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The impact of APOE on HIV and HCV disease course, cognition, and memory has been understudied in minoritized populations. This study examined whether scores on cognition and depression measures differed by APOE ε4 carrier status while considering HCV and HIV seropositivity and whether these measures were moderated by substance use. A retrospective analysis examined cognitive and psychological data from participants (n = 493) in the Miami Adult Studies on HIV (MASH) cohort. APOE genotyping was performed on banked blood samples. Multiple linear regression was employed to examine differences across participants living with and without HIV and/or HCV and by APOE ε4 genotype. APOE ε4 carriers living with HCV who used cannabis had higher depression scores than non-ε4 carriers, while nonusers had fewer depressive symptoms. APOE ε4 carriers living with HCV had better cognition scores after adjusting for cocaine, opiate, and cannabis use than non-ε4 carriers. Scores on cognitive and depression measures did not differ between APOE ε4 carriers and non-ε4 carriers in participants living with HIV, and substance use did not moderate this relationship. This study was the first of its kind to examine substance use as a moderator for cognition and depression among individuals with HIV and/or HCV stratified by APOE genotype. Findings support further research evaluating the frequency and duration of 1) domains of cognitive functioning impacted by APOE genotype relevant to substance use and 2) the influence of substance use on cognitive and depressive outcomes among adults living with HIV and HCV, HIV, or HCV.
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Aerosols impact climate, human health, and the chemistry of the atmosphere, and aerosol pH plays a major role in the physicochemical properties of the aerosol. However, there remains uncertainty as to whether aerosols are acidic, neutral, or basic. In this research, we show that the pH of freshly emitted (nascent) sea spray aerosols is significantly lower than that of sea water (approximately four pH units, with pH being a log scale value) and that smaller aerosol particles below 1 µm in diameter have pH values that are even lower. These measurements of nascent sea spray aerosol pH, performed in a unique ocean-atmosphere facility, provide convincing data to show that acidification occurs "across the interface" within minutes, when aerosols formed from ocean surface waters become airborne. We also show there is a correlation between aerosol acidity and dissolved carbon dioxide but no correlation with marine biology within the seawater. We discuss the mechanisms and contributing factors to this acidity and its implications on atmospheric chemistry.
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Aerosoles/química , Agua de Mar/química , Aire , Atmósfera/química , Ambiente , Humanos , Concentración de Iones de Hidrógeno , Océanos y Mares , Fitoplancton , Agua de Mar/análisisRESUMEN
Ubiquitin-modified tau aggregates are abundantly found in human brains diagnosed with Alzheimer's disease (AD) and other tauopathies. Soluble tau oligomers (TauO) are the most neurotoxic tau species that propagate pathology and elicit cognitive deficits, but whether ubiquitination contributes to tau formation and spreading is not fully understood. Here, we observed that K63-linked, but not K48-linked, ubiquitinated TauO accumulated at higher levels in AD brains compared with age-matched controls. Using mass spectrometry analyses, we identified 11 ubiquitinated sites on AD brain-derived TauO (AD TauO). We found that K63-linked TauO are associated with enhanced seeding activity and propagation in human tau-expressing primary neuronal and tau biosensor cells. Additionally, exposure of tau-inducible HEK cells to AD TauO with different ubiquitin linkages (wild type, K48, and K63) resulted in enhanced formation and secretion of K63-linked TauO, which was associated with impaired proteasome and lysosome functions. Multipathway analysis also revealed the involvement of K63-linked TauO in cell survival pathways, which are impaired in AD. Collectively, our study highlights the significance of selective TauO ubiquitination, which could influence tau aggregation, accumulation, and subsequent pathological propagation. The insights gained from this study hold great promise for targeted therapeutic intervention in AD and related tauopathies.
