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Environmental exposures and gene-exposure interactions are the major causes of some diseases. Early-life exposome studies are needed to elucidate the role of environmental exposures and their complex interactions with biological mechanisms involved in childhood health. This study aimed to determine the contribution of early-life exposome to DNA damage and the modifying effect of genetic polymorphisms involved in air pollutants metabolism, antioxidant defense, and DNA repair. We conducted a cohort study in 416 Colombian children under five years. Blood samples at baseline were collected to measure DNA damage by the Comet assay and to determine GSTT1, GSTM1, CYP1A1, H2AX, OGG1, and SOD2 genetic polymorphisms. The exposome was estimated using geographic information systems, remote sensing, LUR models, and questionnaires. The association exposome-DNA damage was estimated using the Elastic Net linear regression with log link. Our results suggest that exposure to PM2.5 one year before the blood draw (BBD) (0.83, 95 %CI: 0.76; 0.91), soft drinks consumption (0.94, 0.89; 0.98), and GSTM1 null genotype (0.05, 0.01; 0.36) diminished the DNA damage, whereas exposure to PM2.5 one-week BBD (1.18, 1.06; 1.32), NO2 lag-5 days BBD (1.27, 1.18; 1.36), in-house cockroaches (1.10, 1.00; 1.21) at the recruitment, crowding at home (1.34, 1.08; 1.67) at the recruitment, cereal consumption (1.11, 1.04; 1.19) and H2AX (AG/GG vs. AA) (1.44, 1.11; 1.88) increased the DNA damage. The interactions between H2AX (AG/GG vs. AA) genotypes with crowding and PM2.5 one week BBD, GSTM1 (null vs. present) with humidity at the first year of life, and OGG1 (SC/CC vs. SS) with walkability at the first year of life were significant. The early-life exposome contributes to elucidating the effect of environmental exposures on DNA damage in Colombian children under five years old. The exposome-DNA damage effect appears to be modulated by genetic variants in DNA repair and antioxidant defense enzymes.
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Poluentes Atmosféricos , Dano ao DNA , Exposição Ambiental , Interação Gene-Ambiente , Humanos , Pré-Escolar , Colômbia , Masculino , Feminino , Lactente , Expossoma , Estudos de Coortes , Glutationa Transferase/genética , Material Particulado , Polimorfismo Genético , Poluição do Ar/efeitos adversos , Poluição do Ar/estatística & dados numéricosRESUMO
Peripheral mononuclear cells (PBMCs) exhibit robust changes in mitochondrial respiratory capacity in response to health and disease. While these changes do not always reflect what occurs in other tissues, such as skeletal muscle, these cells are an accessible and valuable source of viable mitochondria from human subjects. PBMCs are exposed to systemic signals that impact their bioenergetic state. Thus, expanding our tools to interrogate mitochondrial metabolism in this population will elucidate mechanisms related to disease progression. Functional assays of mitochondria are often limited to using respiratory outputs following maximal substrate, inhibitor, and uncoupler concentrations to determine the full range of respiratory capacity, which may not be achievable in vivo. The conversion of adenosine diphosphate (ADP) to adenosine triphosphate (ATP) by ATP-synthase results in a decrease in mitochondrial membrane potential (mMP) and an increase in oxygen consumption. To provide a more integrated analysis of mitochondrial dynamics, this article describes the use of high-resolution fluorespirometry to measure the simultaneous response of oxygen consumption and mitochondrial membrane potential (mMP) to physiologically relevant concentrations of ADP. This technique uses tetramethylrhodamine methylester (TMRM) to measure mMP polarization in response to ADP titrations following maximal hyperpolarization with complex I and II substrates. This technique can be used to quantify how changes in health status, such as aging and metabolic disease, affect the sensitivity of mitochondrial response to energy demand in PBMCs, T-cells, and monocytes from human subjects.
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Leucócitos Mononucleares , Potencial da Membrana Mitocondrial , Humanos , Potencial da Membrana Mitocondrial/fisiologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/citologia , Rodaminas/química , Difosfato de Adenosina/metabolismo , Difosfato de Adenosina/farmacologia , Consumo de Oxigênio/fisiologia , Mitocôndrias/metabolismo , Corantes Fluorescentes/químicaRESUMO
The growing interest in tin-halide semiconductors for photovoltaic applications demands in-depth knowledge of the fundamental properties of their constituents, starting from the smallest monomers entering the initial stages of formation. In this first-principles work based on time-dependent density-functional theory, we investigate the structural, electronic, and optical properties of tin-halide molecules SnXn 2-n, with n = 1 , 2 , 3 , 4 ${n = 1,2,3,4}$ and X=Cl, Br, I, simulating these compounds in vacuo as well as in an implicit solvent. We find that structural properties are very sensitive to the halogen species while the charge distribution is also affected by stoichiometry. The ionicity of the Sn-X bond is confirmed by the Bader charge analysis albeit charge displacement plots point to more complex metal-halide coordination. Particular focus is posed on the neutral molecules SnX2, for which electronic and optical properties are discussed in detail. Band gaps and absorption onset decrease with increasing size of the halogen species, and despite general common features, each molecule displays peculiar optical signatures. Our results are elaborated in the context of experimental and theoretical literature, including the more widely studied lead-halide analogs, aiming to contribute with microscopic insight to a better understanding of tin-halide perovskites.
