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1.
Int J Mol Sci ; 24(10)2023 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-37240420

RESUMO

Mutation research is crucial for detecting and treating SARS-CoV-2 and developing vaccines. Using over 5,300,000 sequences from SARS-CoV-2 genomes and custom Python programs, we analyzed the mutational landscape of SARS-CoV-2. Although almost every nucleotide in the SARS-CoV-2 genome has mutated at some time, the substantial differences in the frequency and regularity of mutations warrant further examination. C>U mutations are the most common. They are found in the largest number of variants, pangolin lineages, and countries, which indicates that they are a driving force behind the evolution of SARS-CoV-2. Not all SARS-CoV-2 genes have mutated in the same way. Fewer non-synonymous single nucleotide variations are found in genes that encode proteins with a critical role in virus replication than in genes with ancillary roles. Some genes, such as spike (S) and nucleocapsid (N), show more non-synonymous mutations than others. Although the prevalence of mutations in the target regions of COVID-19 diagnostic RT-qPCR tests is generally low, in some cases, such as for some primers that bind to the N gene, it is significant. Therefore, ongoing monitoring of SARS-CoV-2 mutations is crucial. The SARS-CoV-2 Mutation Portal provides access to a database of SARS-CoV-2 mutations.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/genética , Mutação , Nucleotídeos , Genoma Viral
2.
Environ Res ; 204(Pt A): 111904, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34418449

RESUMO

Endocrine disrupting chemicals (EDCs) are ubiquitous in the environment and involve diverse chemical-receptor interactions that can perturb hormone signaling. The Organization for Economic Co-operation and Development has validated several EDC-receptor bioassays to detect endocrine active chemicals and has established guidelines for regulatory testing of EDCs. Focus on testing over the past decade has been initially directed to EATS modalities (estrogen, androgen, thyroid, and steroidogenesis) and validated tests for chemicals that exert effects through non-EATS modalities are less established. Due to recognition that EDCs are vast in their mechanisms of action, novel bioassays are needed to capture the full scope of activity. Here, we highlight the need for validated assays that detect non-EATS modalities and discuss major international efforts underway to develop such tools for regulatory purposes, focusing on non-EATS modalities of high concern (i.e., retinoic acid, aryl hydrocarbon receptor, peroxisome proliferator-activated receptor, and glucocorticoid signaling). Two case studies are presented with strong evidence amongst animals and human studies for non-EATS disruption and associations with wildlife and human disease. This includes metabolic syndrome and insulin signaling (case study 1) and chemicals that impact the cardiovascular system (case study 2). This is relevant as obesity and cardiovascular disease represent two of the most significant health-related crises of our time. Lastly, emerging topics related to EDCs are discussed, including recognition of crosstalk between the EATS and non-EATS axis, complex mixtures containing a variety of EDCs, adverse outcome pathways for chemicals acting through non-EATS mechanisms, and novel models for testing chemicals. Recommendations and considerations for evaluating non-EATS modalities are proposed. Moving forward, improved understanding of the non-EATS modalities will lead to integrated testing strategies that can be used in regulatory bodies to protect environmental, animal, and human health from harmful environmental chemicals.


Assuntos
Disruptores Endócrinos , Animais , Animais Selvagens , Bioensaio , Disruptores Endócrinos/toxicidade , Sistema Endócrino , Humanos , Obesidade
3.
Prev Sci ; 23(4): 488-501, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34714503

