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Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635-0.677) in African and 0.844 (95% CI = 0.840-0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67-2.00) and 2.19 (95% CI = 2.14-2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659-0.700 and AUC = 0.845, 95% CI = 0.841-0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87-2.26 and OR = 2.21, 95% CI = 2.16-2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS269 developed from multi-ancestry GWASs and fine-mapping.
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Predisposição Genética para Doença , Neoplasias da Próstata , Humanos , Masculino , População Negra/genética , Estudo de Associação Genômica Ampla , Herança Multifatorial/genética , Neoplasias da Próstata/genética , Fatores de Risco , População Branca/genéticaRESUMO
OBJECTIVE: To evaluate the postnatal outcome of children with antenatal colonic hyperechogenicity, currently considered as a sign of lysinuria-cystinuria, but which may also be a sign of other disorders with a more severe prognosis. METHOD: We carried out a French multi-centric retrospective study via 15 Multidisciplinary Center for Prenatal Diagnosis from January 2011 to January 2021. We included pregnancies for which fetal colonic hyperechogenicity had been demonstrated. We collected the investigations performed during pregnancy and at birth as well as the main clinical features of the mother and the child. We then established the prevalence of pathologies such as lysinuria-cystinuria (LC), hypotonia-cystinuria syndrome (HC), or lysinuric protein intolerance (LPI). RESULTS: Among the 33 cases of colonic hyperechogenicity collected, and after exclusion of those lost to follow-up, we identified 63% of children with lysinuria-cystinuria, 8% with lysinuric rotein intolerance, and 4% with hypotonia-cystinuria syndrome. CONCLUSION: Management of prenatal hyperechoic colon should include a specialized consultation with a clinical geneticist to discuss further investigations, which could include invasive amniotic fluid sampling for molecular diagnosis. A better understanding of diagnoses and prognosis should improve medical counseling and guide parental decision making.
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Deleção Cromossômica , Anormalidades Craniofaciais , Cistinúria , Deficiência Intelectual , Doenças Mitocondriais , Hipotonia Muscular , Recém-Nascido , Criança , Gravidez , Humanos , Feminino , Cistinúria/diagnóstico , Cistinúria/metabolismo , Estudos Retrospectivos , Diagnóstico Pré-Natal , Líquido Amniótico/metabolismo , Ultrassonografia Pré-Natal , Cromossomos Humanos Par 21RESUMO
To improve palivizumab administration in high-risk infants with congenital heart disease to 80% over 2 years at an academic children's heart center. A multidisciplinary team at our institution implemented a series of interventions over a 2-year prior. Pediatric cardiac patients were identified for palivizumab eligibility, and a baseline rate of administration was obtained. A series of communication and documentation-based interventions were implemented over the course of the next 2 years. Palivizumab eligible infants (n = 114) were determined based on guidelines after review of diagnosis code, oxygen saturation, and medications. Doses of palivizumab were tracked via the electronic health record. The primary outcome measures were the rate of monthly palivizumab doses administered per the number of eligible months and the percentage of infants who received at least 80% of eligible doses during the respiratory syncytial virus season. The rate of monthly palivizumab doses increased from 57.6% during the baseline period to 78.4% during the final year of the project (p = 0.02). The percentage of infants who received 80% of eligible doses increased from 42.1 to 60% but was not statistically significant (p = 0.20). Interventions focused on properly identifying and tracking infants eligible for palivizumab treatment significantly increased the rates of administration.
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Reducing high concentrations of pollutants such as heavy metals, pesticides, drugs, and dyes from water is an emerging necessity. We evaluated the use of Luffa cylindrica (Lc) as a natural non-conventional adsorbent to remove azo dye mixture (ADM) from water. The capacity of Lc at three different doses (2.5, 5.0, and 10.0 g/L) was evaluated using three concentrations of azo dyes (0.125, 0.250, and 0.500 g/L). The removal percent (R%), maximum adsorption capacity (Qm), isotherm and kinetics adsorption models, and pH influence were evaluated, and Fourier-transform infrared spectroscopy and scanning electron microscopy were performed. The maximum R% was 70.8% for 10.0 g L-1Lc and 0.125 g L-1 ADM. The Qm of Lc was 161.29 mg g-1. Adsorption by Lc obeys a Langmuir isotherm and occurs through the pseudo-second-order kinetic model. Statistical analysis showed that the adsorbent dose, the azo dye concentration, and contact time significantly influenced R% and the adsorption capacity. These findings indicate that Lc could be used as a natural non-conventional adsorbent to reduce ADM in water, and it has a potential application in the pretreatment of wastewaters.
