RESUMO
OPINION: All opioids have a risk of causing respiratory depression and reduced cerebral circulation. Fentanyl has the greatest risk of causing both. This is particularly a concern when combined with illicit opioids such as diamorphine (also known as heroin). Fentanyl should not be used as a frontline potent opioid due its significant risks. Buprenorphine, a schedule III opioid, morphine, or hydromorphone is preferred, followed by oxycodone, which has a significant risk of abuse relative to buprenorphine and morphine. Although all opioids were equally effective in producing analgesia, the relative safety of each opioid is no longer a secondary concern when prescribing. In the face of an international opioid epidemic, clinicians need to choose opioid analgesics safely, wisely, and carefully.
Assuntos
Analgésicos Opioides , Insuficiência Respiratória , Humanos , Insuficiência Respiratória/etiologia , Analgésicos Opioides/uso terapêutico , Analgésicos Opioides/efeitos adversosRESUMO
OBJECTIVE: In-hospital formula supplementation places infants at risk for early breastfeeding cessation. The study's aim was to identify predictive and protective factors for in-hospital formula supplementation in individuals documented as wanting to exclusively breastfeed and residing in a geographic region with adverse social determinants of health and low breastfeeding rates. Additionally, we wished to determine if lactation consultation served as a protective factor against supplementation. METHODS: In this cross-sectional study, we retrospectively reviewed 500 randomly selected charts of newborns born in a 12 month period at a regional tertiary care hospital. We included healthy, full-term neonates having a recorded maternal decision to exclusively breastfeed. Maternal-newborn dyad characteristics were compared between those exclusively breastfeeding and those with in-hospital formula supplementation. RESULTS: Of the 500 charts, 70% of individuals desired to exclusively breastfeed. Overall, 41% of breastfed newborns were supplemented with formula before discharge, and 32% of women met with lactation consultants prior to supplementation. No statistically significant association was present between exclusive breastfeeding at discharge and meeting with a hospital lactation consultant (p = 0.55). When controlling for the confounders of maternal demographics and lactation consultation, significant associations with formula supplementation included Cesarean delivery (odd ratio: 2.08, 95% confidence interval: 1.04-4.16), primiparity (2.48, 1.27-4.87), and high school level of education (2.78, 1.33-5.78). CONCLUSIONS: Maternal characteristics of high school level educational, primiparity, and Caesarean delivery place individuals at risk for in-hospital formula supplementation in individuals wishing to exclusively breastfeed. Addressing barriers to exclusive breastfeeding is essential to enhance maternal and newborn health equity.
Assuntos
Aleitamento Materno , Suplementos Nutricionais , Lactente , Gravidez , Recém-Nascido , Humanos , Feminino , Estudos Retrospectivos , Estudos Transversais , Suplementos Nutricionais/efeitos adversos , Hospitais , Fórmulas InfantisRESUMO
BACKGROUND: Despite preventive measures, infections continue to pose significant risks to pediatric allogeneic hematopoietic cell transplantation (allo-HCT) recipients. The gut microbiota has been linked to clinical outcomes following adult allo-HCT. This study evaluated whether similar disruptions or differing microbiota patterns were associated with infection risk in pediatric allo-HCT. METHODS: In a prospective observational study, fecal samples were obtained from 74 children before conditioning and upon neutrophil recovery. Microbiome signatures identified through sequencing were examined for their associations with infections or acute graft-versus-host disease (aGVHD) in the first-year post-HCT using Cox proportional hazards analysis. RESULTS: Microbiome disruption in adults, did not predict infection risk in pediatric allo-HCT. Unique microbiota signatures were associated with different infections or aGVHD. A ratio of strict and facultative anaerobes (eg, Lachnoclostridium, Parabacteroides) prior to conditioning predicted bacteremia risk (Cox hazard ratio [HR], 3.89). A distinct ratio of oral (eg, Rothia, Veillonella) to intestinal anaerobes (eg, Anaerobutyricum, Romboutsia) at neutrophil recovery predicted likelihood of bacterial infections (Cox HR, 1.81) and viral enterocolitis (Cox HR, 1.96). CONCLUSIONS: Interactions between medical interventions, pediatric hosts, and microbial communities contribute to microbiota signatures that predict infections. Further multicenter study is necessary to validate the generalizability of these ratios as biomarkers.