RESUMO

Though treatment integrity measurement is important for research intended to promote social and behavioral outcomes of children at risk for emotional and behavioral disorders (EBDs) in early childhood settings, measurement gaps exist in the field. This paper reports on the development and preliminary psychometric assessment of the treatment integrity measure for early childhood settings (TIMECS), an observational measure designed to address existing measurement gaps related to treatment integrity with tier 2 interventions in the early childhood field. To assess the preliminary score reliability (interrater) and validity (construct, discriminant) of the TIMECS, live observations (N = 650) in early childhood classrooms from 54 teachers (92.6% female, 7.4% male; 61.1% White) and 91 children (M age = 4.53 years, SD = .44; 45.1% female, 54.9% male; 45.1% Black) at risk for EBDs were scored by 12 coders using the TIMECS and an observational measure designed to assess teacher-child interactions. Teachers also self-reported on the quality of the teacher-child relationship. Interrater reliability (intraclass correlation coefficients, ICC [2,2]) for the quantity (i.e., adherence) item scores had a mean of .81 (SD = .07; range from .68 to .95), and the quality (i.e., competence) item scores had a mean of .69 (SD = .08; range from .52 to .80). Scores on the TIMECS Quantity and Quality items and scales showed evidence of construct validity, with the magnitude of the correlations suggesting that the quantity and quality items assess distinct components of treatment integrity. A TIMECS quantity scale also showed promise for intervention evaluation research by discriminating between teachers who had and had not been trained in a specific evidence-based intervention targeting social and behavioral skills in early childhood. The findings support the potential of the TIMECS to assess treatment integrity of teacher-delivered practices designed to address child social and behavioral outcomes of children at risk for EBDs in early childhood settings.


Assuntos
Emoções , Pré-Escolar , Feminino , Humanos , Masculino , Psicometria , Reprodutibilidade dos Testes , Autorrelato
4.
Sensors (Basel) ; 21(1)2021 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-33401627

RESUMO

The paper proposes a novel instance segmentation method for traffic videos devised for deployment on real-time embedded devices. A novel neural network architecture is proposed using a multi-resolution feature extraction backbone and improved network designs for the object detection and instance segmentation branches. A novel post-processing method is introduced to ensure a reduced rate of false detection by evaluating the quality of the output masks. An improved network training procedure is proposed based on a novel label assignment algorithm. An ablation study on speed-vs.-performance trade-off further modifies the two branches and replaces the conventional ResNet-based performance-oriented backbone with a lightweight speed-oriented design. The proposed architectural variations achieve real-time performance when deployed on embedded devices. The experimental results demonstrate that the proposed instance segmentation method for traffic videos outperforms the you only look at coefficients algorithm, the state-of-the-art real-time instance segmentation method. The proposed architecture achieves qualitative results with 31.57 average precision on the COCO dataset, while its speed-oriented variations achieve speeds of up to 66.25 frames per second on the Jetson AGX Xavier module.

5.
Physiol Genomics ; 52(4): 169-177, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32089076

RESUMO

Elucidating molecular pathways regulating neuroimmune communication is critical for therapeutic interventions in conditions characterized by overactive immune responses and dysfunctional autonomic nervous system. We generated a bone marrow-specific adrenergic beta 1 and beta 2 knockout mouse chimera (AdrB1.B2 KO) to determine how sympathetic drive to the bone affects transcripts and miRNAs in the hypothalamic paraventricular nucleus (PVN). This model has previously exhibited a dampened systemic immune response and decreased blood pressure compared with control animals. Reduced sympathetic responsiveness of the bone marrow hematopoietic cells of AdrB1.B2 KO chimera led to suppression of transcriptional networks that included leukocyte cell adhesion and migration and T cell-activation and recruitment. Transcriptome responses related to IL-17a signaling and the renin-angiotensin system were also suppressed in the PVN. Based on the transcriptome response, we next computationally predicted miRNAs in the PVN that may underscore the reduced sympathetic responsiveness of the bone marrow cells. These included miR-27b-3p, miR-150, miR-223-3p, and miR-326. Using real-time PCR, we measured a downregulation in the expression of miR-150-5p, miR-205-5p, miR-223-3p, miR-375-5p, miR-499a-5p, miR-27b-3p, let-7a-5p, and miR-21a-5p in the PVN of AdrB1.B2 KO chimera, confirming computational predictions that these miRNAs are associated with reduced neuro-immune responses and the loss of sympathetic responsiveness in the bone marrow. Intriguingly, directional responses of the miRNA corresponded to mRNAs, suggesting complex temporal or circuit-dependent posttranscriptional control of gene expression in the PVN. This study identifies molecular pathways involved in neural-immune interactions that may act as targets of therapeutic intervention for a dysfunctional autonomic nervous system.


