RESUMO
Social determinants have been increasingly implicated in accelerating HIV vulnerability, particularly for disenfranchised communities. Among these determinants, neighborhood factors play an important role in undermining HIV prevention. However, there has been little research comprehensively examining the impact of neighborhood factors on HIV care continuum participation in the US. To address this, we conducted a systematic review (PROSPERO registration number CRD42022359787) to determine neighborhood factors most frequently associated with diminished HIV care continuum participation. Peer-reviewed studies were included if published between 2013 - 2022, centralized in the US, and analyzed a neighborhood factor with at least one aspect of the HIV care continuum. The review was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. Study quality was guided by LEGEND (Let Evidence Guide Every New Decision) evaluation guidelines. Systematic review analysis was conducted using Covidence software. There were 3,192 studies identified for initial screening. Forty-four were included for review after eliminating duplicates, title/abstract screening, and eligibility assessment. Social and economic disenfranchisement of neighborhoods negatively impacts HIV care continuum participation among persons living with HIV. In particular, five key neighborhood factors (socioeconomic status, segregation, social disorder, stigma, and care access) were associated with challenged HIV care continuum participation. Race moderated relationships between neighborhood quality and HIV care continuum participation. Structural interventions addressing neighborhood social and economic challenges may have favorable downstream effects for improving HIV care continuum participation.
Assuntos
Infecções por HIV , Humanos , Estados Unidos , Infecções por HIV/epidemiologia , Infecções por HIV/terapia , Características de Residência , Continuidade da Assistência ao Paciente , Classe SocialRESUMO
OBJECTIVES: Black Americans bear the greatest burden of HIV, accounting for 43% of new diagnoses. Yet Black Americans also evidence the lowest utilization rates of Pre-Exposure Prophylaxis (PrEP), a highly effective biomedical strategy for preventing HIV infection. Predictors of PrEP acceptance vary; however, little is known about psychological distress, such as post-traumatic stress disorder (PTSD) symptoms, as a predictor. DESIGN: In this cross-sectional study, n = 195 Black Americans, evidencing behaviors found in the research literature to heighten risk for contracting HIV (e.g. sex work, injection drug use) ages 18-29, 55% cisgender women, 39.5% cisgender men, 3% transgender/non-binary, completed audio-computer-assisted self-interviews. RESULTS: Bivariate analyses indicated significant positive associations between PTSD symptoms and PrEP acceptance and self-confidence. In multinomial logistic regression analyses, after controlling for Perceived HIV Risk, participants had a higher likelihood of responding they 'probably would' take PrEP (as opposed to 'definitely would not' take PrEP) if they reported higher levels of PTSD symptoms. Post-hoc analyses revealed a curvilinear relationship between PTSD symptoms and PrEP acceptance with those reporting the highest level of PTSD in the sample having slightly lower PrEP acceptance than those reporting moderately high levels of PTSD. CONCLUSION: Findings are discussed in the context of the negative impacts of high levels of PTSD and potential positive adaptations subsequent to moderate levels of PTSD that could be relevant to advances in HIV prevention efforts.
Assuntos
Infecções por HIV , Profilaxia Pré-Exposição , Transtornos de Estresse Pós-Traumáticos , Feminino , Humanos , Masculino , Adulto Jovem , Negro ou Afro-Americano , Estudos Transversais , Infecções por HIV/prevenção & controle , Infecções por HIV/psicologia , Homossexualidade Masculina/psicologia , IntençãoRESUMO
Xyloglucan, the most abundant hemicellulosic component of the primary cell wall of flowering plants, is composed of a ß-(1,4)-glucan backbone decorated with d-xylosyl residues. Three xyloglucan xylosyltransferases (XXTs) participate in xyloglucan biosynthesis in Arabidopsis (Arabidopsis thaliana). Two of these, XXT1 and XXT2, have been shown to be active in vitro, whereas the catalytic activity of XXT5 has yet to be demonstrated. By optimizing XXT2 expression in a prokaryotic system and in vitro activity assay conditions, we demonstrate that nonglycosylated XXT2 lacking its cytosolic amino-terminal and transmembrane domain displays high catalytic activity. Using this optimized procedure for the expression of XXT5, we report, to our knowledge for the first time, that recombinant XXT5 shows enzymatic activity in vitro, although at a significantly slower rate than XXT1 and XXT2. Kinetic analysis showed that XXT5 has a 7-fold higher Km and 9-fold lower kcat compared with XXT1 and XXT2. Activity assays using XXT5 in combination with XXT1 or XXT2 indicate that XXT5 is not specific for their products. In addition, mutagenesis experiments showed that the in vivo function and in vitro catalytic activity of XXT5 require the aspartate-serine-aspartate motif. These results demonstrate that XXT5 is a catalytically active xylosyltransferase involved in xylosylation of the xyloglucan backbone.
