dissociate MTNPtK@LST-PEI, shedding PEI and releasing LST from mesoporous spheres. The results demonstrated that URNS combined with α-PD-L1 therapy effectively inhibited tumor growth with an inhibition rate as high as 90%, which was 1.7-fold higher than that of the α-PD-L1 treatment in vivo. In summary, the URNS improves the sensitivity of α-PD-L1 therapy by remodeling the TME, which provides promising insights for optimizing cancer immunotherapy.
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Antígeno B7-H1 , Neoplasias , Humanos , Espécies Reativas de Oxigênio , Matriz Extracelular , Imunossupressores , Imunoterapia , Losartan , Polietilenoimina , Microambiente TumoralRESUMO
Surgery is the standard of care for patients with primary renal cell carcinoma. Stereotactic body radiotherapy (SBRT) is a novel alternative for patients who are medically inoperable, technically high risk, or who decline surgery. Evidence for using SBRT in the primary renal cell carcinoma setting is growing, including several rigorously conducted prospective clinical trials. This systematic review was performed to assess the safety and efficacy of SBRT for primary renal cell carcinoma. Review results then formed the basis for the practice guidelines described, on behalf of the International Stereotactic Radiosurgery Society. 3972 publications were screened and 36 studies (822 patients) were included in the analysis. Median local control rate was 94·1% (range 70·0-100), 5-year progression-free survival was 80·5% (95% CI 72-92), and 5-year overall survival was 77·2% (95% CI 65-89). These practice guidelines addressed four key clinical questions. First, the optimal dose fractionation was 25-26 Gy in one fraction, or 42-48 Gy in three fractions for larger tumours. Second, routine post-treatment biopsy is not recommended as it is not predictive of patient outcome. Third, SBRT for primary renal cell carcinoma in a solitary kidney is safe and effective. Finally, guidelines for post-treatment follow-up are described, which include cross-axial imaging of the abdomen including both kidneys, adrenals, and surveillance of the chest initially every 6 months. This systematic review and practice guideline support the practice of SBRT for primary renal cell carcinoma as a safe and effective standard treatment option. Randomised trials with surgery and invasive ablative therapies are needed to further define best practice.
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Carcinoma de Células Renais , Neoplasias Renais , Radiocirurgia , Humanos , Carcinoma de Células Renais/radioterapia , Carcinoma de Células Renais/cirurgia , Rim , Neoplasias Renais/radioterapia , Neoplasias Renais/cirurgia , Estudos Prospectivos , Radiocirurgia/efeitos adversosRESUMO
BACKGROUND & AIMS: Crotonylation, a crotonyl-CoA-based non-enzymatic protein translational modification, affects diverse biological processes, such as spermatogenesis, tissue injury, inflammation, and neuropsychiatric diseases. Crotonylation is decreased in hepatocellular carcinomas (HCCs), but the mechanism remains unknown. In this study, we aim to describe the role of glutaryl-CoA dehydrogenase (GCDH) in tumor suppression. METHODS: Three cohorts containing 40, 248 and 17 pairs of samples were used to evaluate the link between GCDH expression levels and clinical characteristics of HCC, as well as responses to anti-programmed cell death protein 1 (PD-1) treatment. Subcutaneous xenograft, orthotopic xenograft, Trp53Δhep/Δhep; MYC- and Ctnnboe;METoe-driven mouse models were adopted to validate the effects of GCDH on HCC suppression. RESULTS: GCDH depletion promoted HCC growth and metastasis, whereas its overexpression reversed these processes. As GCDH converts glutaryl-CoA to crotonyl-CoA to increase crotonylation levels, we performed lysine crotonylome analysis and identified the pentose phosphate pathway (PPP) and glycolysis-related proteins PGD, TKT, and ALDOC as GCDH-induced crotonylation targets. Crotonyl-bound targets showed allosteric effects that controlled their enzymatic activities, leading to decreases in ribose 5-phosphate and lactate production, further limiting the Warburg effect. PPP blockade also stimulated peroxidation, synergizing with senescent modulators to induce senescence in GCDHhigh cells. These cells induced the infiltration of immune cells by the SASP (senescence-associated secretory cell phenotype) to shape an anti-tumor immune microenvironment. Meanwhile, the GCDHlow population was sensitized to anti-PD-1 therapy. CONCLUSION: GCDH inhibits HCC progression via crotonylation-induced suppression of the PPP and glycolysis, resulting in HCC cell senescence. The senescent cell further shapes an anti-tumor microenvironment via the SASP. The GCDHlow population is responsive to anti-PD-1 therapy because of the increased presence of PD-1+CD8+ T cells. IMPACT AND IMPLICATIONS: Glutaryl-CoA dehydrogenase (GCDH) is a favorable prognostic indicator in liver, lung, and renal cancers. In addition, most GCDH depletion-induced toxic metabolites originate from the liver, accumulate locally, and cannot cross the blood-brain barrier. Herein, we show that GCDH inhibits hepatocellular carcinoma (HCC) progression via crotonylation-induced suppression of the pentose phosphate pathway and glycolysis, resulting in HCC cell senescence. We also found that more PD-1+CD8+ T cells are present in the GCDHlow population, who are thus more responsive to anti-PD-1 therapy. Given that the GCDHlow and GCDHhigh HCC population can be distinguished based on serum glucose and ammonia levels, it will be worthwhile to evaluate the curative effects of pro-senescent and immune-therapeutic strategies based on the expression levels of GCDH.