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Enfermedad de Alzheimer , Ubiquitinación , Proteínas tau , Enfermedad de Alzheimer/fisiopatología , Células Cultivadas , Humanos , Lisina/metabolismo , Neuronas/patología , Tauopatías/fisiopatología , Ubiquitina/metabolismo , Proteínas tau/metabolismoRESUMEN
BACKGROUND: In 2020 COVID-19 was the third leading cause of death in the United States. Increases in suicides, overdoses, and alcohol related deaths were seen-which make up deaths of despair. How deaths of despair compare to COVID-19 across racial, ethnic, and gender subpopulations is relatively unknown. Preliminary studies showed inequalities in COVID-19 mortality for Black and Hispanic Americans in the pandemic's onset. This study analyzes the racial, ethnic and gender disparities in years of life lost due to COVID-19 and deaths of despair (suicide, overdose, and alcohol deaths) in 2020. METHODS: This cross-sectional study calculated and compared years of life lost (YLL) due to Deaths of Despair and COVID-19 by gender, race, and ethnicity. YLL was calculated using the CDC WONDER database to pull death records based on ICD-10 codes and the Social Security Administration Period Life Table was used to get estimated life expectancy for each subpopulation. RESULTS: In 2020, COVID-19 caused 350,831 deaths and 4,405,699 YLL. By contrast, deaths of despair contributed to 178,598 deaths and 6,045,819 YLL. Men had more deaths and YLL than women due to COVID-19 and deaths of despair. Among White Americans and more than one race identification both had greater burden of deaths of despair YLL than COVID-19 YLL. However, for all other racial categories (Native American/Alaskan Native, Asian, Black/African American, Native Hawaiian/Pacific Islander) COVID-19 caused more YLL than deaths of despair. Also, Hispanic or Latino persons had disproportionately higher mortality across all causes: COVID-19 and all deaths of despair causes. CONCLUSIONS: This study found greater deaths of despair mortality burden and differences in burden across gender, race, and ethnicity in 2020. The results indicate the need to bolster behavioral health research, support mental health workforce development and education, increase access to evidence-based substance use treatment, and address systemic inequities and social determinants of deaths of despair and COVID-19.
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COVID-19 , Inequidades en Salud , Mortalidad Prematura , Determinantes Sociales de la Salud , Femenino , Humanos , Masculino , COVID-19/epidemiología , COVID-19/etnología , COVID-19/psicología , Estudios Transversales , Etanol , Etnicidad/psicología , Etnicidad/estadística & datos numéricos , Hispánicos o Latinos/psicología , Hispánicos o Latinos/estadística & datos numéricos , Suicidio/etnología , Suicidio/psicología , Suicidio/estadística & datos numéricos , Estados Unidos/epidemiología , Causas de Muerte , Factores Raciales , Factores Sexuales , Sobredosis de Droga/epidemiología , Sobredosis de Droga/etnología , Sobredosis de Droga/mortalidad , Sobredosis de Droga/psicología , Trastornos Relacionados con Alcohol/epidemiología , Trastornos Relacionados con Alcohol/etnología , Trastornos Relacionados con Alcohol/mortalidad , Trastornos Relacionados con Alcohol/psicología , Negro o Afroamericano/psicología , Negro o Afroamericano/estadística & datos numéricos , Determinantes Sociales de la Salud/etnología , Determinantes Sociales de la Salud/estadística & datos numéricos , Blanco/psicología , Blanco/estadística & datos numéricos , Indio Americano o Nativo de Alaska/psicología , Indio Americano o Nativo de Alaska/estadística & datos numéricos , Asiático/psicología , Asiático/estadística & datos numéricos , Nativos de Hawái y Otras Islas del Pacífico/psicología , Nativos de Hawái y Otras Islas del Pacífico/estadística & datos numéricos , Costo de Enfermedad , Mortalidad Prematura/etnología , Esperanza de Vida/etnologíaRESUMEN
Organic chromophores initiate much of daytime aqueous phase chemistry in the environment. Thus, studying the absorption spectra of commonly used organic photosensitizers is paramount to fully understand their relevance in environmental processes. In this work, we combined UV-Vis spectroscopy, 1H-NMR spectroscopy, quantum chemical calculations, and molecular dynamics simulations to investigate the absorption spectra of 4-benzoyl benzoic acid (4BBA), a widely used photosensitizer and a common proxy of environmentally relevant chromophores. Solutions of 4BBA at different pH values show that protonated and deprotonated species have an effect on its absorbance spectra. Theoretical calculations of these species in water clusters provide physical and chemical insights into the spectra. Quantum chemical calculations were conducted to analyze the UV-Vis absorbance spectra of 4BBA species using various cluster sizes, such as C6H5COC6H4COOH·(H2O)n, where n = 8 for relatively small clusters and n = 30 for larger clusters. While relatively small clusters have been successfully used for smaller chromophores, our results indicate that simulations of protonated species of 4BBA require relatively larger clusters of n = 30. A comparison between the experimental and theoretical results shows good agreement in the pH-dependent spectral shift between the hydrated cluster model and the experimental data. Overall, the theoretical and empirical results indicate that the experimental optical spectra of aqueous phase 4BBA can be represented by the acid-base equilibrium of the keto-forms, with a spectroscopically measured pKa of 3.41 ± 0.04. The results summarized here contribute to a molecular-level understanding of solvated organic molecules through calculations restricted to cluster models, and thereby, broader insight into environmentally relevant chromophores.