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We present the case of a patient with antecedent of tree nuts allergy who developed an anaphylactic reaction after ingesting a piece chocolate. An allergy study detected sensitization to cocoa in skin tests as well as cross-reactivity with tree nuts in the SDS-PAGE immunoblotting-inhibition.
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The ultrafast dynamics of charge carriers in organic donor-acceptor interfaces are of primary importance to understanding the fundamental properties of these systems. In this work, we focus on a charge-transfer complex formed by quaterthiophene p-doped by tetrafluoro-tetracyanoquinodimethane and investigate electron dynamics and vibronic interactions also at finite temperatures by applying a femtosecond pulse in resonance with the two lowest energy excitations of the system with perpendicular and parallel polarization with respect to the interface. The adopted ab initio formalism based on real-time time-dependent density-functional theory coupled to Ehrenfest dynamics enables monitoring the dynamical charge transfer across the interface and assessing the role played by the nuclear motion. Our results show that the strong intermolecular interactions binding the complex already in the ground state influence the dynamics, too. The analysis of the nuclear motion involved in these processes reveals the participation of different vibrational modes depending on the electronic states stimulated by the resonant pulse. Coupled donor-acceptor modes mostly influence the excited state polarized across the interface, while intramolecular vibrations in the donor molecule dominate the excitation in the orthogonal direction. The results obtained at finite temperatures are overall consistent with this picture, although thermal disorder contributes to slightly decreasing interfacial charge transfer.
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The emerging interest in tin halide perovskites demands a robust understanding of the fundamental properties of these materials starting from the earliest steps of their synthesis. In a first-principles work based on time dependent density functional theory, we investigate the structural, energetic, electronic, and optical properties of 14 tin iodide solution complexes formed by the SnI2 unit tetracoordinated with molecules of common solvents, which we classify according to their Gutmann's donor number. We find that all considered complexes are energetically stable and their formation energy expectedly increases with the donating ability of the solvent. The energies of the frontier states are affected by the choice of solvent, with their absolute values decreasing with the donor number. The occupied orbitals are predominantly localized on the tin iodide unit, while the unoccupied ones are distributed also on the solvent molecules. Owing to this partial wave function overlap, the first optical excitation is generally weak, although the spectral weight is red-shifted by the solvent molecules being coordinated to SnI2 in comparison to the reference obtained for this molecule alone. Comparisons with results obtained on the same level of theory on Pb-based counterparts corroborate our analysis. The outcomes of this study provide quantum-mechanical insight into the fundamental properties of tin iodide solution complexes. This knowledge is valuable in the research on lead-free halide perovskites and their precursors.
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BackgroundCurrent studies suggest mitochondrial dysfunction is a major contributor to impaired physical performance and exercise intolerance in chronic kidney disease (CKD). We conducted a clinical trial of coenzyme Q10 (CoQ10) and nicotinamide riboside (NR) to determine their impact on exercise tolerance and metabolic profile in patients with CKD.MethodsWe conducted a randomized, placebo-controlled, double-blind, crossover trial comparing CoQ10, NR, and placebo in 25 patients with an estimated glomerular filtration rate (eGFR) of less than 60mL/min/1.73 m2. Participants received NR (1,000 mg/day), CoQ10 (1,200 mg/day), or placebo for 6 weeks each. The primary outcomes were aerobic capacity measured by peak rate of oxygen consumption (VO2 peak) and work efficiency measured using graded cycle ergometry testing. We performed semitargeted plasma metabolomics and lipidomics.ResultsParticipant mean age was 61.0 ± 11.6 years and mean eGFR was 36.9 ± 9.2 mL/min/1.73 m2. Compared with placebo, we found no differences in VO2 peak (P = 0.30, 0.17), total work (P = 0.47, 0.77), and total work efficiency (P = 0.46, 0.55) after NR or CoQ10 supplementation. NR decreased submaximal VO2 at 30 W (P = 0.03) and VO2 at 60 W (P = 0.07) compared with placebo. No changes in eGFR were observed after NR or CoQ10 treatment (P = 0.14, 0.88). CoQ10 increased free fatty acids and decreased complex medium- and long-chain triglycerides. NR supplementation significantly altered TCA cycle intermediates and glutamate that were involved in reactions that exclusively use NAD+ and NADP+ as cofactors. NR decreased a broad range of lipid groups including triglycerides and ceramides.ConclusionsSix weeks of treatment with NR or CoQ10 improved markers of systemic mitochondrial metabolism and lipid profiles but did not improve VO2 peak or total work efficiency.Trial registrationClinicalTrials.gov NCT03579693.FundingNational Institutes of Diabetes and Digestive and Kidney Diseases (grants R01 DK101509, R03 DK114502, R01 DK125794, and R01 DK101509).