Assuntos
Compostos Azo , Corantes , Luffa , Poluentes Químicos da Água , Purificação da Água , Luffa/química , Compostos Azo/química , Compostos Azo/isolamento & purificação , Adsorção , Poluentes Químicos da Água/química , Poluentes Químicos da Água/isolamento & purificação , Purificação da Água/métodos , Cinética , Corantes/química , Concentração de Íons de Hidrogênio , Espectroscopia de Infravermelho com Transformada de Fourier , Água/químicaRESUMO
The complement system is an important component of transplant rejection. Sertoli cells, an immune regulatory testicular cell, survive long-term when transplanted across immunological barriers; thus, understanding the mechanisms behind this unique survival would be of great benefit to the transplantation field. This study focused on Sertoli cell inhibition of complement as relevant in xenotransplantation. Neonatal pig Sertoli cells (NPSCs) survived activated human complement in vitro while neonatal pig islet (NPI) aggregates and pig aortic endothelial cell (PAEC) survival were diminished to about 65% and 12%, respectively. PAECs cultured in NPSC-conditioned media and human complement demonstrated a 200% increase in survival suggesting that NPSCs secrete complement-inhibiting substances that confer protection. Bioinformatic and molecular analyses identified 21 complement inhibitors expressed by NPSCs with several significantly increased in NPSCs compared to NPIs or PAECs. Lastly, RNA sequencing revealed that NPSCs express 25 other complement factors including cascade components and receptors. Overall, this study identified the most comprehensive Sertoli cell complement signature to date and indicates that the expression of a variety of complement inhibitors ensures a proper regulation of complement through redundant inhibition points. Understanding the regulation of the complement system should be further investigated for extending xenograft viability.
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Proteínas do Sistema Complemento , Rejeição de Enxerto , Células de Sertoli , Humanos , Masculino , Inativadores do Complemento , Proteínas do Sistema Complemento/metabolismo , Rejeição de Enxerto/metabolismo , Xenoenxertos , Células de Sertoli/metabolismo , Transplante Heterólogo , Suínos , AnimaisRESUMO
BACKGROUND: Cadherin-associated protein p120 catenin regulates cell adhesion and migration in cell cultures and is required for axial elongation in embryos. Its roles in adhesion and cell migration are regulated by phosphorylation. We determined the effects of phosphorylation of six serine and three threonine residues in p120 catenin during zebrafish (Danio rerio) embryogenesis. RESULTS: We knocked down endogenous p120 catenin-δ1 with an antisense RNA-splice-site morpholino (Sp-MO) causing defects in axis elongation. These defects were rescued by co-injections of mRNAs for wildtype mouse p120 catenin-δ1-3A or various mutated forms. Several mRNAs containing serine or threonine codons singly or doubly mutated to phosphomimetic glutamic acid rescued, and some nonphosphorylatable mutants did not. CONCLUSIONS: We discovered that phosphorylation of serine residue S252 or S879 is required for convergent extension of zebrafish embryos, since rescue occurred only when these residues were mutated to glutamic acid. In addition, the phosphorylation of either S268 or S269 is required, not both, consistent with the presence of only a single one of these residues in two isoforms of zebrafish and Xenopus laevis. In summary, phosphorylation of multiple serine and threonine residues of p120 catenin activates migration of presomitic mesoderm of zebrafish embryos facilitating elongation of the dorsal axis.