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OBJECTIVE: The primary objective was to estimate the initiation and adherence rates of 17 α-hydroxyprogesterone caproate (17OHPC) among eligible mothers in a statewide population-based cohort of Medicaid enrollees. The secondary objectives were to (1) determine the association of maternal sociodemographic and clinical characteristics with 17OHPC utilization and (2) assess the real-world effectiveness of 17OHPC on recurrent preterm birth prevention and admission to neonatal intensive care unit (NICU). STUDY DESIGN: This is a retrospective cohort study using a linked, longitudinal administrative dataset of birth certificates and medical assistance claims. Medicaid-enrolled mothers in Pennsylvania were included in this study if they had at least one singleton live birth from 2014 to 2016 following at least one spontaneous preterm birth. Maternal Medicaid claims were used to ascertain the use of 17OHPC from various manufacturers, including compounded formulations. Propensity score matching was used to create a covariate balance between 17OHPC treatment and comparison groups. RESULTS: We identified 4,781 Medicaid-covered 17OHPC-eligible pregnancies from 2014 to 2016 in Pennsylvania, 3.4% of all Medicaid-covered singleton live births. The population-based initiation rate was 28.5% among eligible pregnancies. Among initiators, 50% received ≥16 doses as recommended, while 10% received a single dose only. The severity of previous spontaneous preterm birth was the strongest predictor for the initiation and adherence of 17OHPC. In the matched treatment (n = 1,210) and comparison groups (n = 1,210), we found no evidence of 17OHPC effectiveness. The risks of recurrent preterm birth (relative risk [RR] 1.10, 95% confidence interval [CI] 0.97-1.24) and births admitted to NICU (RR 1.00, 95% CI 0.84-1.18) were similar in treated and comparison mothers. CONCLUSION: The 17OHPC-eligible population represented 3.4% of singleton live births. Less than one-third of eligible mothers initiated treatment. Among initiators, 50% were treatment adherent. We found no difference in the risk of recurrent preterm birth or admission to NICU between treatment and comparison groups. KEY POINTS: · About 3.4% of singleton live births were eligible for 17OHPC.. · About 30% of eligible mothers initiated treatment.. · We found no association of 17OHPC with recurrent preterm birth..
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Nacimiento Prematuro , Embarazo , Femenino , Recién Nacido , Humanos , Caproato de 17 alfa-Hidroxiprogesterona/uso terapéutico , Nacimiento Prematuro/epidemiología , Nacimiento Prematuro/prevención & control , Hidroxiprogesteronas/uso terapéutico , Medicaid , Estudios RetrospectivosRESUMEN
Intense exposure to UVB radiation incites excessive production of reactive oxygen species (ROS) and inflammation. The resolution of inflammation is an active process orchestrated by a family of lipid molecules that includes AT-RvD1, a specialized proresolving lipid mediator (SPM). AT-RvD1 is derived from omega-3, which presents anti-inflammatory activity and reduces oxidative stress markers. The present work aims to investigate the protective effect of AT-RvD1 on UVB-induced inflammation and oxidative stress in hairless mice. Animals were first treated with 30, 100, and 300 pg/animal AT-RvD1 (i.v.) and then exposed to UVB (4.14 J/cm2). The results showed that 300 pg/animal of AT-RvD1 could restrict skin edema, neutrophil and mast cell infiltration, COX-2 mRNA expression, cytokine release, and MMP-9 activity and restore skin antioxidant capacity as per FRAP and ABTS assays and control O2â¢- production, lipoperoxidation, epidermal thickening, and sunburn cells development. AT-RvD1 could reverse the UVB-induced downregulation of Nrf2 and its downstream targets GSH, catalase, and NOQ-1. Our results suggest that by upregulating the Nrf2 pathway, AT-RvD1 promotes the expression of ARE genes, restoring the skin's natural antioxidant defense against UVB exposition to avoid oxidative stress, inflammation, and tissue damage.