Assuntos
Proteínas de Arabidopsis/metabolismo , Pentosiltransferases/metabolismo , Motivos de Aminoácidos/genética , Proteínas de Arabidopsis/genética , Escherichia coli/genética , Mutagênese , Oligossacarídeos/metabolismo , Pentosiltransferases/genética , Plantas Geneticamente Modificadas , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Uridina Difosfato Xilose/metabolismoRESUMO
In dicotyledonous plants, xyloglucan (XyG) is the most abundant hemicellulose of the primary cell wall. The enzymes involved in XyG biosynthesis have been identified through reverse-genetics and activity was characterized by heterologous expression. Currently, there is no information on the atomic structures or amino acids involved in activity or substrate binding of any of the Golgi-localized XyG biosynthetic enzymes. A homology model of the xyloglucan xylosyltransferase 2 (XXT2) catalytic domain was built on the basis of the crystal structure of A64Rp. Molecular dynamics simulations revealed that the homology model retains the glycosyltransferase (GT)-A fold of the template structure used to build the homology model indicating that XXT2 likely has a GT-A fold. According to the XXT2 homology model, six amino acids (Phe204, Lys207, Asp228, Ser229, Asp230, His378) were selected and their contribution in catalytic activity was investigated. Site-directed mutagenesis studies show that Asp228, Asp230 and His378 are critical for XXT2 activity and are predicted to be involved in coordination of manganese ion. Lys207 was also found to be critical for protein activity and the homology model indicates a critical role in substrate binding. Additionally, Phe204 mutants have less of an impact on XXT2 activity with the largest effect when replaced with a polar residue. This is the first study that investigates the amino acids involved in substrate binding of the XyG-synthesizing xylosyltransferases and contributes to the understanding of the mechanisms of polysaccharide-synthesizing GTs and XyG biosynthesis.
Assuntos
Aminoácidos/química , Parede Celular/química , Pentosiltransferases/química , Conformação Proteica , Sequência de Aminoácidos/genética , Aminoácidos/genética , Arabidopsis/química , Arabidopsis/genética , Sítios de Ligação , Domínio Catalítico , Parede Celular/enzimologia , Glucanos/biossíntese , Glucanos/química , Modelos Moleculares , Mutagênese Sítio-Dirigida , Pentosiltransferases/genética , Ligação Proteica , Homologia Estrutural de Proteína , Especificidade por Substrato , Xilanos/biossíntese , Xilanos/químicaRESUMO
Young Black men who have sex with men (MSM) living with HIV evidence the lowest rates of linkage to care and viral suppression of all US MSM. Kentucky, identified by the US Department of Health and Human Services as a "hot spot" state with elevated HIV incidence compared to the rest of the country, exhibits similar racialized outcomes. Structural, interpersonal, and individual drivers of engagement along the HIV care continuum among people living with HIV have been identified, primarily through quantitative designs. However, the mechanisms by which these factors shape HIV care engagement, and the ways they may combine or reinforce each other, as well as from the lived experience of young Black MSM living with HIV, have been studied to a lesser extent. In this study, a purposive sample of n = 29 HIV-positive young Black MSM (age M = 25 years old; 38% retained in care) residing in Kentucky participated in in-depth interviews. Factors that were most influential on engagement varied along the continuum, with health insurance status and knowledge of HIV being relatively more influential to diagnosis, and housing stability, psychological processes, and interpersonal relationships being more influential on retention. For some participants, barriers to care at multiple levels had a mutually influencing and intensifying impact on care engagement. Additional efforts to center the voices of young Black MSM living with HIV will help illuminate acceptable and sustainable interventions for increasing their care engagement and narrowing persistent racial disparities in HIV morbidity and mortality.