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OBJECTIVES: To evaluate carbapenem prescribing rates for initial definitive treatment of urinary tract infections and clinical outcomes before and after removing ESBL status labels on antibiotic susceptibility reports. METHODS: This was a retrospective cohort study of adult patients treated for at least 48â h for an ESBL-producing/ceftriaxone-resistant Enterobacterales urinary tract infection. ESBL status reporting ceased in September 2022 for a network of seven community hospitals within the USA. The primary endpoint was the rate of carbapenem prescribing for initial definitive treatment of urinary tract infections. Secondary endpoints included total days of therapy for initial definitive treatment with carbapenems, clinical cure rates, time to transition to oral antibiotic therapy for initial definitive treatment, rate of guideline-compliant therapy, rate of relapsed infection within 30â days, 30â day readmission rate, and 30â day all-cause in-hospital mortality. RESULTS: Of 3055 patients screened, 199 were included in the pre group and 153 were included in the post group. The rate of carbapenem prescribing for initial definitive treatment was 156 patients (78%) in the pre group, compared with 93 patients (61%) in the post group (Pâ=â<0.01). Days of therapy for initial definitive therapy with carbapenem was 620 in the pre group compared with 372 in the post group (Pâ<â0.01). There was no difference between other secondary outcomes. CONCLUSIONS: Removing ESBL status labels from laboratory reports reduced carbapenem use for initial definitive treatment of urinary tract infections from 78% to 61% (Pâ<â0.01) without impacting clinical outcomes.
Assuntos
Antibacterianos , Carbapenêmicos , Infecções por Enterobacteriaceae , Infecções Urinárias , beta-Lactamases , Humanos , Carbapenêmicos/uso terapêutico , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Estudos Retrospectivos , Feminino , Masculino , Pessoa de Meia-Idade , Antibacterianos/uso terapêutico , Idoso , Infecções por Enterobacteriaceae/tratamento farmacológico , Infecções por Enterobacteriaceae/microbiologia , Testes de Sensibilidade Microbiana , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/enzimologia , Enterobacteriaceae/isolamento & purificação , Adulto , Idoso de 80 Anos ou mais , Gestão de AntimicrobianosRESUMO
The first ruthenium-catalyzed carboamination of olefins with α-carbonyl sulfoxonium ylides is reported. The utilization of an inexpensive ruthenium catalyst enables the concise synthesis of pharmaceutically important isoindolin-1-ones, which possess both a stereogenic center and ß-carbonyl side chain. This method is mild, efficient, and scalable and allows for the coupling of a wide range of aryl-, heteroaryl-, alkenyl-, and alkyl-substituted sulfoxonium ylides. Moreover, the carbonyl side chain in the resulting product provides a good handle for downstream transformations. For mechanistic studies, a ruthacyle complex is obtained and proven to be the key intermediate in both catalytic and stoichiometric reactions.