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Antioxidantes , Aspirina , Animales , Ratones , Antioxidantes/farmacología , Aspirina/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Inflamación , Ácidos Docosahexaenoicos/farmacología , Rayos UltravioletaRESUMEN
OBJECTIVE: In 2007, Congress changed the military's sexual assault laws as part of an effort to improve sexual assault case processing. This study looked at the U.S. Army law enforcement investigative finding for every sexual assault reported to the Army from 2004 through June 2012, along with every nonsexual assault. Our objective was to measure whether the legal intervention affected the investigative findings made by Army law enforcement officers in sexual assault cases (penetrative, nonpenetrative, and combined) as compared to assault cases (aggravated, simple, and combined). HYPOTHESES: We hypothesized that we would not find evidence that the legal intervention affected the rate of sexual assault cases labeled as "founded" by Army law enforcement, such that for the best-fitting time-series models, any difference in the residuals of the means before and after the intervention would not be statistically significant. METHOD: We received data from the U.S. Army on all sexual assaults and nonsexual assaults from 2004 through June 2012. The data comprised 47,058 observations. We used time-series analysis with autoregressive integrated moving average modeling. The variable tracked over time was the ratio of the proportion of founded sexual assault cases to the proportion of founded nonsexual assault cases. We then conducted t tests of the means of the residuals before and after the legal intervention. RESULTS: The difference in the means of the residuals before and after the intervention was not statistically significant for combined sexual assaults versus combined assaults, penetrative sexual assaults versus aggravated assaults, or nonpenetrative sexual assaults versus simple assaults. CONCLUSIONS: This reform to sexual assault laws does not appear to have affected sexual assault case processing by U.S. Army law enforcement. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
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Víctimas de Crimen , Personal Militar , Delitos Sexuales , Humanos , Aplicación de la Ley , PoliciaRESUMEN
The pathological aggregation of tau plays an important role in Alzheimer's disease and many other related neurodegenerative diseases, collectively referred to as tauopathies. Recent evidence has demonstrated that tau oligomers, small and soluble prefibrillar aggregates, are highly toxic due to their strong ability to seed tau misfolding and propagate the pathology seen across different neurodegenerative diseases. We previously showed that novel curcumin derivatives affect preformed tau oligomer aggregation pathways by promoting the formation of more aggregated and nontoxic tau aggregates. To further investigate their therapeutic potential, we have extended our studies o disease-relevant brain-derived tau oligomers (BDTOs). Herein, using well-characterized BDTOs, isolated from brain tissues of different tauopathies, including Alzheimer's disease, progressive supranuclear palsy, and dementia with Lewy bodies, we found that curcumin derivatives modulate the aggregation state of BDTOs by reshaping them and rescue neurons from BDTO-associated toxicity. Interestingly, compound CL3 showed an effect on the aggregation pattern of BDTOs from different tauopathies, resulting in the formation of less neurotoxic larger tau aggregates with decreased hydrophobicity and seeding propensity. Our results lay the groundwork for potential investigations of the efficacy and beneficial effects of CL3 and other promising compounds for the treatment of tauopathies. Furthermore, CL3 may aid in the development of tau imaging agent for the detection of tau oligomeric strains and differential diagnosis of the tauopathies, thus enabling earlier interventions.
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Biopolímeros/química , Bibliotecas de Moléculas Pequeñas/farmacología , Tauopatías/tratamiento farmacológico , Proteínas tau/metabolismo , Biopolímeros/metabolismo , Encéfalo/citología , Encéfalo/metabolismo , Células Cultivadas , Curcumina/análogos & derivados , Curcumina/farmacología , Diagnóstico Diferencial , Humanos , Neuronas/metabolismo , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Tauopatías/diagnóstico , Proteínas tau/efectos de los fármacosRESUMEN
OBJECTIVES: This cost-effectiveness analysis (CEA) of 4CMenB infant vaccination in England comprehensively considers the broad burden of serogroup B invasive meningococcal disease (MenB IMD), which has not been considered, or was only partially considered in previous CEAs. METHODS: A review of previous MenB vaccination CEAs was conducted to identify aspects considered in the evaluation of costs and health outcomes of the disease burden of MenB IMD. To inform the model structure and comprehensive analysis, the aspects were grouped into 5 categories. A stepwise analysis was conducted to analyze the impact of each category, and the more comprehensive consideration of disease burden, on the incremental cost-effectiveness ratio (ICER). RESULTS: MenB IMD incidence decreased by 46.0% in infants and children 0-4 years old within 5 years after introduction of the program. Stepwise inclusion of the 5 disease burden categories to a conventional narrow CEA setting reduced the ICER from £360 595 to £18 645-that is, considering the impact of all 5 categories, 4CMenB infant vaccination is cost-effective at a threshold of £20 000 per QALY gained. CONCLUSIONS: When considering comprehensively the MenB IMD burden, 4CMenB infant vaccination can be cost-effective, a finding contrary to previous CEAs. This analysis allows policy decision-makers globally to infer the impact of current disease burden considerations on the cost-effectiveness and the comprehensive assessment necessary for MenB IMD. Although this comprehensive CEA can help inform decision making today, it may be limited in capturing the full disease burden and complex interactions of health and economics of MenB IMD.