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Insuficiência Renal Crônica , Humanos , Pessoa de Meia-Idade , Idoso , Estudos Cross-Over , Insuficiência Renal Crônica/tratamento farmacológico , TriglicerídeosRESUMO
BACKGROUND: Biologics have revolutionized the treatment of many diseases. In this regard, omalizumab (OMA), an anti-IgE monoclonal antibody, is the recommended therapeutic option for patients with chronic spontaneous urticaria (CSU) refractory to second-generation H1-antihistamines. Several studies confirm the efficacy and safety of the drug. However, the literature focusing on the elderly population is scarce, as this age group is often excluded from clinical trials. Therefore, the pharmacological treatment of CSU in elderly patients is a challenge that is increased by their comorbidities and consequent polypharmacy. OBJECTIVES: We describe the real-life safety profile of OMA in elderly patients (≥70 years) with CSU and chronic inducible urticaria (CIndU). We aimed to provide data for daily clinical practice in this vulnerable patient group. METHOD: A retrospective review was performed of the records of patients with CSU/CIndU from May 2003 to December 2019 in the Hospital Universitario La Paz. We describe qualitative and quantitative data according to measures of central tendency. Comparisons between qualitative and quantitative data were performed with the Mann-Whitney U test and the Fisher's test for qualitative variables. A p value <0.05 was considered statistically significant. RESULTS AND CONCLUSIONS: Eighty-nine patients were included, divided into two groups (<70 vs. ≥70 years). The overall rate of adverse events (AEs) was 48%, mainly mild. No association between age and AE was found (p = 0.789). No serious AE such as anaphylaxis was detected. CSU predominated in both groups. CIndU was less prevalent in the elderly (p = 0.017). There was no association between age and the other variables. Although the frequency of neoplasms was slightly higher in the elderly with OMA, we found no difference compared to the incidence of neoplasms in the general population. Therefore, our data suggest that OMA may be a safe treatment in elderly people with CSU/CIndU for prolonged periods of treatment, although further studies with larger samples are needed to corroborate our observations.
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Antialérgicos , Urticária Crônica , Neoplasias , Urticária , Humanos , Idoso , Omalizumab/uso terapêutico , Antialérgicos/efeitos adversos , Urticária/tratamento farmacológico , Urticária/epidemiologia , Doença Crônica , Urticária Crônica/tratamento farmacológico , Imunossupressores/uso terapêutico , Urticária Crônica Induzida , Neoplasias/tratamento farmacológico , Resultado do TratamentoRESUMO
The ability to respond to physical stress that disrupts normal physiological homeostasis at an older age embraces the concept of resilience to aging. A physical stressor could be used to induce physiological responses that are age-related, since resilience declines with increasing age. Increased fat and sugar intake is a nutritional stress with a high prevalence of obesity in older people. In order to determine the effect of this type of diet on resilience to aging, 18-month-old C57BL/6J male mice were fed a diet high in saturated fat (lard) and sucrose (HFS) for ten months. At the end of the 10-month study, mice fed the HFS diet showed increased cognitive impairment, decreased cardiac function, decreased strength and agility, and increased severity of renal pathology compared to mice fed a rodent chow diet low in saturated fat and sucrose (LFS). The degree of response aligned with decreased resilience to the long-term adverse effects of the diet with characteristics of accelerated aging. This observation suggests additional studies could be conducted to investigate the relationship between an accelerated decline in resilience to aging and enhanced resilience to aging under different dietary conditions.