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Carbon emission reduction is an important measure to mitigate the greenhouse effect, which has become a hotspot in global climate change research. To contribute to this, here, we fabricated two Co-based metal-organic frameworks (Co-MOFs), namely, {[Co3(NTB)2(bib)]·(DMA)2·(H2O)4}n (DZU-211) and {[Co3(NTB)2(bmip)]·(DMA)2}n (DZU-212) (H3NTB = 4,4',4â³-nitrilotribenzoic acid, bib = 1,4-bis(imidazol-1-yl)-butane, bmip = 1,3-bis(2-methyl-1H-imidazol-1-yl)propane) to realize efficient CO2/N2 separation by dividing coordination spaces into suitable pores with narrow windows. DZU-211 reveals a 3D open porous framework, while DZU-212 exhibits a 3D double-fold interpenetrated structure. The two MOFs both possess large coordination spaces and small open pore sizes, via the bib ligand insertion and framework interpenetration, respectively. Comparatively, DZU-211 reveals superior selective CO2 uptake properties due to its more suitable pore characteristics. Gas sorption experiments show that DZU-211 has a CO2 uptake of 52.6 cm3 g-1 with a high simulated CO2/N2 selectivity of 101.7 (298 K, 1 atm) and a moderate initial adsorption heat of 38.1 kJ mol-1. Moreover, dynamic breakthrough experiments confirm the potential application of DZU-211 as a CO2 separation material from postcombustion flue gases.
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Photoactive conjugated microporous polymers (CMPs) as heterogeneous photocatalysts provide a sustainable alternative to classical metal-based semiconductor photosensitizers. However, previously reported CMPs are typically synthesized through metal catalyzed coupling reactions, which bears product separation, but also increases the price of materials. Herein, a new type of sp2 carbon linked DCM-CMPs are successfully designed and synthesized by organic base catalyzed Knoevenagel reaction using 2,6-Dimethyl-4H-pyran-4-ylidene-malononitrile and aromatic polyaldehydes as monomers. The new polymers feature inherent porosity, excellent stability, and fully π-conjugated skeleton with broad visible-light absorption. They effectively induce the synthesis of benzimidazole compounds under light irradiation, and exhibit wide substrate adaptability with outstanding recyclability.
Assuntos
Nitrilas , Processos Fotoquímicos , Polímeros , Catálise , Nitrilas/química , Porosidade , Polímeros/química , Polímeros/síntese química , Estrutura Molecular , Luz , Piranos/química , Piranos/síntese química , Propriedades de Superfície , Benzimidazóis/química , Tamanho da PartículaRESUMO
A brand-new class of interstitial cells, called telocytes, has been detected in the heart. Telocytes can connect and transmit signals to almost all cardiomyocytes; this is highly interrelated with the occurrence and development of heart diseases. Modern studies have shown that berberine has a therapeutic effect on cardiovascular health. However, berberine's mechanism of action on the cardiovascular system through cardiac telocytes is unclear. Interestingly, 5 µm of berberine remarkably decreased the concentration of intracellular calcium and membrane depolarization in cultured telocytes, upregulated the expression of CX43 and ß-catenin, and downregulated the expressions of TRPV4 and TRPV1. Here, telocytes were identified in the vascular adventitia and intima, endocardium, myocardium, adventitia, and heart valves. Moreover, telocytes were broadly dispersed around cardiac vessels and interacted directly through gap junctions and indirectly through extracellular vesicles. Together, cardiac telocytes interact with berberine and then deliver drug information to the heart. Telocytes may be an essential cellular target for drug therapy of the cardiovascular system.
Assuntos
Berberina , Telócitos , Animais , Coelhos , Berberina/farmacologia , Miocárdio/metabolismo , Telócitos/metabolismo , Endocárdio/metabolismo , Miócitos CardíacosRESUMO
In recent years, there has been explosive development in artificial intelligence (AI), which has been widely applied in the health care field. As a typical AI technology, machine learning models have emerged with great potential in predicting cardiovascular diseases by leveraging large amounts of medical data for training and optimization, which are expected to play a crucial role in reducing the incidence and mortality rates of cardiovascular diseases. Although the field has become a research hot spot, there are still many pitfalls that researchers need to pay close attention to. These pitfalls may affect the predictive performance, credibility, reliability, and reproducibility of the studied models, ultimately reducing the value of the research and affecting the prospects for clinical application. Therefore, identifying and avoiding these pitfalls is a crucial task before implementing the research. However, there is currently a lack of a comprehensive summary on this topic. This viewpoint aims to analyze the existing problems in terms of data quality, data set characteristics, model design, and statistical methods, as well as clinical implications, and provide possible solutions to these problems, such as gathering objective data, improving training, repeating measurements, increasing sample size, preventing overfitting using statistical methods, using specific AI algorithms to address targeted issues, standardizing outcomes and evaluation criteria, and enhancing fairness and replicability, with the goal of offering reference and assistance to researchers, algorithm developers, policy makers, and clinical practitioners.