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Infecciones Meningocócicas/prevención & control , Infecciones Meningocócicas/psicología , Vacunas Meningococicas/administración & dosificación , Vacunas Meningococicas/economía , Preescolar , Comportamiento del Consumidor , Costo de Enfermedad , Análisis Costo-Beneficio , Eficiencia , Inglaterra/epidemiología , Gastos en Salud , Humanos , Lactante , Infecciones Meningocócicas/economía , Infecciones Meningocócicas/epidemiología , Modelos Económicos , Neisseria meningitidis Serogrupo B , Años de Vida Ajustados por Calidad de VidaRESUMEN
Nitrous acid (HONO) is a toxic household pollutant and a major source of indoor OH radicals. The high surface-to-volume ratio and diverse lighting conditions make the indoor photochemistry of HONO complex. This study demonstrates surface uptake of NO2 and gaseous HNO3 followed by gas-phase HONO generation on gypsum surfaces, model system for drywall, under reaction conditions appropriate for an indoor air environment. Tens of parts per billion of steady-state HONO are detected under these experimental conditions. Mechanistic insight into this heterogeneous photochemistry is obtained by exploring the roles of material compositions, relative humidities, and light sources. NO2 and HNO3 are adsorbed onto drywall surfaces, which can generate HONO under illumination and under dark conditions. Photoenhanced HONO generation is observed for illumination with a solar simulator as well as with the common indoor light sources such as compact fluorescence light and incandescent light bulbs. Incandescent light sources release more HONO and NO2 near the light source compared to the solar radiation. Overall, HONO production on the gypsum surface increases with the increase of RH up to 70% relative humidity; above that, the gaseous HONO level decreases due to surface loss. Heterogeneous hydrolysis of NO2 is predicted to be the dominant HONO generation channel, where NO2 is produced through the photolysis of surface-adsorbed nitrates. This hydrolysis reaction predominantly occurs in the first layer of surface-adsorbed water.
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Sulfato de Calcio , Dióxido de Nitrógeno , Humedad , Ácido Nitroso , FotólisisRESUMEN
PURPOSE: The Health Resources and Services Administration's Maternal and Child Health Bureau (HRSA MCHB) developed a three-tiered performance measure framework for the Title V Maternal and Child Health Block Grant program (MCH Title V). The third tier, evidence-based/informed strategy measures (ESMs) are developed by states to address National Performance Measures (NPM) goals. To support states' efforts, MCHB funded the "Strengthen the Evidence for Maternal and Child Health" (STE) to: (1) define the concept of evidence for the field with an emphasis on strength; (2) identify available evidence for each NPM, (3) translate ESM research for use at the state level; and (4) provide technical assistance (TA) to states to facilitate implementation. DESCRIPTION: The program conducted evidence reviews defining an "evidence continuum" emphasizing a continuum of strength, provided individual and group TA to MCH Title V grantees, launched a TA referral system, and reviewed state ESMs to assess use of evidence-based/informed strategies. ASSESSMENT: Ten evidence reviews identified multiple strategies as having "emerging" or "moderate" evidence. TA reached all MCH Title V programs, encompassing 59 US states and jurisdictions, and the TA referral system effectively partnered with MCHB resources. All MCH Title V states and territories submitted ESMs for the Block Grant program's first year reporting requirement. CONCLUSION: STE is the first program to review available evidence on effective strategies addressing NPMs for MCH Title V. Identifying actionable next steps responsive to state needs will be a key factor for continued implementation of ESMs and achieving improvements in MCH.