Assuntos
Microbioma Gastrointestinal , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Adulto , Humanos , Criança , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Bactérias/genética , Fezes/microbiologiaRESUMO
Evaluating the efficacy of management actions to control invasive species is crucial for maintaining funding and to provide feedback for the continual improvement of management efforts. However, it is often difficult to assess the efficacy of control methods due to limited resources for monitoring. Managers may view effort on monitoring as effort taken away from performing management actions. We developed a method to estimate invasive species abundance, evaluate management effectiveness, and evaluate population growth over time from a combination of removal activities (e.g., trapping, ground shooting) using only data collected during removal efforts (method of removal, date, location, number of animals removed, and effort). This dynamic approach allows for abundance estimation at discrete time points and the estimation of population growth between removal periods. To test this approach, we simulated over 1 million conditions, including varying the length of the study, the size of the area examined, the number of removal events, the capture rates, and the area impacted by removal efforts. Our estimates were unbiased (within 10% of truth) 81% of the time and were correlated with truth 91% of the time. This method performs well overall and, in particular, at monitoring trends in abundances over time. We applied this method to removal data from Mingo National Wildlife Refuge in Missouri from December 2015 to September 2019, where the management objective is elimination. Populations of feral swine on Mingo NWR have fluctuated over time but showed marked declines in the last 3-6 months of the time series corresponding to increased removal pressure. Our approach allows for the estimation of population growth across time (from both births and immigration) and therefore, provides a target removal rate (above that of the population growth) to ensure the population will decline. In Mingo NWR, the target monthly removal rate is 18% to cause a population decline. Our method provides advancement over traditional removal modeling approaches because it can be applied to evaluate management programs that use a broad range of removal techniques concurrently and whose management effort and spatial coverage vary across time.
Assuntos
Animais Selvagens , Espécies Introduzidas , Animais , Coleta de Dados , Densidade Demográfica , SuínosRESUMO
Oral baiting is used to deliver vaccines to wildlife to prevent, control, and eliminate infectious diseases. A central challenge is how to spatially distribute baits to maximize encounters by target animal populations, particularly in urban and suburban areas where wildlife such as raccoons (Procyon lotor) are abundant and baits are delivered along roads. Methods from movement ecology that quantify movement and habitat selection could help to optimize baiting strategies by more effectively targeting wildlife populations across space. We developed a spatially explicit, individual-based model of raccoon movement and oral rabies vaccine seroconversion to examine whether and when baiting strategies that match raccoon movement patterns perform better than currently used baiting strategies in an oral rabies vaccination zone in greater Burlington, Vermont, USA. Habitat selection patterns estimated from locally radio-collared raccoons were used to parameterize movement simulations. We then used our simulations to estimate raccoon population rabies seroprevalence under currently used baiting strategies (actual baiting) relative to habitat selection-based baiting strategies (habitat baiting). We conducted simulations on the Burlington landscape and artificial landscapes that varied in heterogeneity relative to Burlington in the proportion and patch size of preferred habitats. We found that the benefits of habitat baiting strongly depended on the magnitude and variability of raccoon habitat selection and the degree of landscape heterogeneity within the baiting area. Habitat baiting improved seroprevalence over actual baiting for raccoons characterized as habitat specialists but not for raccoons that displayed weak habitat selection similar to radiocollared individuals, except when baits were delivered off roads where preferred habitat coverage and complexity was more pronounced. In contrast, in artificial landscapes with either more strongly juxtaposed favored habitats and/or higher proportions of favored habitats, habitat baiting performed better than actual baiting, even when raccoons displayed weak habitat preferences and where baiting was constrained to roads. Our results suggest that habitat selection-based baiting could increase raccoon population seroprevalence in urban-suburban areas, where practical, given the heterogeneity and availability of preferred habitat types in those areas. Our novel simulation approach provides a flexible framework to test alternative baiting strategies in multiclass landscapes to optimize bait-distribution strategies.