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Doenças Cardiovasculares , Aprendizado de Máquina , Humanos , Reprodutibilidade dos Testes , AlgoritmosRESUMO
OBJECTIVES: Many epidemiological studies have shown that coronavirus disease 2019 (COVID-19) disproportionately affects males, compared with females, although other studies show that there were no such differences. The aim of the present study was to assess differences in the prevalence of hospitalizations and in-hospital outcomes between the sexes, using a larger administrative database. METHODS: We used the 2020 California State Inpatient Database for this retrospective analysis. International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis code U07.1 was used to identify COVID-19 hospitalizations. These hospitalizations were subsequently stratified by male and female sex. Diagnosis and procedures were identified using the International Classification of Diseases, Tenth Revision, Clinical Modification codes. The primary outcome of the study was hospitalization rate, and secondary outcomes were in-hospital mortality, prolonged length of stay, vasopressor use, mechanical ventilation, and intensive care unit (ICU) admission. RESULTS: There were 95,180 COVID-19 hospitalizations among patients 18 years and older, 52,465 (55.1%) of which were among men and 42,715 (44.9%) were among women. In-hospital mortality (12.4% vs 10.1%), prolonged length of hospital stays (30.6% vs 25.8%), vasopressor use (2.6% vs 1.6%), mechanical ventilation (11.8% vs 8.0%), and ICU admission rates (11.4% versus 7.8%) were significantly higher among male compared with female hospitalizations. Conditional logistic regression analysis showed that the odds of mortality (odds ratio [OR] 1.38, 95% confidence interval [CI] 1.38-1.44), hospital lengths of stay (OR 1.35, 95% CI 1.31-1.39), vasopressor use (OR 1.59, 95% CI 1.51-1.66), mechanical ventilation (OR 1.62, 95% CI 1.47-1.78), and ICU admission rates (OR 1.58, 95% CI 1.51-1.66) were significantly higher among male hospitalizations. CONCLUSION: Our findings show that male sex is an independent and strong risk factor associated with COVID-19 severity.
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COVID-19 , Humanos , Masculino , Feminino , COVID-19/epidemiologia , COVID-19/terapia , Estudos Retrospectivos , Fatores Sexuais , Hospitalização , Unidades de Terapia Intensiva , Hospitais , Mortalidade HospitalarRESUMO
Depression is a major psychological disorder with a growing impact worldwide. Traditional methods for detecting the risk of depression, predominantly reliant on psychiatric evaluations and self-assessment questionnaires, are often criticized for their inefficiency and lack of objectivity. Advancements in deep learning have paved the way for innovations in depression risk detection methods that fuse multimodal data. This paper introduces a novel framework, the Audio, Video, and Text Fusion-Three Branch Network (AVTF-TBN), designed to amalgamate auditory, visual, and textual cues for a comprehensive analysis of depression risk. Our approach encompasses three dedicated branches-Audio Branch, Video Branch, and Text Branch-each responsible for extracting salient features from the corresponding modality. These features are subsequently fused through a multimodal fusion (MMF) module, yielding a robust feature vector that feeds into a predictive modeling layer. To further our research, we devised an emotion elicitation paradigm based on two distinct tasks-reading and interviewing-implemented to gather a rich, sensor-based depression risk detection dataset. The sensory equipment, such as cameras, captures subtle facial expressions and vocal characteristics essential for our analysis. The research thoroughly investigates the data generated by varying emotional stimuli and evaluates the contribution of different tasks to emotion evocation. During the experiment, the AVTF-TBN model has the best performance when the data from the two tasks are simultaneously used for detection, where the F1 Score is 0.78, Precision is 0.76, and Recall is 0.81. Our experimental results confirm the validity of the paradigm and demonstrate the efficacy of the AVTF-TBN model in detecting depression risk, showcasing the crucial role of sensor-based data in mental health detection.