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Medicina Basada en la Evidencia/normas , Financiación Gubernamental , Fuerza Laboral en Salud , Centros de Salud Materno-Infantil/organización & administración , Servicios de Salud Materno-Infantil/organización & administración , Evaluación de Programas y Proyectos de Salud/métodos , Adulto , Niño , Servicios de Salud del Niño , Femenino , Humanos , Masculino , Servicios de Salud Materna , Competencia Profesional , Salud Pública , Práctica de Salud Pública , Desarrollo de Personal/métodosRESUMEN
A novel series of quinoline-based symmetrical and unsymmetrical bis-chalcones was synthesized via a Claisen-Schmidt condensation reaction between 3-formyl-quinoline/quinolone derivatives with acetone or arylidene acetones, respectively, by using KOH/MeOH/H2 O as a reaction medium. Twelve of the obtained compounds were evaluated for their in vitro cytotoxic activity against 60 different human cancer cell lines according to the National Cancer Institute protocol. Among the screened compounds, the symmetrical N-butyl bis-quinolinyl-chalcone 14g and the unsymmetrical quinolinyl-bis-chalcone 17o bearing a 7-chloro-substitution on the N-benzylquinoline moiety and 4-hydroxy-3-methoxy substituent on the phenyl ring, respectively, exhibited the highest overall cytotoxicity against the evaluated cell lines with a GI50 range of 0.16-5.45 µM, with HCT-116 (GI50 = 0.16) and HT29 (GI50 = 0.42 µM) (colon cancer) representing best-case scenarios. Notably, several GI50 values for these compounds were lower than those of the reference drugs doxorubicin and 5-FU. Docking studies performed on selected derivatives yielded very good binding energies in the active site of proteins that participate in key carcinogenic pathways.
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Antineoplásicos/farmacología , Chalconas/farmacología , Neoplasias/tratamiento farmacológico , Quinolinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Chalconas/síntesis química , Chalconas/química , Doxorrubicina/farmacología , Fluorouracilo/farmacología , Células HCT116 , Células HT29 , Humanos , Simulación del Acoplamiento Molecular , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-ActividadRESUMEN
A close connection between inflammation and the risk of developing colon cancer has been suggested in the last few years. It has been estimated that patients diagnosed with some types of inflammatory bowel disease, such as ulcerative colitis or Crohn's disease, have up to a 30% increased risk of developing colon cancer. However, there is also evidence showing that the activation of anti-inflammatory pathways, such as the IL-4 receptor-mediated pathway, may favor the development of colon tumors. Using an experimental model of colitis-associated colon cancer (CAC), we found that the decrease in tumor development in global IL4Rα knockout mice (IL4RαKO) was apparently associated with an inflammatory response mediated by the infiltration of M1 macrophages (F480+TLR2+STAT1+) and iNOS expression in colon tissue. However, when we developed mice with a specific deletion of IL4Rα in macrophages (LysMcreIL4Rα-/lox mice) and subjected them to CAC, it was found that despite presenting a large infiltration of M1 macrophages into the colon, these mice were as susceptible to colon-tumorigenesis as WT mice. These data suggest that in the tumor microenvironment the absence of IL4Rα expression on macrophages, as well as the recruitment of M1 macrophages, may not be directly associated with resistance to developing colon tumors. Therefore, it is possible that IL4Rα expression in other cell types, such as colonic epithelial cells, could have an important role in promoting the development of colitis-associated colon tumorigenesis.
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Colitis/patología , Neoplasias del Colon/patología , Macrófagos/patología , Receptores de Superficie Celular/genética , Animales , Neoplasias del Colon/etiología , Neoplasias del Colon/genética , Citocinas/metabolismo , Femenino , Macrófagos/fisiología , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones Transgénicos , Neoplasias Experimentales , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Receptores de Superficie Celular/metabolismo , Macrófagos Asociados a Tumores/patologíaRESUMEN
Proteinaceous aggregates are major hallmarks of several neurodegenerative diseases. Aggregates of post-translationally modified transactive response (TAR)-DNA binding protein 43 (TDP-43) in cytoplasmic inclusion bodies are characteristic features in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Recent studies have also reported TDP-43 aggregation in Alzheimer's disease (AD). TDP-43 is an RNA/DNA binding protein (RBP) mainly present in the nucleus. In addition to several RBPs, TDP-43 has also been reported in stress granules in FTD and ALS pathologies. Despite knowledge of cytoplasmic mislocalization of TDP-43, the cellular effects of TDP-43 aggregates and their cytotoxic mechanism(s) remain to be clarified. We hypothesize that TDP-43 forms oligomeric assemblies that associate with tau, another key protein involved in ALS and FTD. However, no prior studies have investigated the interactions between TDP-43 oligomers and tau. It is therefore important to thoroughly investigate the cross-seeding properties and cellular localization of both TDP-43 and tau oligomers in neurodegenerative diseases. Here, we demonstrate the effect of tau on the cellular localization of TDP-43 in WT and P301L tau-inducible cell models (iHEK) and in WT HEK-293 cells treated exogenously with soluble human recombinant tau oligomers (Exo-rTauO). We observed cytoplasmic TDP-43 accumulation o in the presence of tau in these cell models. We also studied the occurrence of TDP-43 oligomers in AD, ALS, and FTD human brain tissue using novel antibodies generated against TDP-43 oligomers as well as generic TDP-43 antibodies. Finally, we examined the cross-seeding property of AD, ALS, and FTD brain-derived TDP-43 oligomers (BDT43Os) on tau aggregation using biochemical and biophysical assays. Our results allow us to speculate that TDP-43/tau interactions might play a role in AD, ALS, and FTD.