Assuntos
Negro ou Afro-Americano , Infecções por HIV , Acessibilidade aos Serviços de Saúde , Disparidades em Assistência à Saúde , Minorias Sexuais e de Gênero , Determinantes Sociais da Saúde , Adulto , Humanos , Masculino , População Negra/estatística & dados numéricos , Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , Infecções por HIV/etnologia , Infecções por HIV/terapia , Homossexualidade Masculina/psicologia , Homossexualidade Masculina/estatística & dados numéricos , Grupos Raciais , Minorias Sexuais e de Gênero/psicologia , Minorias Sexuais e de Gênero/estatística & dados numéricos , Negro ou Afro-Americano/psicologia , Negro ou Afro-Americano/estatística & dados numéricos , Kentucky/epidemiologia , Disparidades em Assistência à Saúde/etnologia , Disparidades em Assistência à Saúde/estatística & dados numéricos , Determinantes Sociais da Saúde/etnologia , Determinantes Sociais da Saúde/estatística & dados numéricos , Acessibilidade aos Serviços de Saúde/estatística & dados numéricosRESUMO
Importance: Maternal mortality and severe maternal morbidity (SMM) are important focus areas in public health. Further understanding trends, health disparities, and risk factors for these adverse outcomes is vital to public health decision-making. Objective: To describe trends and risk factors for delivery-related maternal deaths and SMM in the United States. Design, Setting, and Participants: This is a retrospective cross-sectional study using data from a large, geographically diverse, all-payer hospital administrative database. Hospital discharges from January 2008 to December 2021 with any Medicare Severity Diagnosis Related Group, International Classification of Diseases, Ninth Revision, Clinical Modification, or International Classification of Diseases, Tenth Revision, Clinical Modification delivery diagnosis or procedure code were included. Data analysis took place from February 2021 to March 2023. Exposures: Year, quarter (Q), age, race and ethnicity, delivery method. Main Outcomes and Measures: Maternal mortality, SMM during delivery-related hospitalization. Results: Overall, 11â¯628â¯438 unique hospital discharges were analyzed, with a mean (SD) age of 28 (6) years. There were 437â¯579 (3.8%) Asian, 92â¯547 (0.8%) American Indian, 1â¯640â¯355 (14.1%) Black, 1â¯762â¯392 (15.2%) Hispanic, 83â¯189 (0.7%) Pacific Islander, and 6â¯194â¯139 (53.3%) White patients. Regression-adjusted maternal mortality per 100â¯000 discharges declined from 10.6 deaths in Q1 2008 to 4.6 deaths in Q4 2021. Mortality was significantly higher among patients with advanced maternal age (eg, age 35-44 years vs 25-34 years: adjusted odds ratio [aOR], 1.49; 95% CI, 1.22-1.84). Other significant risk factors for mortality included cesarean delivery, comorbid conditions, complications, and COVID-19 diagnosis (eg, cesarean delivery: aOR, 2.28; 95% CI, 1.87-2.79). The prevalence of any SMM increased from 146.8 per 10â¯000 discharges in Q1 of 2008 to 179.8 per 10â¯000 discharges in Q4 of 2021. SMM risk factors included age 24 years or younger or age 35 years or older, belonging to a racial or ethnic minority group, cesarean delivery, Medicaid insurance, and having 1 or more comorbidities (eg, age 10-19 years: aOR, 1.39; 95% CI, 1.36-1.42). Conclusions and Relevance: This cross-sectional study found that delivery-related mortality in US hospitals decreased for all racial and ethnic groups, age groups, and modes of delivery during 2008 to 2021, likely demonstrating the impact of national strategies focused on improving maternal quality of care provided during delivery-related hospitalizations. SMM prevalence increased for all patients, with higher rates for racial and ethnic minority patients of any age. Advanced maternal age, racial or ethnic minority group status, cesarean delivery, and comorbidities were associated with higher odds of mortality and SMM.