Assuntos
Vacina Antirrábica , Raiva , Administração Oral , Animais , Animais Selvagens , Raiva/epidemiologia , Raiva/prevenção & controle , Raiva/veterinária , Guaxinins , Estudos Soroepidemiológicos , Vacinação/métodos , Vacinação/veterináriaRESUMO
Dispersal drives invasion dynamics of nonnative species and pathogens. Applying knowledge of dispersal to optimize the management of invasions can mean the difference between a failed and a successful control program and dramatically improve the return on investment of control efforts. A common approach to identifying optimal management solutions for invasions is to optimize dynamic spatial models that incorporate dispersal. Optimizing these spatial models can be very challenging because the interaction of time, space, and uncertainty rapidly amplifies the number of dimensions being considered. Addressing such problems requires advances in and the integration of techniques from multiple fields, including ecology, decision analysis, bioeconomics, natural resource management, and optimization. By synthesizing recent advances from these diverse fields, we provide a workflow for applying ecological theory to advance optimal management science and highlight priorities for optimizing the control of invasions. One of the striking gaps we identify is the extremely limited consideration of dispersal uncertainty in optimal management frameworks, even though dispersal estimates are highly uncertain and greatly influence invasion outcomes. In addition, optimization frameworks rarely consider multiple types of uncertainty (we describe five major types) and their interrelationships. Thus, feedbacks from management or other sources that could magnify uncertainty in dispersal are rarely considered. Incorporating uncertainty is crucial for improving transparency in decision risks and identifying optimal management strategies. We discuss gaps and solutions to the challenges of optimization using dynamic spatial models to increase the practical application of these important tools and improve the consistency and robustness of management recommendations for invasions.
Assuntos
Espécies Introduzidas , IncertezaRESUMO
Bartonella henselae infection can cause a wide spectrum of diseases in both the immunocompetent and immunocompromised host with BA a severe form relegated to immunocompromised hosts, including solid organ transplant population. There are established criteria for diagnosis of Bartonella infection based on clinical presentation, serologic testing, imaging studies and, when indicated, tissue sampling for histopathological evaluation, particularly for BA. However, treatment recommendations for BA are inconclusive. Furthermore, there are no studies in the pediatric solid organ transplant population for antimicrobial therapy during BA secondary to Bartonella henselae infection. A case of BA following heart transplant is presented along with a literature review of clinical presentation; diagnosis and therapy for BA in the pediatric solid organ transplant population.
Assuntos
Doença da Arranhadura de Gato/diagnóstico , Doença da Arranhadura de Gato/imunologia , Transplante de Coração , Animais , Antibacterianos/uso terapêutico , Azitromicina/uso terapêutico , Bartonella henselae , Doença da Arranhadura de Gato/tratamento farmacológico , Gatos , Criança , Humanos , Hospedeiro ImunocomprometidoRESUMO
Since their discovery in the United States in 1963, outbreaks of infection with equine influenza virus (H3N8) have been associated with serious respiratory disease in horses worldwide. Genomic analysis suggests that equine H3 viruses are of an avian lineage, likely originating in wild birds. Equine-like internal genes have been identified in avian influenza viruses isolated from wild birds in the Southern Cone of South America. However, an equine-like H3 hemagglutinin has not been identified. We isolated 6 distinct H3 viruses from wild birds in Chile that have hemagglutinin, nucleoprotein, nonstructural protein 1, and polymerase acidic genes with high nucleotide homology to the 1963 H3N8 equine influenza virus lineage. Despite the nucleotide similarity, viruses from Chile were antigenically more closely related to avian viruses and transmitted effectively in chickens, suggesting adaptation to the avian host. These studies provide the initial demonstration that equine-like H3 hemagglutinin continues to circulate in a wild bird reservoir.