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Serina , Peixe-Zebra , Camundongos , Animais , Fosforilação , Peixe-Zebra/metabolismo , Serina/metabolismo , Ácido Glutâmico/metabolismo , Cateninas/genética , Cateninas/metabolismo , Caderinas/genética , Caderinas/metabolismo , Mesoderma/metabolismo , Treonina/metabolismoRESUMO
Methyl parathion is an organophosphorus pesticide widely employed worldwide to control pests in agricultural and domestic environments. However, due to its intensive use, high toxicity, and environmental persistence, methyl parathion is recognized as an important ecosystem and human health threat, causing severe environmental pollution events and numerous human poisoning and deaths each year. Therefore, identifying and characterizing microorganisms capable of fully degrading methyl parathion and its degradation metabolites is a crucial environmental task for the bioremediation of pesticide-polluted sites. Burkholderia zhejiangensis CEIB S4-3 is a bacterial strain isolated from agricultural soils capable of immediately hydrolyzing methyl parathion at a concentration of 50 mg/L and degrading the 100% of the released p-nitrophenol in a 12-hour lapse when cultured in minimal salt medium. In this study, a comparative proteomic analysis was conducted in the presence and absence of methyl parathion to evaluate the biological mechanisms implicated in the methyl parathion biodegradation and resistance by the strain B. zhejiangensis CEIB S4-3. In each treatment, the changes in the protein expression patterns were evaluated at three sampling times, zero, three, and nine hours through the use of two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), and the differentially expressed proteins were identified by mass spectrometry (MALDI-TOF). The proteomic analysis allowed the identification of 72 proteins with differential expression, 35 proteins in the absence of the pesticide, and 37 proteins in the experimental condition in the presence of methyl parathion. The identified proteins are involved in different metabolic processes such as the carbohydrate and amino acids metabolism, carbon metabolism and energy production, fatty acids ß-oxidation, and the aromatic compounds catabolism, including enzymes of the both p-nitrophenol degradation pathways (Hydroquinone dioxygenase and Hydroxyquinol 1,2 dioxygenase), as well as the overexpression of proteins implicated in cellular damage defense mechanisms such as the response and protection of the oxidative stress, reactive oxygen species defense, detoxification of xenobiotics, and DNA repair processes. According to these data, B. zhejiangensis CEIB S4-3 overexpress different proteins related to aromatic compounds catabolism and with the p-nitrophenol degradation pathways, the higher expression levels observed in the two subunits of the enzyme Hydroquinone dioxygenase, suggest a preferential use of the Hydroquinone metabolic pathway in the p-nitrophenol degradation process. Moreover the overexpression of several proteins implicated in the oxidative stress response, xenobiotics detoxification, and DNA damage repair reveals the mechanisms employed by B. zhejiangensis CEIB S4-3 to counteract the adverse effects caused by the methyl parathion and p-nitrophenol exposure.
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Dioxigenases , Metil Paration , Praguicidas , Aminoácidos , Burkholderiaceae , Carboidratos , Carbono , Ecossistema , Ácidos Graxos , Hidroquinonas/análise , Metil Paration/análise , Metil Paration/química , Metil Paration/toxicidade , Nitrofenóis , Compostos Organofosforados , Proteômica , Espécies Reativas de Oxigênio , SoloRESUMO
The spread of multidrug resistant bacteria owing to the intensive use of antibiotics is challenging current antibiotic therapies, and making the discovery and evaluation of new antimicrobial agents a high priority. The evaluation of novel peptide sequences of predicted antimicrobial peptides from different sources is valuable approach to identify alternative antibiotic leads. Two strategies were pursued in this study to evaluate novel antimicrobial peptides from the human ß-defensin family (hBD). In the first, a 32-residue peptide was designed based on the alignment of all available hBD primary structures, while in the second a putative 35-residue peptide, hBD10, was mined from the gene DEFB110. Both hBDconsensus and hBD10 were chemically synthesized, folded and purified. They showed antimicrobial activity against Escherichia coli, Staphylococcus aureus, and Mycobacterium tuberculosis, but were not hemolytic on human red blood cells. The NMR-based solution structure of hBDconsensus revealed that it adopts a classical ß-defensin fold and disulfide connectivities. Even though the mass spectrum of hBD10 confirmed the formation of three disulfide bonds, it showed limited dispersion in 1 H NMR spectra and structural studies were not pursued. The evaluation of different ß-defensin structures may identify new antimicrobial agents effective against multidrug-resistant bacterial strains.