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Esclerosis Amiotrófica Lateral/metabolismo , Proteínas de Unión al ADN/metabolismo , Demencia Frontotemporal/metabolismo , Proteínas tau/metabolismo , Enfermedad de Alzheimer/metabolismo , Demencia Frontotemporal/patología , Humanos , Enfermedad de Pick/fisiopatología , Agregación Patológica de Proteínas/metabolismo , Proteínas de Unión al ARN/metabolismoRESUMEN
Arthritis can be defined as a painful musculoskeletal disorder that affects the joints. Hesperidin methyl chalcone (HMC) is a flavonoid with analgesic, anti-inflammatory, and antioxidant effects. However, its effects on a specific cell type and in the zymosan-induced inflammation are unknown. We aimed at evaluating the effects of HMC in a zymosan-induced arthritis model. A dose-response curve of HMC (10, 30, or 100 mg/kg) was performed to determine the most effective analgesic dose after intra-articular zymosan stimuli. Knee joint oedema was determined using a calliper. Leukocyte recruitment was performed by cell counting on knee joint wash as well as histopathological analysis. Oxidative stress was measured by colorimetric assays (GSH, FRAP, ABTS and NBT) and RT-qPCR (gp91phox and HO-1 mRNA expression) performed. In vitro, oxidative stress was assessed by DCFDA assay using RAW 264.7 macrophages. Cytokine production was evaluated in vivo and in vitro by ELISA. In vitro NF-κB activation was analysed by immunofluorescence. We observed HMC reduced mechanical hypersensitivity and knee joint oedema, leukocyte recruitment, and pro-inflammatory cytokine levels. We also observed a reduction in zymosan-induced oxidative stress as per increase in total antioxidant capacity and reduction in gp91phox and increase in HO-1 mRNA expression. Accordingly, total ROS production and macrophage NFκB activation were diminished. HMC interaction with NFκB p65 at Ser276 was revealed using molecular docking analysis. Thus, data presented in this work suggest the usefulness of HMC as an analgesic and anti-inflammatory in a zymosan-induced arthritis model, possibly by targeting NFκB activation in macrophages.
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Artralgia/tratamiento farmacológico , Chalconas/farmacología , Hesperidina/análogos & derivados , Inflamación/tratamiento farmacológico , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , FN-kappa B/metabolismo , Zimosan/farmacología , Analgésicos/farmacología , Animales , Antiinflamatorios/farmacología , Antioxidantes/fisiología , Artralgia/inducido químicamente , Artralgia/metabolismo , Artritis Experimental/inducido químicamente , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Línea Celular , Citocinas/metabolismo , Modelos Animales de Enfermedad , Edema/inducido químicamente , Edema/tratamiento farmacológico , Edema/metabolismo , Hesperidina/farmacología , Inflamación/inducido químicamente , Inflamación/metabolismo , Macrófagos/metabolismo , Ratones , Simulación del Acoplamiento Molecular/métodos , Estrés Oxidativo/efectos de los fármacos , Células RAW 264.7 , Transducción de Señal/efectos de los fármacosRESUMEN
In this work, we present two-dimensional beam steering in the near-infrared using a SiN integrated circuit, containing optical phased arrays. Beam steering was achieved over a range of 17.6° × 3°, at a fixed wavelength of 905 nm. The first dimension was steered via phase differences between the optical phased array channels. The second dimension was accessed by actively switching between various optical phased array sub-devices containing output diffraction gratings with different periods. The characterisation was performed on a wafer-level test station.