Assuntos
Vírus da Influenza A Subtipo H3N8 , Influenza Aviária , Animais , Galinhas , Chile/epidemiologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Cavalos , Vírus da Influenza A Subtipo H3N8/genética , Influenza Aviária/epidemiologia , FilogeniaRESUMO
Populations of invasive species often spread heterogeneously across a landscape, consisting of local populations that cluster in space but are connected by dispersal. A fundamental dilemma for invasive species control is how to optimally allocate limited fiscal resources across local populations. Theoretical work based on perfect knowledge of demographic connectivity suggests that targeting local populations from which migrants originate (sources) can be optimal. However, demographic processes such as abundance and dispersal can be highly uncertain, and the relationship between local population density and damage costs (damage function) is rarely known. We used a metapopulation model to understand how budget and uncertainty in abundance, connectivity, and the damage function, together impact return on investment (ROI) for optimal control strategies. Budget, observational uncertainty, and the damage function had strong effects on the optimal resource allocation strategy. Uncertainty in dispersal probability was the least important determinant of ROI. The damage function determined which resource prioritization strategy was optimal when connectivity was symmetric but not when it was asymmetric. When connectivity was asymmetric, prioritizing source populations had a higher ROI than allocating effort equally across local populations, regardless of the damage function, but uncertainty in connectivity structure and abundance reduced ROI of the optimal prioritization strategy by 57% on average depending on the control budget. With low budgets (monthly removal rate of 6.7% of population), there was little advantage to prioritizing resources, especially when connectivity was high or symmetric, and observational uncertainty had only minor effects on ROI. Allotting funding for improved monitoring appeared to be most important when budgets were moderate (monthly removal of 13-20% of the population). Our result showed that multiple sources of observational uncertainty should be considered concurrently for optimizing ROI. Accurate estimates of connectivity direction and abundance were more important than accurate estimates of dispersal rates. Developing cost-effective surveillance methods to reduce observational uncertainties, and quantitative frameworks for determining how resources should be spatially apportioned to multiple monitoring and control activities are important and challenging future directions for optimizing ROI for invasive species control programs.
Assuntos
Conservação dos Recursos Naturais , Espécies Introduzidas , Modelos Biológicos , Densidade Demográfica , IncertezaRESUMO
Industrial hemp (Cannabis sativa L., Cannabaceae) is an ancient cultivated plant originating from Central Asia and historically has been a multi-use crop valued for its fiber, food, and medicinal uses. Various oriental and Asian cultures kept records of its production and numerous uses. Due to the similarities between industrial hemp (fiber and grain) and the narcotic/medical type of Cannabis, the production of industrial hemp was prohibited in most countries, wiping out centuries of learning and genetic resources. In the past two decades, most countries have legalized industrial hemp production, prompting a significant amount of research on the health benefits of hemp and hemp products. Current research is yet to verify the various health claims of the numerous commercially available hemp products. Hence, this review aims to compile recent advances in the science of industrial hemp, with respect to its use as value-added functional food ingredients/nutraceuticals and health benefits, while also highlighting gaps in our current knowledge and avenues of future research on this high-value multi-use plant for the global food chain.
Assuntos
Cannabis/química , Suplementos Nutricionais/análise , Ingredientes de Alimentos/análise , Alimento Funcional/análise , Valor Nutritivo , Plantas Comestíveis/química , Animais , Estudos Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Óleos de Plantas/química , Óleos de Plantas/isolamento & purificação , Sementes/química , Resultado do TratamentoRESUMO
Trypanosoma brucei uses multiple mechanisms to evade detection by its insect and mammalian hosts. The flagellar pocket (FP) is the exclusive site of uptake from the environment in trypanosomes and shields receptors from exposure to the host. The FP neck is tightly associated with the flagellum via a series of cytoskeletal structures that include the hook complex (HC) and the centrin arm. These structures are implicated in facilitating macromolecule entry into the FP and nucleating the flagellum attachment zone (FAZ), which adheres the flagellum to the cell surface. TbSmee1 (Tb927.10.8820) is a component of the HC and a putative substrate of polo-like kinase (TbPLK), which is essential for centrin arm and FAZ duplication. We show that depletion of TbSmee1 in the insect-resident (procyclic) form of the parasite causes a 40% growth decrease and the appearance of multinucleated cells that result from defective cytokinesis. Cells lacking TbSmee1 contain HCs with aberrant morphology and show delayed uptake of both fluid-phase and membrane markers. TbPLK localization to the tip of the new FAZ is also blocked. These results argue that TbSmee1 is necessary for maintaining HC morphology, which is important for the parasite's ability to take up molecules from its environment.