Assuntos
COVID-19 , Etnicidade , Gravidez , Feminino , Humanos , Idoso , Estados Unidos/epidemiologia , Adulto , Adulto Jovem , Criança , Adolescente , Estudos Retrospectivos , Mortalidade Materna , Estudos Transversais , Teste para COVID-19 , Grupos Minoritários , Medicare , COVID-19/epidemiologia , HospitalizaçãoRESUMO
Background: Mining can directly and indirectly affect social and environmental systems in a range of positive and negative ways, and may result in societal benefits, but may also cause conflicts, not least in relation to land use. Mining always affects the environment, whilst remediation and mitigation efforts may effectively ameliorate some negative environmental impacts. Social and environmental systems in Arctic and boreal regions are particularly sensitive to impacts from development for numerous reasons, not least of which are the reliance of Indigenous peoples on subsistence livelihoods and long recovery times of fragile ecosystems. With growing metal demand, mining in the Arctic is expected to increase, demanding a better understand its social and environmental impacts. We report here the results of a systematic mapping of research evidence of the impacts of metal mining in Arctic and boreal regions. Methods: We searched multiple bibliographic databases and organisational websites for relevant research using tested search strategies. We also collected evidence from stakeholders and rightsholders identified in the wider 3MK project (Mapping the impacts of Mining using Multiple Knowledges, https://osf.io/cvh3u). We screened articles at three stages (title, abstract, and full text) according to a predetermined set of inclusion criteria, with consistency checks between reviewers at each level. We extracted data relating to causal linkages between actions or impacts and measured outcomes, along with descriptive information about the articles and studies. We have produced an interactive database along with interactive visualisations, and identify knowledge gaps and clusters using heat maps. Review findings: Searches identified over 32,000 potentially relevant records, which resulted in a total of 585 articles being retained in the systematic map. This corresponded to 902 lines of data on impact or mitigation pathways. The evidence was relatively evenly spread across topics, but there was a bias towards research in Canada (35% of the evidence base). Research was focused on copper (23%), gold (18%), and zinc (16%) extraction as the top three minerals, and open pit mines were most commonly studied (33%). Research most commonly focused on operation stages, followed by abandonment and post-closure, with little evidence on early stages (prospecting, exploration, construction; 2%), expansion (0.2%), or decommissioning/closure (0.3%). Mitigation measures were not frequently studied (18% articles), with groundwater mitigation most frequently investigated (54% of mitigations), followed by soil quality (12%) and flora species groups (10%). Control-impact study designs were most common (68%) with reference sites as the most frequently used comparator (43%). Only 7 articles investigated social and environmental outcomes together. the most commonly reported system was biodiversity (39%), followed by water (34%), societies (20%), and soil/geology (6%), with air the least common (1%). Conclusions: The evidence found highlights a suite of potential knowledge gaps, namely: on early stages prior to operation; effectiveness of mitigation measures; stronger causal inference study designs; migration and demography; cumulative impacts; and impacts on local and Indigenous communities. We also tentatively suggest subtopics where the number of studies could allow systematic reviews: operation, post-closure, and abandonment stages; individual faunal species, surface water quality, water sediment quality; and, groundwater mitigation measure effectiveness. Supplementary Information: The online version contains supplementary material available at 10.1186/s13750-022-00282-y.
RESUMO
Although a causal role of genetic alterations in human cancer is well established, it is still unclear whether dietary fat can modulate cancer risk in a predisposed population. Epidemiological studies suggest that diets rich in omega-3 polyunsaturated fatty acids reduce cancer incidence. To determine the influence of fatty acids on prostate cancer risk in animals with a defined genetic lesion, we used prostate-specific Pten-knockout mice, an immune-competent, orthotopic prostate cancer model, and diets with defined polyunsaturated fatty acid levels. We found that omega-3 fatty acids reduced prostate tumor growth, slowed histopathological progression, and increased survival, whereas omega-6 fatty acids had opposite effects. Introducing an omega-3 desaturase, which converts omega-6 to omega-3 fatty acids, into the Pten-knockout mice reduced tumor growth similarly to the omega-3 diet. Tumors from mice on the omega-3 diet had lower proportions of phosphorylated Bad and higher apoptotic indexes compared with those from mice on omega-6 diet. Knockdown of Bad eliminated omega-3-induced cell death, and introduction of exogenous Bad restored the sensitivity to omega-3 fatty acids. Our data suggest that modulation of prostate cancer development by polyunsaturated fatty acids is mediated in part through Bad-dependent apoptosis. This study highlights the importance of gene-diet interactions in prostate cancer.