Assuntos
Regulação da Expressão Gênica , Redes Reguladoras de Genes , MicroRNAs/genética , Núcleo Hipotalâmico Paraventricular/metabolismo , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 2/genética , Transcriptoma , Animais , Medula Óssea/metabolismo , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Masculino , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Sistema Renina-Angiotensina/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Sistema Nervoso Simpático/metabolismo
6.
Int J Mol Sci ; 21(20)2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33050175

RESUMO

The recent identification of senescent cells in periodontal tissues has the potential to provide new insights into the underlying mechanisms of periodontal disease etiology. DNA damage-driven senescence is perhaps one of the most underappreciated delayed consequences of persistent Gram-negative bacterial infection and inflammation. Although the host immune response rapidly protects against bacterial invasion, oxidative stress generated during inflammation can indirectly deteriorate periodontal tissues through the damage to vital cell macromolecules, including DNA. What happens to those healthy cells that reside in this harmful environment? Emerging evidence indicates that cells that survive irreparable genomic damage undergo cellular senescence, a crucial intermediate mechanism connecting DNA damage and the immune response. In this review, we hypothesize that sustained Gram-negative bacterial challenge, chronic inflammation itself, and the constant renewal of damaged tissues create a permissive environment for the abnormal accumulation of senescent cells. Based on emerging data we propose a model in which the dysfunctional presence of senescent cells may aggravate the initial immune reaction against pathogens. Further understanding of the role of senescent cells in periodontal disease pathogenesis may have clinical implications by providing more sophisticated therapeutic strategies to combat tissue destruction.


Assuntos
Senescência Celular , Suscetibilidade a Doenças , Doenças Periodontais/etiologia , Doenças Periodontais/metabolismo , Infecções Bacterianas/complicações , Infecções Bacterianas/microbiologia , Microambiente Celular , Dano ao DNA , Gerenciamento Clínico , Suscetibilidade a Doenças/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Inflamação/complicações , Inflamação/etiologia , Inflamação/metabolismo , NF-kappa B/metabolismo , Saúde Bucal , Doenças Periodontais/patologia , Doenças Periodontais/terapia , Periodonto/imunologia , Periodonto/metabolismo , Periodonto/patologia , Transdução de Sinais , Estresse Fisiológico
7.
Anthropol Med ; 27(4): 363-379, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31801356

RESUMO

The Mexico-Guatemala border is the site of significant movement of people whose principal destination is the USA. The first step, to cross Mexico, is considered as one of the most dangerous routes in the world for undocumented migrants. For some male migrants and displaced persons from Honduras, El Salvador and Guatemala, initiating sex work in the Mexican border city of Tapachula has become a way to earn money to survive during the trip northward - providing funds to keep traveling and decrease the danger of being killed or kidnaped by organized crime groups. Non-injected drug use during sex work with men and/or women is a common praxis for this purpose, and is linked to HIV risk activities such as unprotected sex. Our study is based on ethnographic fieldwork with observation and interviews and within a relational approach understanding the processes subject/structure, sociopolitical/cultural and global/local, not as oppositions, rather as linkages visible through actors' points of view and praxis. The productions of politics and cultures related to structural vulnerability to HIV infection are embedded in local and global borderization processes where legal and illegal transnational forces, states' frameworks and social groups play a linked role. The economies of structural, symbolic and direct violence affect migratory patterns, institutional interactions and social and cultural relations with the local population. In this context, social representations and praxis about unprotected sex and drug use are the locus of struggling bodies at the border.