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Anti-Infecciosos/química , beta-Defensinas/química , Sequência de Aminoácidos , Anti-Infecciosos/farmacologia , Infecções Bacterianas/tratamento farmacológico , Descoberta de Drogas , Escherichia coli/efeitos dos fármacos , Humanos , Modelos Moleculares , Mycobacterium tuberculosis/efeitos dos fármacos , Ressonância Magnética Nuclear Biomolecular , Conformação Proteica , Dobramento de Proteína , Staphylococcus aureus/efeitos dos fármacos , beta-Defensinas/farmacologiaRESUMO
Pesticides are xenobiotic molecules necessary to control pests in agriculture, home, and industry. However, water and soil can become contaminated as a consequence of their extensive use. Therefore, because of its eco-friendly characteristics and efficiency, bioremediation of contaminated sites is a powerful tool with advantages over other kinds of treatments. For an efficient pesticides bioremediation, it is necessary to take into account different aspects related to the microbial metabolism and physiology. In this respect, OMICs studies such as genomics, transcriptomics, proteomics, and metabolomics are essential to generate relevant information about the genes and proteins involved in pesticide degradation, the metabolites generated by microbial pesticide degradation, and the cellular strategies to contend against stress caused by pesticide exposition. Pesticides as organochlorines and organophosphorus are the more commonly studied using OMIC approaches. To date, many genomes of microorganisms capable of degrading pesticides have been published, mainly bacterial strains from Burkholderia, Pseudomonas, and Rhodococcus genera. Following the genomic reports, transcriptomic studies, using microarrays and more recently next-generation sequencing technology RNA-Seq, in pesticide microbial degradation are the most numerous. Proteomics, metabolomics, as well as studies that combine different OMIC are gained interest. This review aims to describe a brief overview of pesticide biodegradation mechanisms; new tools to study microorganisms in natural environments; basic concepts of the OMICs approaches; as well as advances in methodologies associated with the analysis of that tools. Additionally, the most recent reports on genomics, transcriptomics, proteomics, and metabolomics during the degradation of pesticides are also analyzed.
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Bactérias/metabolismo , Biodegradação Ambiental , Genômica , Metabolômica , Praguicidas/metabolismo , Proteômica , Bactérias/genética , Biologia Computacional/métodos , HumanosRESUMO
The ubiquitous Internet of Things (IoT) devices nowadays are generating various and numerous data from everywhere at any time. Since it is not always necessary to centralize and analyze IoT data cumulatively (e.g., the Monte Carlo analytics and Convergence analytics demonstrated in this article), the traditional implementations of big data analytics (BDA) will suffer from unnecessary and expensive data transmissions as a result of the tight coupling between computing resource management and data processing logics. Inspired by software-defined infrastructure (SDI), we propose the "microservice-oriented platform" to break the environmental monolith and further decouple data processing logics from their underlying resource management in order to facilitate BDA implementations in the IoT environment (which we name "IoBDA"). Given predesigned standard microservices with respect to specific data processing logics, the proposed platform is expected to largely reduce the complexity in and relieve inexperienced practices of IoBDA implementations. The potential contributions to the relevant communities include (1) new theories of a microservice-oriented platform on top of SDI and (2) a functional microservice-oriented platform for IoBDA with a group of predesigned microservices.
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Communication between stem and niche supporting cells maintains the homeostasis of adult tissues. Wnt signaling is a crucial regulator of the stem cell niche, but the mechanism that governs Wnt ligand delivery in this compartment has not been fully investigated. We identified that Wnt secretion is partly dependent on Rab8a-mediated anterograde transport of Gpr177 (wntless), a Wnt-specific transmembrane transporter. Gpr177 binds to Rab8a, depletion of which compromises Gpr177 traffic, thereby weakening the secretion of multiple Wnts. Analyses of generic Wnt/ß-catenin targets in Rab8a knockout mouse intestinal crypts indicate reduced signaling activities; maturation of Paneth cells - a Wnt-dependent cell type - is severely affected. Rab8a knockout crypts show an expansion of Lgr5(+) and Hopx(+) cells in vivo. However, in vitro, the knockout enteroids exhibit significantly weakened growth that can be partly restored by exogenous Wnts or Gsk3ß inhibitors. Immunogold labeling and surface protein isolation identified decreased plasma membrane localization of Gpr177 in Rab8a knockout Paneth cells and fibroblasts. Upon stimulation by exogenous Wnts, Rab8a-deficient cells show ligand-induced Lrp6 phosphorylation and transcriptional reporter activation. Rab8a thus controls Wnt delivery in producing cells and is crucial for Paneth cell maturation. Our data highlight the profound tissue plasticity that occurs in response to stress induced by depletion of a stem cell niche signal.