Assuntos
Trypanosoma brucei brucei/genética , Trypanosoma brucei brucei/metabolismo , Transporte Biológico , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular , Membrana Celular/metabolismo , Proteínas do Citoesqueleto/metabolismo , Citoesqueleto/metabolismo , Flagelos/metabolismo , Proteínas Serina-Treonina Quinases , Transporte Proteico , Proteínas Proto-Oncogênicas , Proteínas de Protozoários/metabolismo , Quinase 1 Polo-LikeRESUMO
The protist parasite Trypanosoma brucei is an obligate extracellular pathogen that retains its highly polarized morphology during cell division and has evolved a novel cytokinetic process independent of non-muscle myosin II. The polo-like kinase homolog TbPLK is essential for transmission of cell polarity during division and for cytokinesis. We previously identified a putative TbPLK substrate named Tip of the Extending FAZ 1 (TOEFAZ1) as an essential kinetoplastid-specific component of the T. brucei cytokinetic machinery. We performed a proximity-dependent biotinylation identification (BioID) screen using TOEFAZ1 as a means to identify additional proteins that are involved in cytokinesis. Using quantitative proteomic methods, we identified nearly 500 TOEFAZ1-proximal proteins and characterized 59 in further detail. Among the candidates, we identified an essential putative phosphatase that regulates the expression level and localization of both TOEFAZ1 and TbPLK, a previously uncharacterized protein that is necessary for the assembly of a new cell posterior, and a microtubule plus-end directed orphan kinesin that is required for completing cleavage furrow ingression. The identification of these proteins provides new insight into T. brucei cytokinesis and establishes TOEFAZ1 as a key component of this essential and uniquely configured process in kinetoplastids.
Assuntos
Citocinese/fisiologia , Glicoproteínas de Membrana/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Protozoários/metabolismo , Trypanosoma brucei brucei/fisiologia , Divisão Celular , Linhagem Celular , Polaridade Celular , Flagelos/metabolismo , Glicoproteínas de Membrana/genética , Microtúbulos/metabolismo , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteômica , Proteínas de Protozoários/genética , Trypanosoma brucei brucei/genéticaRESUMO
Horizontal transfer of plasmids encoding antimicrobial resistance and virulence determinants has been instrumental in Staphylococcus aureus evolution, including the emergence of community-associated methicillin-resistant S. aureus (CA-MRSA). In the early 1990s, the first CA-MRSA strain isolated in Western Australia (WA), WA-5, encoded cadmium, tetracycline, and penicillin resistance genes on plasmid pWBG753 (â¼30 kb). WA-5 and pWBG753 appeared only briefly in WA; however, fusidic acid resistance plasmids related to pWBG753 were also present in the first European CA-MRSA isolates at the time. Here, we characterize a 72-kb conjugative plasmid, pWBG731, present in multiresistant WA-5-like clones from the same period. pWBG731 was a cointegrant formed from pWBG753 and a pWBG749 family conjugative plasmid. pWBG731 carried mupirocin, trimethoprim, cadmium, and penicillin resistance genes. The stepwise evolution of pWBG731 likely occurred through the combined actions of IS257, IS257-dependent miniature inverted-repeat transposable elements (MITEs), and the BinL resolution system of the ß-lactamase transposon Tn552 An evolutionarily intermediate â¼42-kb nonconjugative plasmid, pWBG715, possessed the same resistance genes as pWBG731 but retained an integrated copy of the small tetracycline resistance plasmid pT181. IS257 likely facilitated the replacement of pT181 with conjugation genes on pWBG731, thus enabling autonomous transfer. Like conjugative plasmid pWBG749, pWBG731 also mobilized nonconjugative plasmids carrying oriT mimics. It seems likely that pWBG731 represents the product of multiple recombination events between the WA-5 pWBG753 plasmid and other mobile genetic elements present in indigenous community-associated methicillin-sensitive S. aureus (CA-MSSA) isolates. The molecular evolution of pWBG731 saliently illustrates how diverse mobile genetic elements can together facilitate rapid accrual and horizontal dissemination of multiresistance in S. aureus CA-MRSA.
Assuntos
Staphylococcus aureus Resistente à Meticilina/genética , Plasmídeos/genética , Infecções Comunitárias Adquiridas/epidemiologia , Infecções Comunitárias Adquiridas/microbiologia , Farmacorresistência Bacteriana Múltipla/genética , Genes Bacterianos/genética , Humanos , Alinhamento de Sequência , Análise de Sequência de DNA , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/microbiologia , Austrália Ocidental/epidemiologiaRESUMO
The parasite Trypanosoma brucei is highly polarized, including a flagellum that is attached along the cell surface by the flagellum attachment zone (FAZ). During cell division, the new FAZ positions the cleavage furrow, which ingresses from the anterior tip of the cell towards the posterior. We recently identified TOEFAZ1 (for 'Tip of the Extending FAZ protein 1') as an essential protein in trypanosome cytokinesis. Here, we analyzed the localization and function of TOEFAZ1 domains by performing overexpression and RNAi complementation experiments. TOEFAZ1 comprises three domains with separable functions: an N-terminal α-helical domain that may be involved in FAZ recruitment, a central intrinsically disordered domain that keeps the morphogenic kinase TbPLK at the new FAZ tip, and a C-terminal zinc finger domain necessary for TOEFAZ1 oligomerization. Both the N-terminal and C-terminal domains are essential for TOEFAZ1 function, but TbPLK retention at the FAZ is not necessary for cytokinesis. The feasibility of alternative cytokinetic pathways that do not employ TOEFAZ1 are also assessed. Our results show that TOEFAZ1 is a multimeric scaffold for recruiting proteins that control the timing and location of cleavage furrow ingression.