Assuntos
Infecções por HIV/etnologia , Trabalho Sexual/etnologia , Migrantes , Violência/etnologia , Adolescente , Adulto , Antropologia Médica , Feminino , Guatemala/etnologia , Humanos , Masculino , México/etnologia , Refugiados , Transtornos Relacionados ao Uso de Substâncias/etnologia , Adulto Jovem
8.
Bioorg Med Chem Lett ; 29(16): 2428-2436, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31133531

RESUMO

Treatment of hepatitis C virus (HCV) infection has been historically challenging due the high viral genetic complexity wherein there are eight distinct genotypes and at least 86 viral subtypes. While HCV NS3/4A protease inhibitors are an established treatment option for genotype 1 infection, limited coverage of genotypes 2 and/or 3 combined with serum alanine transaminase (ALT) elevations for some compounds has limited the broad utility of this therapeutic class. Our discovery efforts were focused on identifying an NS3/4A protease inhibitor with pan-genotypic antiviral activity, improved coverage of resistance associated substitutions, and a decreased risk of hepatotoxicity. Towards this goal, distinct interactions with the conserved catalytic triad of the NS3/4A protease were identified that improved genotype 3 antiviral activity. We further discovered that protein adduct formation strongly correlated with clinical ALT elevation for this therapeutic class. Improving metabolic stability and decreasing protein adduct formation through structural modifications ultimately resulted in voxilaprevir. Voxilaprevir, in combination with sofosbuvir and velpatasvir, has demonstrated pan-genotypic antiviral clinical activity. Furthermore, hepatotoxicity was not observed in Phase 3 clinical trials with voxilaprevir, consistent with our design strategy. Vosevi® (sofosbuvir, velpatasvir, and voxilaprevir) is now an approved pan-genotypic treatment option for the most difficult-to-cure individuals who have previously failed direct acting antiviral therapy.


Assuntos
Antivirais/farmacologia , Carbamatos/química , Descoberta de Drogas , Hepacivirus/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Inibidores de Proteases/farmacologia , Sofosbuvir/química , Sulfonamidas/química , Sulfonamidas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Ácidos Aminoisobutíricos , Antivirais/síntese química , Antivirais/química , Ciclopropanos , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Hepacivirus/genética , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Compostos Macrocíclicos/síntese química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Prolina/análogos & derivados , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Quinoxalinas , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
9.
Environ Sci Technol ; 53(22): 13427-13439, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31609598

RESUMO

The novel PFOS alternatives, 6:2 chlorinated polyfluorinated ether sulfonate (F-53B) and sodium p-perfluorous nonenoxybenzenesulfonate (OBS), are emerging in the Chinese market, but little is known about their ecological risks. In this study, zebrafish embryos were exposed to PFOS, F-53B, and OBS to evaluate their bioconcentration and acute metabolic consequences. Per- and polyfluoroalkyl substances (PFASs) accumulated in larvae in the order of F-53B > PFOS > OBS, with the bioconcentration factors ranging from 20 to 357. Exposure to F-53B and PFOS, but not OBS, increased energy expenditure, and reduced feed intake in a concentration-dependent manner and the expression of genes involved in metabolic pathways at the transcriptional and translational levels. Molecular docking revealed that the binding affinities of PFASs to glucokinase were decreased in the following order: F-53B > PFOS > OBS. Finally, the results of Point of Departure (PoD) indicate that metabolic end points at the molecular and organismal level are most sensitive to F-53B followed by PFOS and OBS. Collectively, F-53B has the highest bioconcentration potential and the strongest metabolism-disrupting effects, followed by PFOS and OBS. Our findings have important implications for the assessment of early developmental metabolic effects of PFOS alternatives F-53B and OBS in wildlife and humans.


Assuntos
Ácidos Alcanossulfônicos , Fluorocarbonos , Poluentes Químicos da Água , Animais , Humanos , Simulação de Acoplamento Molecular , Peixe-Zebra
10.
Bioorg Med Chem ; 27(3): 457-469, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30606676

RESUMO

The bromodomain and extra-terminal (BET) family of proteins, consisting of the bromodomains containing protein 2 (BRD2), BRD3, BRD4, and the testis-specific BRDT, are key epigenetic regulators of gene transcription and has emerged as an attractive target for anticancer therapy. Herein, we describe the discovery of a novel potent BET bromodomain inhibitor, using a systematic structure-based approach focused on improving potency, metabolic stability, and permeability. The optimized dimethylisoxazole aryl-benzimidazole inhibitor exhibited high potency towards BRD4 and related BET proteins in biochemical and cell-based assays and inhibited tumor growth in two proof-of-concept preclinical animal models.