Assuntos
Celulas de Paneth/citologia , Nicho de Células-Tronco/fisiologia , Células-Tronco/citologia , Proteínas rab de Ligação ao GTP/metabolismo , Animais , Proliferação de Células , Células Cultivadas , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta , Proteínas de Homeodomínio/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Camundongos , Camundongos Knockout , Fosforilação , Receptores Acoplados a Proteínas G/metabolismo , Ativação Transcricional , Proteínas Wnt/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Proteínas rab de Ligação ao GTP/genéticaRESUMO
Cyclophilin A (CypA) is overexpressed in a number of human cancer types, but the mechanisms by which the protein promotes oncogenic properties of cells are not understood. Here we demonstrate that CypA binds the CrkII adaptor protein and prevents it from switching to the inhibited state. CrkII influences cell motility and invasion by mediating signaling through its SH2 and SH3 domains. CrkII Tyr221 phosphorylation by the Abl or EGFR kinases induces an inhibited state of CrkII by means of an intramolecular SH2-pTyr221 interaction, causing signaling interruption. We show that the CrkII phosphorylation site constitutes a binding site for CypA. Recruitment of CypA sterically restricts the accessibility of Tyr221 to kinases, thereby suppressing CrkII phosphorylation and promoting the active state. Structural, biophysical and in vivo data show that CypA augments CrkII-mediated signaling. A strong stimulation of cell migration is observed in cancer cells wherein both CypA and CrkII are greatly upregulated.
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Ciclofilina A/farmacologia , Proteínas Oncogênicas v-abl/metabolismo , Proteínas Proto-Oncogênicas c-crk/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sequência de Aminoácidos , Western Blotting , Calorimetria , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Dados de Sequência MolecularRESUMO
There are many difficulties in undertaking independent clinical research without support from the pharmaceutical industry. In this retrospective observational study, some design characteristics, the clinical trial public register and the publication rate of noncommercial clinical trials were compared to those of commercial clinical trials. A total of 809 applications of drug-evaluation clinical trials were submitted from May 2004 to May 2009 to the research ethics committee of a tertiary hospital, and 16.3% of trials were noncommercial. They were mainly phase IV, multicentre national, and unmasked controlled trials, compared to the commercial trials that were mainly phase II or III, multicentre international, and double-blind masked trials. The commercial trials were registered and published more often than noncommercial trials. More funding for noncommercial research is still needed. The results of the research, commercial or noncommercial, should be disseminated in order not to compromise either its scientific or its social value.
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Ensaios Clínicos Controlados como Assunto/economia , Ensaios Clínicos Controlados como Assunto/métodos , Indústria Farmacêutica/economia , Comitês de Ética em Pesquisa , Projetos de Pesquisa , Apoio à Pesquisa como Assunto/economia , Ensaios Clínicos Fase II como Assunto/economia , Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Fase III como Assunto/economia , Ensaios Clínicos Fase III como Assunto/métodos , Ensaios Clínicos Fase IV como Assunto/economia , Ensaios Clínicos Fase IV como Assunto/métodos , Ensaios Clínicos Controlados como Assunto/ética , Indústria Farmacêutica/ética , Humanos , Estudos Multicêntricos como Assunto/economia , Estudos Multicêntricos como Assunto/métodos , Sistema de Registros , Apoio à Pesquisa como Assunto/ética , Estudos RetrospectivosRESUMO
OBJECTIVE: To analyze trends in management and outcomes of patients infected with the human immunodeficiency virus (HIV) undergoing percutaneous coronary intervention (PCI) for an acute myocardial infarction (AMI) in the United States. BACKGROUND: Infection with HIV is an independent risk factor for accelerated atherosclerosis associated with higher rates of AMI. Current trends and outcomes of HIV-infected individuals presenting with AMI in the United States remain unknown. METHODS: Using the Healthcare Cost and Utilization Project National Inpatient Sample database we identified HIV-infected individuals who underwent PCI for an AMI from 2002 to 2013. Multivariable logistic regression and propensity-score matching were performed to analyze outcomes. RESULTS: We identified a total of 59 194 patients of which 7841 underwent PCI during index hospitalization (13.3%). Most patients were men (71%), ≥50 years of age (82%), and white (74%). ST-elevation myocardial infarction was present in 21% of cases. Charlson comorbidity index (CCI) was 5.67 ± 0.4. Predictors of post-procedural complications included female sex, black race, higher CCI, and placement of a bare metal stent, whereas predictors of mortality included occurrence of a complication, ST-elevation myocardial infarction, age ≥70 years, and higher CCI. Conversely, placement of a drug-eluting stent was associated with a reduced risk of complications and mortality. After propensity-score matching, HIV-infected individuals were less likely to undergo PCI and receive a drug-eluting stent, while having longer length of stay, higher hospitalization costs, and higher in-hospital mortality when compared to non-infected individuals. CONCLUSION: Significant disparities continue to affect HIV-infected individuals undergoing PCI for AMI in the United States.