Assuntos
Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-6/farmacologia , Predisposição Genética para Doença , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Animais , Apoptose , Progressão da Doença , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/metabolismo , Deleção de Genes , Masculino , Camundongos , Camundongos Transgênicos , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosforilação , Neoplasias da Próstata/dietoterapia , Taxa de Sobrevida , Proteína de Morte Celular Associada a bcl/metabolismoRESUMO
We have shown that the intentional engineering of a natural product biosynthesis pathway is a useful way to generate stereochemically complex scaffolds for use in the generation of combinatorial libraries that capture the structural features of both natural products and synthetic compounds. Analysis of a prototype library based upon nonactic acid lead to the discovery of triazole-containing nonactic acid analogs, a new structural class of antibiotic that exhibits bactericidal activity against drug resistant, Gram-positive pathogens including Staphylococcus aureus and Enterococcus faecalis.
Assuntos
Antibacterianos/química , Produtos Biológicos/química , Bactérias Gram-Positivas/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/farmacologia , Produtos Biológicos/síntese química , Produtos Biológicos/farmacologia , Farmacorresistência Bacteriana , Enterococcus faecalis/efeitos dos fármacos , Macrolídeos/síntese química , Macrolídeos/química , Macrolídeos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estereoisomerismo , Triazóis/química , Vancomicina/farmacologiaRESUMO
BACKGROUND: Academic medical centers have expanded their inpatient medicine services with advanced practice clinicians (APCs) or nonteaching hospitalists in response to patient volumes, residency work hour restrictions, and recently, COVID-19. Reports of clinical outcomes, cost, and resource utilization differ among inpatient team structures. OBJECTIVE: Directly compare outcomes among resident, APC, and solo hospitalist inpatient general medicine teams. DESIGN: Retrospective cohort study using multivariable analysis adjusted for time of admission, interhospital transfer, and comorbidities that compares clinical outcomes, cost, and resource utilization. SUBJECTS: Patients 18 years or older discharged from an inpatient medicine service between July 2015 and July 2018 (N = 12,716). MAIN MEASURES: Length of stay (LOS), 30-day readmission, inpatient mortality, normalized total direct cost, discharge time, and consultation utilization. KEY RESULTS: Resident teams admitted fewer patients at night (32.0%; P < .001) than did APC (49.5%) and hospitalist (48.6%) teams. APCs received nearly 4% more outside transfer patients (P = .015). Hospitalists discharged patients 26 minutes earlier than did residents (mean hours after midnight [95% CI], 14.58 [14.44-14.72] vs 15.02 [14.97-15.08]). Adjusted consult utilization was 15% higher for APCs (adjusted mean consults per admission [95% CI], 1.00 [0.96-1.03]) and 8% higher for residents (0.93 [0.90-0.95]) than it was for hospitalists (0.85 [0.80-0.90]). No differences in LOS, readmission, mortality, or cost were observed between the teams. CONCLUSION: We observed similar costs, LOS, 30-day readmission, and mortality among hospitalist, APC, and resident teams. Our results suggest clinical outcomes are not significantly affected by team structure. The addition of APC or hospitalist teams represent safe and effective alternatives to traditional inpatient resident teams.