Assuntos
Benzimidazóis/farmacologia , Descoberta de Drogas , Isoxazóis/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Fatores de Transcrição/antagonistas & inibidores , Administração Oral , Animais , Benzimidazóis/química , Benzimidazóis/metabolismo , Disponibilidade Biológica , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Isoxazóis/administração & dosagem , Isoxazóis/química , Isoxazóis/metabolismo , Camundongos , Estrutura Molecular , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Domínios Proteicos/efeitos dos fármacos , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo
11.
Tetrahedron ; 75(24): 3140-3144, 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31896888

RESUMO

Lindenane oligomers isolated from Chloranthus pose significant challenges for chemical synthesis. The structure of a proposed biosynthetic monomer, lindenatriene, was recently called into question. Its attempted synthesis produced a compound whose 1H NMR spectrum differed significantly from the spectrum of a monomer produced by oligomer pyrolysis. Here we propose that the original structural assignment after pyrolysis was correct and instead the spectra of synthetic materials were misinterpreted. Reanalysis of 2D NMR data suggest that lindenatriene isomerizes (formal [1,7]-hydrogen shift) upon treatment with base.

12.
J Community Health ; 44(1): 127-136, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30094723

RESUMO

U.S.-Mexico border communities are uniquely vulnerable to sexually transmitted infection (STI) transmission given the economic and social challenges these communities face. This study examines how marginalized statuses of U.S. border residents are associated with STI awareness and sexual behaviors. We surveyed low-income residents receiving STI testing and/or HIV/AIDS care in the lower Rio Grande Valley of southernmost Texas. Respondents aged 18+ took a self-administered survey available in English or Spanish in a clinic waiting room (N = 282). Approximately 52% of respondents reported being HIV+, and 32% of respondents reported having a prior STI other than HIV. Although most respondents had heard of HPV (72%), awareness of the HPV vaccine was low across all subgroups (28%), including women (< 35%), reflecting previous findings that border residents are less knowledgeable about the HPV vaccine. Almost half of respondents reported always using a condom (45%), which is higher than elsewhere in the U.S. Male and non-Hispanic respondents had higher estimated prevalence ratios (PR) of lifetime partners [PR 1.39 (95% confidence interval 1.43-3.68), PR 1.88 (1.04-3.41), respectively] and sexual partners met online [PR 3.73 (1.00-14.06), PR 19.98 (5.70-70.10), respectively]. Sexual minority, non-Hispanic, and male respondents had higher adjusted odds ratios (AOR) of utilizing the internet to find sexual partners than their peers [AOR 2.45 (1.60-3.87), AOR 1.52 (1.11-2.07), AOR 1.97 (1.20-3.24), respectively], placing them at greater STI-transmission risk. We found diversity in dimensions of STI awareness and sexual behaviors in our sample. Results can help tailor public health interventions to the unique STI risks of marginalized groups in border communities.


Assuntos
Hispânico ou Latino/estatística & dados numéricos , Pobreza/estatística & dados numéricos , Infecções Sexualmente Transmissíveis/epidemiologia , Determinantes Sociais da Saúde/estatística & dados numéricos , Adolescente , Adulto , Feminino , Infecções por HIV/prevenção & controle , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , México , Comportamento Sexual/estatística & dados numéricos , Parceiros Sexuais , Texas , Adulto Jovem
13.
Proc Natl Acad Sci U S A ; 113(31): E4558-66, 2016 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-27432991