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Infecções por HIV/complicações , Infarto do Miocárdio/cirurgia , Intervenção Coronária Percutânea , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Feminino , Custos Hospitalares , Mortalidade Hospitalar , Hospitalização/economia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/virologia , Pontuação de Propensão , Fatores de Risco , Stents , Resultado do Tratamento , Estados UnidosRESUMO
Epithelial cell-cell contact stimulates actin cytoskeleton remodeling to down-regulate branched filament polymerization-driven lamellar protrusion and subsequently to assemble linear actin filaments required for E-cadherin anchoring during adherens junction complex assembly. In this manuscript, we demonstrate that de novo protein synthesis, the ß-actin 3' UTR, and the ß-actin mRNA zipcode are required for epithelial adherens junction complex assembly but not maintenance. Specifically, we demonstrate that perturbing cell-cell contact-localized ß-actin monomer synthesis causes epithelial adherens junction assembly defects. Consequently, inhibiting ß-actin mRNA zipcode/ZBP1 interactions with ß-actin mRNA zipcode antisense oligonucleotides, to intentionally delocalize ß-actin monomer synthesis, is sufficient to perturb adherens junction assembly following epithelial cell-cell contact. Additionally, we demonstrate active RhoA, the signal required to drive zipcode-mediated ß-actin mRNA targeting, is localized at epithelial cell-cell contact sites in a ß-actin mRNA zipcode-dependent manner. Moreover, chemically inhibiting Src kinase activity prevents the local stimulation of ß-actin monomer synthesis at cell-cell contact sites while inhibiting epithelial adherens junction assembly. Together, these data demonstrate that epithelial cell-cell contact stimulates ß-actin mRNA zipcode-mediated monomer synthesis to spatially regulate actin filament remodeling, thereby controlling adherens junction assembly to modulate cell and tissue adhesion.
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Actinas/genética , Adesão Celular/genética , Proteínas de Ligação a DNA/genética , RNA Mensageiro/genética , Citoesqueleto de Actina/genética , Actinas/metabolismo , Junções Aderentes/genética , Junções Aderentes/metabolismo , Animais , Cães , Células Epiteliais/metabolismo , Células Madin Darby de Rim Canino , Biossíntese de Proteínas , Proteínas de Ligação a RNA , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
After the export from the nucleus it turns out that all mRNAs are not treated equally. Not only is mRNA subject to translation, but also through RNA-binding proteins and other trans-acting factors, eukaryotic cells interpret codes for spatial sorting within the mRNA sequence. These codes instruct the cytoskeleton and translation apparatus to make decisions about where to transport and when to translate the intended protein product. Signaling pathways decode extra-cellular cues and can modify transport and translation factors in the appropriate cytoplasmic space to achieve translation locally. Identifying regulatory sites on transport factors as well as novel physiological functions for well-known translation factors has provided significant advances in how spatially controlled translation impacts cell function.