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Depressão , Humanos , Depressão/diagnóstico , Gravação em Vídeo , Emoções/fisiologia , Aprendizado Profundo , Expressão Facial , Feminino , Masculino , Adulto , Redes Neurais de ComputaçãoRESUMO
The interactions between plants and rhizosphere microbes mediated by plant root exudates are increasingly being investigated. The root-derived metabolites of medicinal plants are relatively diverse and have unique characteristics. However, whether medicinal plants influence their rhizosphere microbial community remains unknown. How medicinal plant species drive rhizosphere microbial community changes should be clarified. In this study involving high-throughput sequencing of rhizosphere microbes and an analysis of root exudates using a gas chromatograph coupled with a time-of-flight mass spectrometer, we revealed that the root exudate metabolites and microorganisms differed among the rhizosphere soils of five medicinal plants. Moreover, the results of a correlation analysis indicated that bacterial and fungal profiles in the rhizosphere soils of the five medicinal plants were extremely significantly or significantly affected by 10 root-associated metabolites. Furthermore, among the 10 root exudate metabolites, two (carvone and zymosterol) had opposite effects on rhizosphere bacteria and fungi. Our study findings suggest that plant-derived exudates modulate changes to rhizosphere microbial communities.
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Bactérias , Microbiota , Raízes de Plantas , Plantas Medicinais , Rizosfera , Microbiologia do Solo , Raízes de Plantas/microbiologia , Raízes de Plantas/metabolismo , Plantas Medicinais/microbiologia , Plantas Medicinais/metabolismo , Bactérias/metabolismo , Bactérias/classificação , Bactérias/genética , Exsudatos de Plantas/metabolismo , Fungos/metabolismoRESUMO
Two-dimensional covalent organic frameworks (2D-COFs) have recently emerged as fascinating scaffolds for solar-to-chemical energy conversion because of their customizable structures and functionalities. Herein, two tris(triazolo)triazine-based COF materials (namely COF-JLU51 and COF-JLU52) featuring large surface area, high crystallinity, excellent stability and photoelectric properties were designed and constructed for the first time. Remarkably, COF-JLU51 gave an outstanding H2O2 production rate of over 4200â µmol g-1 h-1 with excellent reusability in pure water and O2 under one standard sun light, that higher than its isomorphic COF-JLU52 and most of the reported metal-free materials, owing to its superior generation, separation and transport of photogenerated carriers. Experimental and theoretical researches prove that the photocatalytic process undergoes a combination of indirect 2e- O2 reduction reaction (ORR) and 4e- H2O oxidation reaction (WOR). Specifically, an ultrahigh yield of 7624.7â µmol g-1 h-1 with apparent quantum yield of 18.2 % for COF-JLU52 was achieved in a 1 : 1 ratio of benzyl alcohol and water system. This finding contributes novel, nitrogen-rich and high-quality tris(triazolo)triazine-based COF materials, and also designate their bright future in photocatalytic solar transformations.
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Two-dimensional covalent-organic frameworks (2D COFs) have recently emerged as great prospects for their applications as new photocatalytic platforms in solar-to-hydrogen conversion; nevertheless, their inefficient solar energy capture and fast charge recombination hinder the improvement of photocatalytic hydrogen production performance. Herein, two photoactive three-component donor-π-acceptor (TCDA) materials were constructed using a multicomponent synthesis strategy by introducing electron-deficient triazine and electron-rich benzotrithiophene moieties into frameworks through sp2 carbon and imine linkages, respectively. Compared with two-component COFs, the novel TCDA-COFs are more convenient in regulating the inherent photophysical properties, thereby realizing outstanding photocatalytic activity for hydrogen evolution from water. Remarkably, the first sp2 carbon-linked TCDA-COF displays an impressive hydrogen evolution rate of 70.8 ± 1.9 mmol g-1 h-1 with excellent reusability in the presence of 1 wt % Pt under visible-light illumination (420-780 nm). Utilizing the combination of diversified spectroscopy and theoretical prediction, we show that the full π-conjugated linkage not only effectively broadens the visible-light harvesting of COFs but also enhances charge transfer and separation efficiency.
RESUMO
Exploring efficient and low-cost electrocatalysts for the oxygen reduction reaction (ORR) is important for renewable energy conversion. Covalent organic frameworks (COFs) have recently risen as ideal candidates for catalyzing ORR, but this field is still in its infancy. Herein, a new framework material (named as COF-JLU82) containing bifluorenylidene and benzoselenadiazole units with periodic alternating arrangement is designed and synthesized. The metal-free COF-JLU82 exhibits good electrocatalytic activity with a half-wave potential of 0.68 V, Tafel slope of 72.79 mV dec-1 and the conversion frequency (TOF) of 0.0044 s-1 , which is better than the previously reported COF-JLU23. This study enriches the types of COF-based ORR electrocatalysts and promotes the development of more highly efficient metal-free ORR electrocatalysts.