RESUMO

Bromodomain and extraterminal domain protein inhibitors (BETi) hold great promise as a novel class of cancer therapeutics. Because acquired resistance typically limits durable responses to targeted therapies, it is important to understand mechanisms by which tumor cells adapt to BETi. Here, through pooled shRNA screening of colorectal cancer cells, we identified tripartite motif-containing protein 33 (TRIM33) as a factor promoting sensitivity to BETi. We demonstrate that loss of TRIM33 reprograms cancer cells to a more resistant state through at least two mechanisms. TRIM33 silencing attenuates down-regulation of MYC in response to BETi. Moreover, loss of TRIM33 enhances TGF-ß receptor expression and signaling, and blocking TGF-ß receptor activity potentiates the antiproliferative effect of BETi. These results describe a mechanism for BETi resistance and suggest that combining inhibition of TGF-ß signaling with BET bromodomain inhibition may offer new therapeutic benefits.


Assuntos
Azepinas/farmacologia , Proteínas/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Triazóis/farmacologia , Azepinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Resistência a Medicamentos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Células HEK293 , Humanos , Estrutura Molecular , Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Interferência de RNA , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fatores de Transcrição/genética , Fator de Crescimento Transformador beta/genética , Triazóis/química
14.
Int J Exp Pathol ; 99(4): 180-188, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30198103

RESUMO

Carnosine (ß-alanyl-L-histidine) is synthesized in the olfactory system, has antioxidant activity as a scavenger of free radicals and has been reported to have neuroprotective action in diseases which have been attributed to oxidative damage. In neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases, impairment of olfactory function has been described. Vanadium derivatives are environmental pollutants, and its toxicity has been associated with oxidative stress. Vanadium toxicity on the olfactory bulb was reported previously. This study investigates the neuroprotective effect of carnosine on the olfactory bulb in a mice model of vanadium inhalation. Male mice were divided into four groups: vanadium pentoxide (V2 O5 ) [0.02 mol/L] inhalation for one hour twice a week; V2 O5 inhalation plus 1 mg/kg of carnosine administered daily; carnosine only, and the control group that inhaled saline. The olfactory function was evaluated using the odorant test. Animals were sacrificed four weeks after exposure. The olfactory bulbs were dissected and processed using the rapid Golgi method; cytological and ultrastructural analysis was performed and malondialdehyde (MDA) concentrations were measured. The results showed evidence of olfactory dysfunction caused by vanadium exposure and also an increase in MDA levels, loss of dendritic spines and necrotic neuronal death in the granule cells. But, in contrast, vanadium-exposed mice treated with carnosine showed an increase in dendritic spines and a decrease in neuronal death and in MDA levels when compared with the group exposed to vanadium without carnosine. These results suggest that dendritic spine loss and ultrastructural alterations in the granule cells induced by vanadium are mediated by oxidative stress and that carnosine may modulate the neurotoxic vanadium action, improving the olfactory function.


Assuntos
Carnosina/farmacologia , Fármacos Neuroprotetores/farmacologia , Bulbo Olfatório/efeitos dos fármacos , Coluna Vertebral/patologia , Animais , Modelos Animais de Doenças , Síndromes Neurotóxicas/tratamento farmacológico , Bulbo Olfatório/patologia , Estresse Oxidativo/efeitos dos fármacos , Coluna Vertebral/efeitos dos fármacos , Compostos de Vanádio/farmacologia
15.
Chem Rev ; 116(15): 8912-9000, 2016 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-27461578

RESUMO

Cofactor-mimetic aerobic oxidation has conceptually merged with catalysis of syngas reactions to form a wide range of Markovnikov-selective olefin radical hydrofunctionalizations. We cover the development of the field and review contributions to reaction invention, mechanism, and application to complex molecule synthesis. We also provide a mechanistic framework for understanding this compendium of radical reactions.