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Células/citologia , Células/metabolismo , Biossíntese de Proteínas , Animais , Adesão Celular , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Sinapses/metabolismoRESUMO
Glyphosate is a broad spectrum and non-selective herbicide employed to control different weeds in agricultural and urban zones and to facilitate the harvest of various crops. Currently, glyphosate-based formulations are the most employed herbicides in agriculture worldwide. Extensive use of glyphosate has been related to environmental pollution events and adverse effects on non-target organisms, including humans. Reducing the presence of glyphosate in the environment and its potential adverse effects requires the development of remediation and treatment alternatives. Bioremediation with microorganisms has been proposed as a feasible alternative for treating glyphosate pollution. The present study reports the glyphosate resistance profile and degradation capacity of the bacterial strain Burkholderia cenocepacia CEIB S5-2, isolated from an agricultural field in Morelos-México. According to the agar plates and the liquid media inhibition assays, the bacterial strain can resist glyphosate exposure at high concentrations, 2000 mg·L-1. In the degradation assays, the bacterial strain was capable of fast degrading glyphosate (50 mg·L-1) and the primary degradation metabolite aminomethylphosphonic acid (AMPA) in just eight hours. The analysis of the genomic data of B. cenocepacia CEIB S5-2 revealed the presence of genes that encode enzymes implicated in glyphosate biodegradation through the two metabolic pathways reported, sarcosine and AMPA. This investigation provides novel information about the potential of species of the genus Burkholderia in the degradation of the herbicide glyphosate and its main degradation metabolite (AMPA). Furthermore, the analysis of genomic information allowed us to propose for the first time a metabolic route related to the degradation of glyphosate in this bacterial group. According to the findings of this study, B. cenocepacia CEIB S5-2 displays a great glyphosate biodegradation capability and has the potential to be implemented in glyphosate bioremediation approaches.
Assuntos
Biodegradação Ambiental , Burkholderia cenocepacia , Glicina , Glifosato , Herbicidas , Glicina/análogos & derivados , Burkholderia cenocepacia/metabolismo , Herbicidas/metabolismoRESUMO
Phytoremediation is a useful, low-cost, and environmentally friendly alternative for the rehabilitation of heavy-metal-contaminated (HM) soils. This technology takes advantage of the ability of certain plant species to accumulate HMs in their tissues. Crotalaria pumila is a herbaceous plant with a wide geographical distribution that grows naturally in environments polluted with HMs. In this work, the bioaccumulation capacity of roots and leaves in relation to five HMs (Cr, Cu, Fe, Pb, and Zn) was evaluated, as well as the morphological changes presented in C. pumila growing in control substrate (without HMs) and mine-tailing substrate (with HMs) under greenhouse conditions for 150 days. Four metals with the following concentration pattern were detected in both tissues and substrates: Fe > Pb > Cu > Zn. Fe, Pb, and Zn concentrations were significantly higher in the roots and leaves of individuals growing on mine-tailing substrate compared to the control substrate. In contrast, Cu concentration increased over time in the exposed individuals. The bioconcentration factor showed a similar pattern in root and leaf: Cu > Fe > Pb > Zn. Around 87.5% of the morphological characters evaluated in this species decreased significantly in individuals exposed to HMs. The bioconcentration factor shows that C. pumila is efficient at absorbing Cu, Fe, and Pb from the mine-tailing substrate, in the root and leaf tissue, and the translocation factor shows its efficiency in translocating Cu from the roots to the leaves. Therefore, C. pumila may be considered as a HM accumulator plant with potential for phytoremediation of polluted soils with Cu, Pb, and Fe, along with the ability to establish itself naturally in contaminated environments, without affecting its germination rates. Also, it exhibits wide geographical distribution, it has a short life cycle, exhibits rapid growth, and can retain the mine-tailing substrate, extracting HMs in a short time.
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Large-scale diffusion MRI tractography remains a significant challenge. Users must orchestrate a complex sequence of instructions that requires many software packages with complex dependencies and high computational costs. We developed MaPPeRTrac, an edge-centric tractography pipeline that simplifies and accelerates this process in a wide range of high-performance computing (HPC) environments. It fully automates either probabilistic or deterministic tractography, starting from a subject's magnetic resonance imaging (MRI) data, including structural and diffusion MRI images, to the edge density image (EDI) of their structural connectomes. Dependencies are containerized with Singularity (now called Apptainer) and decoupled from code to enable rapid prototyping and modification. Data derivatives are organized with the Brain Imaging Data Structure (BIDS) to ensure that they are findable, accessible, interoperable, and reusable following FAIR principles. The pipeline takes full advantage of HPC resources using the Parsl parallel programming framework, resulting in the creation of connectome datasets of unprecedented size. MaPPeRTrac is publicly available and tested on commercial and scientific hardware, so it can accelerate brain connectome research for a broader user community. MaPPeRTrac is available at: https://github.com/LLNL/mappertrac .