Assuntos
Citocinese , Proteínas de Protozoários/metabolismo , Trypanosoma brucei brucei/citologia , Células Cultivadas , Flagelos/metabolismo , Domínios Proteicos , Proteínas Serina-Treonina Quinases/metabolismo , Transporte Proteico , Proteínas de Protozoários/química , Trypanosoma brucei brucei/metabolismoRESUMO
Influenza viruses use distinct antibody escape mechanisms depending on the overall complexity of the antibody response that is encountered. When grown in the presence of a hemagglutinin (HA) monoclonal antibody, influenza viruses typically acquire a single HA mutation that reduces the binding of that specific monoclonal antibody. In contrast, when confronted with mixtures of HA monoclonal antibodies or polyclonal sera that have antibodies that bind several HA epitopes, influenza viruses acquire mutations that increase HA binding to host cells. Recent data from our laboratory and others suggest that some humans possess antibodies that are narrowly focused on HA epitopes that were present in influenza virus strains that they were likely exposed to in childhood. Here, we completed a series of experiments to determine if humans with narrowly focused HA antibody responses are able to select for influenza virus antigenic escape variants in ovo We identified three human donors that possessed HA antibody responses that were heavily focused on a single HA antigenic site. Sera from all three of these donors selected single HA escape mutations during in ovo passage experiments, similar to what has been previously reported for single monoclonal antibodies. These single HA mutations directly reduced binding of serum antibodies used for selection. We propose that new antigenic variants of influenza viruses might originate in individuals who produce antibodies that are narrowly focused on HA epitopes that were present in viral strains that they encountered in childhood.IMPORTANCE Influenza vaccine strains must be updated frequently since circulating viral strains continuously change in antigenically important epitopes. Our previous studies have demonstrated that some individuals possess antibody responses that are narrowly focused on epitopes that were present in viral strains that they encountered during childhood. Here, we show that influenza viruses rapidly escape this type of polyclonal antibody response when grown in ovo by acquiring single mutations that directly prevent antibody binding. These studies improve our understanding of how influenza viruses evolve when confronted with narrowly focused polyclonal human antibodies.
Assuntos
Antígenos Virais/imunologia , Epitopos/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Evasão da Resposta Imune/genética , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/imunologia , Mutação , Animais , Anticorpos Neutralizantes/biossíntese , Anticorpos Neutralizantes/química , Anticorpos Antivirais/biossíntese , Anticorpos Antivirais/química , Variação Antigênica , Antígenos Virais/genética , Embrião de Galinha , Epitopos/química , Epitopos/genética , Expressão Gênica , Testes de Inibição da Hemaglutinação , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Humanos , Soros Imunes/química , Vírus da Influenza A Subtipo H1N1/genética , Influenza Humana/genética , Influenza Humana/virologia , Modelos Moleculares , Testes de Neutralização , Zigoto/imunologia , Zigoto/virologiaRESUMO
Gastrointestinal stromal tumors (GISTs) are rare in children. Succinate dehydrogenase (SDH)-deficient GISTs are wild type and lack KIT proto-oncogene receptor tyrosine kinase and platelet-derived growth factor receptor A ( KIT or PDGFRA) mutations. These tumors result from germline SDH mutations, somatic SDH mutations, or SDH epimutants. Germline mutations in SDH genes ( SDHA, SDHB, SDHC, or SDHD) suggest Carney-Stratakis syndrome, a paraganglioma syndrome with predisposition for GIST. Negative immunohistochemistry for SDHB indicates dysfunction of the mitochondrial complex regardless of the subunit affected. We present an adolescent male with an SDH-deficient GIST and SDHC germline mutation who developed bilateral renal cysts and neck cysts, not previously described in children with this mutation. Germline testing is critical when SDH mutations are discovered due to treatment and surveillance implications. Further investigations are necessary to fully define the phenotypic expression of this mutation.