16.
Prev Sci ; 18(2): 204-213, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27562037

RESUMO

Educators are increasingly being encouraged to implement evidence-based interventions and practices to address the social, emotional, and behavioral needs of young children who exhibit problem behavior in early childhood settings. Given the nature of social-emotional learning during the early childhood years and the lack of a common set of core evidence-based practices within the early childhood literature, selection of instructional practices that foster positive social, emotional, and behavioral outcomes for children in early childhood settings can be difficult. The purpose of this paper is to report findings from a study designed to identify common practice elements found in comprehensive intervention models (i.e., manualized interventions that include a number of components) or discrete practices (i.e., a specific behavior or action) designed to target social, emotional, and behavioral learning of young children who exhibit problem behavior. We conducted a systematic review of early childhood classroom interventions that had been evaluated in randomized group designs, quasi-experimental designs, and single-case experimental designs. A total of 49 published articles were identified, and an iterative process was used to identify common practice elements. The practice elements were subsequently reviewed by experts in social-emotional and behavioral interventions for young children. Twenty-four practice elements were identified and classified into content (the goal or general principle that guides a practice element) and delivery (the way in which a teacher provides instruction to the child) categories. We discuss implications that the identification of these practice elements found in the early childhood literature has for efforts to implement models and practices.


Assuntos
Comportamento Infantil , Emoções , Promoção da Saúde/métodos , Aprendizado Social , Criança , Feminino , Humanos , Masculino
17.
Gac Med Mex ; 153(5): 581-589, 2017.
Artigo em Espanhol | MEDLINE | ID: mdl-29099103

RESUMO

Objective: To identify the most frequent Candida species in specimens from patients hospitalized in different medical centers of Mexico City, with suspected fungal infection. Methods: Specimens were grown on Sabouraud dextrose agar at 28°C for 72 h. In addition, DNA was extracted. Isolates were grown on CHROMagar Candida™, at 37°C for 48 h. The molecular identification was performed by polymerase chain reaction (PCR) using primers specific for four species. Results: Eighty one specimens were processed and included: bronchial lavage, pleural, cerebrospinal, peritoneal, ascites and bile fluids; blood, sputum, bone marrow, oro-tracheal cannula and ganglion. By culture, 30 samples (37%) were positive, and by PCR, 41 (50.6%). By PCR, the frequency of species was: Candida albicans 82.9%, Candida tropicalis 31.7%, Candida glabrata 24.4%, and Candida parapsilosis 4.9%. In 34.1% of specimens a species mixture was detected suggesting a co-infection: Two species in five specimens (C. albicans-C tropicalis and C. albicans-C glabrata), and three species in three specimens (C. albicans-C. glabrata-C. tropicalis). Conclusions: The PCR is an useful tool for detection the most common Candida species causing infection in hospitalized patients, it avoids the requirement of culture weather we start from clinical specimen and it favors the early diagnosis of invasive candidiasis.


Assuntos
Candida/isolamento & purificação , Candidíase/epidemiologia , Hospitalização , Reação em Cadeia da Polimerase/métodos , Adulto , Idoso , Candidíase/diagnóstico , Candidíase/microbiologia , Feminino , Humanos , Masculino , México , Pessoa de Meia-Idade , Adulto Jovem
18.
J Am Chem Soc ; 138(14): 4962-71, 2016 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-26984323

RESUMO

We report the discovery of an outstanding reductant for metal-catalyzed radical hydrofunctionalization reactions. Observations of unexpected silane solvolysis distributions in the HAT-initiated hydrogenation of alkenes reveal that phenylsilane is not the kinetically preferred reductant in many of these transformations. Instead, isopropoxy(phenyl)silane forms under the reaction conditions, suggesting that alcohols function as important silane ligands to promote the formation of metal hydrides. Study of its reactivity showed that isopropoxy(phenyl)silane is an exceptionally efficient stoichiometric reductant, and it is now possible to significantly decrease catalyst loadings, lower reaction temperatures, broaden functional group tolerance, and use diverse, aprotic solvents in iron- and manganese-catalyzed hydrofunctionalizations. As representative examples, we have improved the yields and rates of alkene reduction, hydration, hydroamination, and conjugate addition. Discovery of this broadly applicable, chemoselective, and solvent-versatile reagent should allow an easier interface with existing radical reactions. Finally, isotope-labeling experiments rule out the alternative hypothesis of hydrogen atom transfer from a redox-active ß-diketonate ligand in the HAT step. Instead, initial HAT from a metal hydride to directly generate a carbon-centered radical appears to be the most reasonable hypothesis.