Assuntos
Centros Médicos Acadêmicos , Recursos em Saúde/economia , Médicos Hospitalares/economia , Medicina Interna , Internato e Residência , Avaliação de Resultados da Assistência ao Paciente , Feminino , Humanos , Medicina Interna/economia , Medicina Interna/educação , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente , Qualidade da Assistência à Saúde/estatística & dados numéricos , Estudos RetrospectivosRESUMO
Nonactin is a polyketide antibiotic produced by Streptomyces griseus ETH A7796 and is an ionophore that is selective for K(+) ions. It is a cyclic tetraester generated from two monomers of (+)-nonactic acid and two of (-)-nonactic acid, arranged (+)-(-)-(+)-(-) so that nonactin has S4 symmetry and is achiral. To understand why achiral nonactin is the naturally generated diastereoisomer, we generated two alternate diastereoisomers of nonactin, one prepared solely from (+)-nonactic acid and one prepared solely from (-)-nonactic acid, referred to here as 'all-(+)-nonactin' and 'all-(-)-nonactin', respectively. Both non-natural diastereoisomers were 500-fold less active against gram positive organisms than nonactin confirming that the natural stereochemistry is necessary for biological activity. We used isothermal calorimetry to obtain the K(a), DeltaG, DeltaH, and DeltaS of formation for the K(+), Na(+), and NH(4)(+) complexes of nonactin and all-(-)-nonactin; the natural diastereoisomer bound K(+) 880-fold better than all-(-)-nonactin. A picrate partitioning assay confirmed that all-(-)-nonactin, unlike nonactin, could not partition K(+) ions into organic solvent. To complement the thermodynamic data we used a simple model system to show that K(+) transport was facilitated by nonactin but not by all-(-)-nonactin. Modeling of the K(+) complexes of nonactin and all-(-)-nonactin suggested that poor steric interactions in the latter complex precluded tight binding to K(+). Overall, the data show that both enantiomers of nonactic acid are needed for the formation of a nonactin diastereoisomer that can act as an ionophore and has antibacterial activity.
Assuntos
Antibacterianos/química , Compostos Macrocíclicos/química , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Íons , Compostos Macrocíclicos/farmacologia , Macrolídeos/química , Testes de Sensibilidade Microbiana , EstereoisomerismoRESUMO
Candida glabrata is a lethal fungal pathogen resistant to many antifungal agents and has emerged as a critical target for drug discovery. Over the past several years, we have been developing a class of propargyl-linked antifolates as antimicrobials and hypothesized that these compounds could be effective inhibitors of dihydrofolate reductase (DHFR) from C. glabrata. We initially screened a small collection of these inhibitors and found modest levels of potency. Subsequently, we determined the crystal structure of C. glabrata DHFR bound to a representative inhibitor with data to 1.6 A resolution. Using this structure, we designed and synthesized second-generation inhibitors. These inhibitors bind the C. glabrata DHFR enzyme with subnanomolar potency, display greater than 2000-fold levels of selectivity over the human enzyme, and inhibit the growth of C. glabrata at levels observed with clinically employed therapeutics.
Assuntos
Antifúngicos/química , Antifúngicos/farmacologia , Candida glabrata/efeitos dos fármacos , Candida glabrata/enzimologia , Antagonistas do Ácido Fólico/química , Antagonistas do Ácido Fólico/farmacologia , Tetra-Hidrofolato Desidrogenase/metabolismo , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Ligantes , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Molecular , Ligação Proteica , Alinhamento de Sequência , Relação Estrutura-Atividade , Tetra-Hidrofolato Desidrogenase/químicaRESUMO
In order to develop new antifungal agents effective against two species of Candida, we have designed a series of dihydrofolate reductase (DHFR) inhibitors. Here, we explore the structure-activity relationships of these inhibitors toward Candida albicans DHFR by evaluating enzyme inhibition, antifungal activity and toxicity to mammalian cells. Analysis of docked complexes of the enzyme and inhibitors yields the structural basis of relative potency. The meta-biphenyl series of this class exhibits the greatest enzyme inhibition, selectivity and antifungal activity.
Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Antagonistas do Ácido Fólico/farmacologia , Proteínas Fúngicas/metabolismo , Pirimidinas/farmacologia , Tetra-Hidrofolato Desidrogenase/metabolismo , Antifúngicos/química , Antifúngicos/toxicidade , Candida albicans/enzimologia , Candida albicans/crescimento & desenvolvimento , Candida glabrata/efeitos dos fármacos , Candida glabrata/enzimologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Antagonistas do Ácido Fólico/química , Antagonistas do Ácido Fólico/toxicidade , Proteínas Fúngicas/química , Humanos , Modelos Moleculares , Estrutura Molecular , Pargilina/química , Pargilina/farmacologia , Pargilina/toxicidade , Ligação Proteica , Conformação Proteica , Pirimidinas/química , Pirimidinas/toxicidade , Relação Estrutura-Atividade , Especificidade por Substrato , Tetra-Hidrofolato Desidrogenase/químicaRESUMO
Parkinson's Disease (PD) is a common neurodegenerative disorder currently diagnosed based on the presentation of characteristic movement symptoms. Unfortunately, patients exhibiting these symptoms have already undergone significant dopaminergic neuronal loss. Earlier diagnosis, aided by molecular biomarkers specific to PD, would improve overall patient care. Epigenetic mechanisms, which are modified by both environment and disease pathophysiology, are emerging as important components of neurodegeneration. Alterations to the PD methylome have been reported in epigenome-wide association studies. However, the extent to which methylation changes correlate with disease progression has not yet been reported; nor the degree to which methylation is affected by PD medication. We performed a longitudinal genome-wide methylation study surveying ~850,000 CpG sites in whole blood from 189 well-characterized PD patients and 191 control individuals obtained at baseline and at a follow-up visit ~2 y later. We identified distinct patterns of methylation in PD cases versus controls. Importantly, we identified genomic sites where methylation changes longitudinally as the disease progresses. Moreover, we identified methylation changes associated with PD pathology through the analysis of PD cases that were not exposed to anti-parkinsonian therapy. In addition, we identified methylation sites modulated by exposure to dopamine replacement drugs. These results indicate that DNA methylation is dynamic in PD and changes over time during disease progression. To the best of our knowledge, this is the first longitudinal epigenome-wide methylation analysis for Parkinson's disease and reveals changes associated with disease progression and in response to dopaminergic medications in the blood methylome.
Assuntos
Metilação de DNA , Doença de Parkinson/genética , Idoso , Biomarcadores/sangue , Ilhas de CpG , DNA/sangue , DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/patologiaRESUMO
Individual differences in cognitive function are due to a combination of heritable and non-heritable factors. A large body of evidence from clinical, cognitive, and pharmacological neuroscience implicates dopaminergic gene variants as modulators of cognitive functions. Neuroepigenetic studies demonstrate environmental factors also influence complex phenotypes by affecting gene expression regulation. To evaluate the mechanism of environmental influence on cognitive abilities, we examined if epigenetic regulation of dopaminergic genes plays a role in cognition. Using a DNA methylation profiling microarray, we used a monozygotic (MZ) twin difference design to evaluate if co-twin differences in methylation of CpG sites near six dopaminergic genes predicted differences in response inhibition and memory performance. Studying MZ twins allows us to assess if environmentally driven differences in methylation affect differences in phenotype while controlling for the influence of genotype and shared family environment. Response inhibition was assessed with the flanker task and short-term and working memory were assessed with digit span recall. We found MZ co-twin differences in DRD4 gene methylation predicted differences in short-term memory. MZ differences in COMT, DBH, DAT1, DRD1, and DRD2 gene methylation predicted differences in response inhibition. Taken together, findings suggest methylation status of dopaminergic genes may influence cognitive functions in a dissociable manner. Our results highlight the importance of the epigenome and environment, over and above the influence of genotype, in supporting complex cognitive functions.
Assuntos
Cognição/fisiologia , Metilação de DNA , Catecol O-Metiltransferase/genética , Criança , Ilhas de CpG , Dopamina/genética , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Feminino , Humanos , Masculino , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/genética , Receptores de Dopamina D4/genética , Gêmeos MonozigóticosRESUMO
The synthesis of a library of nonactic acid-derived triazoloamide derivatives and their evaluation as antimicrobial agents is described.