Assuntos
Neoplasias Gastrointestinais/genética , Tumores do Estroma Gastrointestinal/genética , Proteínas de Membrana/genética , Succinato Desidrogenase/genética , Adolescente , Cistos/diagnóstico por imagem , Cistos/genética , Cistos/patologia , Neoplasias Gastrointestinais/diagnóstico por imagem , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/diagnóstico por imagem , Tumores do Estroma Gastrointestinal/patologia , Mutação em Linhagem Germinativa , Humanos , Imuno-Histoquímica , Rim/diagnóstico por imagem , Rim/patologia , Masculino , Pescoço/diagnóstico por imagem , Pescoço/patologia , Fenótipo , Proto-Oncogene MasRESUMO
AID/APOBEC family enzymes are best known for deaminating cytosine bases to uracil in single-stranded DNA, with characteristic sequence preferences that can produce mutational signatures in targets such as retroviral and cancer cell genomes. These deaminases have also been proposed to function in DNA demethylation via deamination of either 5-methylcytosine (mC) or TET-oxidized mC bases (ox-mCs), which include 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine. One specific family member, APOBEC3A (A3A), has been shown to readily deaminate mC, raising the prospect of broader activity on ox-mCs. To investigate this claim, we developed a novel assay that allows for parallel profiling of activity on all modified cytosines. Our steady-state kinetic analysis reveals that A3A discriminates against all ox-mCs by >3700-fold, arguing that ox-mC deamination does not contribute substantially to demethylation. A3A is, by contrast, highly proficient at C/mC deamination. Under conditions of excess enzyme, C/mC bases can be deaminated to completion in long DNA segments, regardless of sequence context. Interestingly, under limiting A3A, the sequence preferences observed with targeting unmodified cytosine are further exaggerated when deaminating mC. Our study informs how methylation, oxidation, and deamination can interplay in the genome and suggests A3A's potential utility as a biotechnological tool to discriminate between cytosine modification states.
Assuntos
Citidina Desaminase/metabolismo , Citosina/química , DNA/química , DNA/metabolismo , Proteínas/metabolismo , 5-Metilcitosina/química , Sequência de Bases , Metilação de DNA , Humanos , Técnicas In Vitro , Cinética , Modelos Biológicos , Oxirredução , Proteínas Recombinantes/metabolismo , Especificidade por SubstratoRESUMO
Obesity is a major international health concern. Neighborhood greenery has been identified as a critical factor for promoting health in urban areas, due in part to its apparent role in facilitating healthy weight by promoting physical activity. However, studies have used diverse greenery measures and spatial analysis units to ascertain this relationship. This study examined associations between street greenery and weight status at the residential address level across 500 to 2000m buffers in two climatically distinct communities, Phoenix, AZ, and Portland, OR. Greenery was measured using one-meter landcover data. Street greenery measures were designed to quantify the pedestrian environment along a gradient of suitability for promoting physical exercise. Weight status was defined by body mass index (BMI) calculated from weight and height information on driver's license records. BMI values were dichotomized at 25 into overweight or obese vs. neither. Approximately 500,000 BMI values in Phoenix and 225,000 in Portland were modelled by community using logistic regression. Street tree cover was consistently protective for healthy weight status across all buffer sizes after adjusting for potential confounders. Herbaceous street cover showed protective associations in Phoenix but harmful associations in Portland. Every 10% increase in street tree cover within 2000m was associated with 18% lower odds of being overweight or obese (adjusted odds ratio [AOR]: 0.82, 95% CI: 0.81 - 0.84 in Phoenix; 0.82, 95% CI: 0.81 - 0.83 in Portland). When compared to residents with less than 10% street tree cover within 2000m, those with greater than 10% tree cover had at least 13% (AOR for Portland: 0.87, 95% CI: 0.81 - 0.92) lower odds of being overweight or obese. Findings support the importance of urban street trees in very different climates for facilitating healthy weight status. They can inform greenery management to prioritize vegetation type and allocation decisions in limited urban spaces.