Assuntos
Alcenos/química , Hidrogênio/química , Compostos de Organossilício/química , Alcanos/síntese química , Catálise , Cristalografia por Raios X , Indóis/síntese química , Oxirredução
19.
J Virol ; 89(4): 2121-35, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25473051

RESUMO

UNLABELLED: Nuclear delivery of the adenoviral genome requires that the capsid cross the limiting membrane of the endocytic compartment and traverse the cytosol to reach the nucleus. This endosomal escape is initiated upon internalization and involves a highly coordinated process of partial disassembly of the entering capsid to release the membrane lytic internal capsid protein VI. Using wild-type and protein VI-mutated human adenovirus serotype 5 (HAdV-C5), we show that capsid stability and membrane rupture are major determinants of entry-related sorting of incoming adenovirus virions. Furthermore, by using electron cryomicroscopy, as well as penton- and protein VI-specific antibodies, we show that the amphipathic helix of protein VI contributes to capsid stability by preventing premature disassembly and deployment of pentons and protein VI. Thus, the helix has a dual function in maintaining the metastable state of the capsid by preventing premature disassembly and mediating efficient membrane lysis to evade lysosomal targeting. Based on these findings and structural data from cryo-electron microscopy, we suggest a refined disassembly mechanism upon entry. IMPORTANCE: In this study, we show the intricate connection of adenovirus particle stability and the entry-dependent release of the membrane-lytic capsid protein VI required for endosomal escape. We show that the amphipathic helix of the adenovirus internal protein VI is required to stabilize pentons in the particle while coinciding with penton release upon entry and that release of protein VI mediates membrane lysis, thereby preventing lysosomal sorting. We suggest that this dual functionality of protein VI ensures an optimal disassembly process by balancing the metastable state of the mature adenovirus particle.


Assuntos
Adenovírus Humanos/fisiologia , Proteínas do Capsídeo/metabolismo , Internalização do Vírus , Desenvelopamento do Vírus , Adenovírus Humanos/genética , Proteínas do Capsídeo/genética , Linhagem Celular , Microscopia Crioeletrônica , Humanos
20.
Toxicol Pathol ; 43(2): 282-91, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25492423

RESUMO

Neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases, have olfaction impairment. These pathologies have also been linked to environmental pollutants. Vanadium is a pollutant, and its toxic mechanisms are related to the production of oxidative stress. In this study, we evaluated the effects of inhaled vanadium on olfaction, the olfactory bulb antioxidant, through histological and ultrastructural changes in granule cells. Mice in control group were made to inhale saline; the experimental group inhaled 0.02-M vanadium pentoxide (V2O5) for 1 hr twice a week for 4 weeks. Animals were sacrificed at 1, 2, 3, and 4 weeks after inhalation. Olfactory function was evaluated by the odorant test. The activity of glutathione peroxidase (GPx) and glutathione reductase (GR) was assayed in olfactory bulbs and processed for rapid Golgi method and ultrastructural analysis. Results show that olfactory function decreased at 4-week vanadium exposure; granule cells showed a decrease in dendritic spine density and increased lipofuscin, Golgi apparatus vacuolation, apoptosis, and necrosis. The activity of GPx and GR in the olfactory bulb was increased compared to that of the controls. Our results demonstrate that vanadium inhalation disturbs olfaction, histology, and the ultrastructure of the granule cells that might be associated with oxidative stress, a risk factor in neurodegenerative diseases.


Assuntos
Poluentes Ambientais/toxicidade , Bulbo Olfatório/metabolismo , Bulbo Olfatório/patologia , Compostos de Vanádio/administração & dosagem , Compostos de Vanádio/toxicidade , Administração por Inalação , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/patologia , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Masculino , Camundongos , Necrose , Bulbo Olfatório/efeitos dos fármacos , Olfato/efeitos dos fármacos
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