Assuntos
Anti-Infecciosos/farmacologia , Química Farmacêutica/métodos , Triazóis/química , Aminas , Anti-Infecciosos/química , Catálise , Cloretos/química , Cobre/química , Desenho de Fármacos , Furanos/química , Bactérias Gram-Negativas/metabolismo , Bactérias Gram-Positivas/metabolismo , Macrolídeos/síntese química , Macrolídeos/química , Modelos QuímicosRESUMO
BACKGROUND: Lepirudin is a recombinant hirudin that exerts its anticoagulant effect by direct inhibition of thrombin. Lepirudin is indicated for anticoagulation in patients with heparin-induced thrombocytopenia (HIT) and associated thromboembolic disease to prevent further thromboembolic complications. OBJECTIVE: This review addresses various clinical uses of lepirudin including but not limited to FDA approved indication. The objective is to provide an updated overview of the clinical use and pharmacology of the agent. In addition, we address certain areas of controversy especially pertaining to dosing of lepirudin and its use in different clinical situations. METHODS: Literature was reviewed using appropriate search terms in Pubmed and Ovid medline databases. RESULTS/CONCLUSION: Lepirudin continues to be a valuable anticoagulant in the management of HIT. Lepirudin has the highest recommendation in treatment of HIT based on evidence from clinical trials. Minor modifications in dosing over the standard label recommendations may simplify its use and enhance safety.
Assuntos
Anticoagulantes/administração & dosagem , Hirudinas/administração & dosagem , Trombocitopenia/tratamento farmacológico , Anticoagulantes/efeitos adversos , Anticoagulantes/farmacocinética , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Heparina/efeitos adversos , Hirudinas/efeitos adversos , Hirudinas/farmacocinética , Humanos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacocinética , Trombocitopenia/induzido quimicamenteRESUMO
Xyloglucan is the most abundant hemicellulose in the primary cell wall of dicotyledonous plants. In Arabidopsis, three xyloglucan xylosyltransferases, XXT1, XXT2, and XXT5, participate in xylosylation of the xyloglucan backbone. Despite the importance of these enzymes, there is a lack of information on their structure and the critical residues required for substrate binding and transferase activity. In this study, the roles of different domains of XX2 in protein expression and catalytic activity were investigated by constructing a series of N- and C-terminal truncations. XXT2 with an N-terminal truncation of 31 amino acids after the predicted transmembrane domain showed the highest protein expression, but truncations of more than 31 residues decreased protein expression and catalytic activity. XXT2 constructs with C-terminal truncations showed increased protein expression but decreased activity, particularly for truncations of 44 or more amino acids. Site-directed mutagenesis was also used to investigate six positively charged residues near the C-terminus and found that four of the mutants showed decreased enzymatic activity. We conclude that the N- and C-termini of XXT2 have important roles in protein folding and enzymatic activity: the stem region (particularly the N-terminus of the catalytic domain) is critical for protein folding and the C-terminus is essential for enzymatic activity but not for protein folding.
Assuntos
Glucanos/química , Pentosiltransferases/química , Xilanos/química , Arabidopsis/enzimologia , Arabidopsis/metabolismo , Parede Celular/metabolismo , Mutagênese Sítio-Dirigida , Pentosiltransferases/genética , Pentosiltransferases/metabolismo , Caules de Planta/metabolismoRESUMO
PURPOSE: Little is known about trans womens' experiences accessing gender-segregated health and housing services, particularly services for marginalized individuals living in poverty. As such, we conducted a qualitative investigation into experiences of accessing women-specific health and housing services among trans women and two-spirit persons in a downtown neighborhood of Vancouver, Canada. METHODS: Between June 2012 and May 2013 interviews were conducted with 32 trans women and two-spirit individuals who had accessed women-specific health and/or housing services. Participants were recruited from four open prospective cohorts of sex workers and individuals who use drugs. Interview data were analyzed using a participatory analysis approach with two participants who were hired as research assistants. RESULTS: Participants were generally able to access women-specific services in the neighborhood. However, there were reports of discrimination related to gender identity, discrimination based on gender expression (e.g., requirement of a feminine gender expression), and lack of staff intervention in harassment from other service users. CONCLUSION: Trans women and two-spirit persons in our study relied upon services for their health and safety and, therefore, exclusion from women-specific services had potentially severe adverse consequences such as homelessness and sexual violence. Recommendations to improve accessibility, including policy development and procedural recommendations, are put forth.