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PURPOSE: The purpose of this study was to review electronic tools that might improve the delivery of epilepsy care, reduce medical care costs, and empower families to improve self-management capability. METHOD: We reviewed the epilepsy-specific literature about self-management, electronic patient-reported or provider-reported outcomes, on-going remote surveillance, and alerting/warning systems. CONCLUSIONS: The improved care delivery system that we envision includes self-management, electronic patient (or provider)-reported outcomes, on-going remote surveillance, and alerting/warning systems. This system and variants have the potential to reduce seizure burden through improved management, keep children out of the emergency department and hospital, and even reduce the number of outpatient visits.
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Atención Ambulatoria/métodos , Epilepsia/terapia , Automanejo/métodos , Telemedicina/métodos , Atención Ambulatoria/tendencias , Niño , Atención a la Salud/métodos , Atención a la Salud/tendencias , Servicio de Urgencia en Hospital/tendencias , Epilepsia/diagnóstico , Epilepsia/epidemiología , Costos de la Atención en Salud/tendencias , Humanos , Pacientes Ambulatorios , Automanejo/tendencias , Telemedicina/tendenciasRESUMEN
Historically, d-glyceric aciduria was thought to cause an uncharacterized blockage to the glycine cleavage enzyme system (GCS) causing nonketotic hyperglycinemia (NKH) as a secondary phenomenon. This inference was reached based on the clinical and biochemical results from the first d-glyceric aciduria patient reported in 1974. Along with elevated glyceric acid excretion, this patient exhibited severe neurological symptoms of myoclonic epilepsy and absent development, and had elevated glycine levels and decreased glycine cleavage system enzyme activity. Mutations in the GLYCTK gene (encoding d-glycerate kinase) causing glyceric aciduria were previously noted. Since glycine changes were not observed in almost all of the subsequently reported cases of d-glyceric aciduria, this theory of NKH as a secondary syndrome of d-glyceric aciduria was revisited in this work. We showed that this historic patient harbored a homozygous missense mutation in AMT c.350C>T, p.Ser117Leu, and enzymatic assay of the expressed mutation confirmed the pathogeneity of the p.Ser117Leu mutation. We conclude that the original d-glyceric aciduria patient also had classic NKH and that this co-occurrence of two inborn errors of metabolism explains the original presentation. We conclude that no evidence remains that d-glyceric aciduria would cause NKH.
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Ácidos Glicéricos/orina , Hiperglicinemia no Cetósica/complicaciones , Hiperoxaluria Primaria/complicaciones , Hiperoxaluria Primaria/genética , Aminoácido Oxidorreductasas/genética , Aminoácido Oxidorreductasas/metabolismo , Aminometiltransferasa/genética , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Diagnóstico Diferencial , Epilepsia , Ácidos Glicéricos/metabolismo , Glicina/metabolismo , Homocigoto , Humanos , Hiperglicinemia no Cetósica/diagnóstico , Hiperglicinemia no Cetósica/etiología , Hiperglicinemia no Cetósica/genética , Hiperoxaluria Primaria/diagnóstico , Masculino , Complejos Multienzimáticos/genética , Complejos Multienzimáticos/metabolismo , Mutación Missense , Fosfotransferasas (Aceptor de Grupo Alcohol)/deficiencia , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Transferasas/genética , Transferasas/metabolismoRESUMEN
HIV/AIDS related stigma remains a major global health issue with detrimental consequences for the treatment and health of people with HIV/AIDS (PWHA), especially when manifested by health professionals. Research on HIV/AIDS stigma has successfully documented negative attitudes towards PWHA among health professionals. However, fewer studies have examined how stigma is manifested behaviorally by health professionals during clinical interactions. Therefore, this study aimed to: (1) examine the behavioral manifestations of HIV/AIDS stigma among physicians in training during clinical interactions, and (2) document the interrelation between HIV/AIDS stigma attitudes and behaviors. We implemented an experimental design using Standardized Patient (SP) simulations, observational techniques, and quantitative questionnaires. The sample consisted of 66 physicians in training in Puerto Rico who engaged in SP encounters with two scenarios: (1) PWHA infected via illegal drug use (experimental condition), and (2) a person with a common cold (control condition). Results evidenced statistically significant differences between both simulations (p = .047), with a higher number of stigma behaviors manifested in the experimental condition. HIV/AIDS stigma attitudes were not correlated with stigma behaviors. Negative emotions associated with drug use were positively associated with drug-related stigmatizing behaviors.