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Aging and poor diet are independent risk factors for heart disease, but the impact of high-sucrose (HS) consumption in the aging heart is understudied. Aging leads to impairments in mitochondrial function that result in muscle dysfunction (e.g., cardiac remodeling and sarcopenia). We tested whether HS diet (60%kcal sucrose) would accelerate muscle dysfunction in 24-month-old male CB6F1 mice. By week 1 on HS diet, mice developed significant cardiac hypertrophy compared to age-matched chow-fed controls. The increased weight of the heart persisted throughout the 4-week treatment, while body weight and strength declined more rapidly than controls. We then tested whether HS diet could worsen cardiac dysfunction in old mice and if the mitochondrial-targeted drug, elamipretide (ELAM), could prevent the diet-induced effect. Old and young mice were treated with either ELAM or saline as a control for 2 weeks, and provided with HS diet or chow on the last week. As demonstrated in the previous experiment, old mice had age-related cardiac hypertrophy that worsened after one week on HS and was prevented by ELAM treatment, while the HS diet had no detectable effect on hypertrophy in the young mice. As expected, mitochondrial respiration and reactive oxygen species (ROS) production were altered by age, but were not significantly affected by HS diet or ELAM. Our findings highlight the vulnerability of the aged heart to HS diet that can be prevented by systemic targeting of the mitochondria with ELAM.
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Cardiopatias , Açúcares , Camundongos , Masculino , Animais , Cardiomegalia/etiologia , Envelhecimento , Cardiopatias/complicações , Sacarose , Açúcares da DietaRESUMO
Background: Disruption of metabolic and bioenergetic homeostasis related to mitochondrial dysfunction is a key driver of aging biology. Therefore, targeting mitochondrial function would be a rational approach to slowing aging. Elamipretide (Elam, a.k.a. SS-31) is a peptide known to target mitochondria and suppress mammalian signs of aging. The present study was designed to examine the phenotypic effects of long-term Elam treatment on aging in C57BL/6 mice starting at 18 months of age. Methods: Mice were fed regular chow (RC diet) or a diet high in fat and sugar (HF diet) and treated with 3 mg/kg of Elam or saline subcutaneously 5 days per week for 10 months. Physiological performance assessments were conducted at 28 months of age. Results: Elam improved the physical performance of males but not females, while in females Elam improved cognitive performance and enhanced the maintenance of body weight and fat mass. It also improved diastolic function in both males and females, but to a greater extent in males. The HF diet over 10 months had a negative effect on health span, as it increased body fat and decreased muscle strength and heart function, especially in females. Conclusions: Elam enhanced healthy aging and cardiac function in both male and female mice, although the specific effects on function differed between sexes. In females, the treatment led to better cognitive performance and maintenance of body composition, while in males, performance on a rotating rod was preserved. These overall observations have translational implications for considering additional studies using Elam in therapeutic or preventive approaches for aging and age-related diseases.
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The design of low-dimensional organic-inorganic interfaces for the next generation of opto-electronic applications requires in-depth understanding of the microscopic mechanisms ruling electronic interactions in these systems. In this work, we present a first-principles study based on density-functional theory inspecting the structural, energetic, and electronic properties of five molecular donors and acceptors adsorbed on freestanding hexagonal boron nitride (hBN) and molybdenum disulfide (MoS2) monolayers. All considered interfaces are stable, due to the crucial contribution of dispersion interactions, which are maximized by the overall flat arrangement of the physisorbed molecules on both substrates. The level alignment of the hybrid systems depends on the characteristics of the constituents. On hBN, both type-I and type-II interfaces may form, depending on the relative energies of the frontier orbitals with respect to the vacuum level. On the other hand, all MoS2-based hybrid systems exhibit a type-II level alignment, with the molecular frontier orbitals positioned across the energy gap of the semiconductor. The electronic structure of the hybrid materials is further determined by the formation of interfacial dipole moments and by the wave-function hybridization between the organic and inorganic constituents. These results provide important indications for the design of novel low-dimensional hybrid materials with suitable characteristics for opto-electronics.
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Spinal dural arteriovenous fistula (SDAVF) is characterized by an abnormal connection between a radicular artery and the venous plexus producing spinal cord venous congestion. It manifests with nonspecific sensory and motor symptoms. We present three cases of SDAVF with different forms of presentation; in two cases, an autoimmune etiology was considered, and in the third case, the initial diagnosis was chronic radiculopathy. In all three cases, a serpentine enhancement was observed after the gadolinium in the dorsal region of the spinal cord corresponded to flow voids in T2-weighted images, which guided the diagnosis. SDAVF should be considered in atypical clinical presentations of radiculopathies or spinal cord syndromes, especially spinal conus or epicone syndrome. Likewise, it should be part of the differential diagnosis of spinal cord presentations of demyelinating diseases such as multiple sclerosis or neuromyelitis optica spectrum disorders.
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Human immune responses to viral infections are highly variable, but the genetic factors that contribute to this variability are not well characterized. We used VirScan, a high-throughput epitope scanning technology, to analyze pan-viral antibody reactivity profiles of twins and SNP-genotyped individuals. Using these data, we determined the heritability and genomic loci associated with antibody epitope selection, response breadth, and control of Epstein-Barr virus (EBV) viral load. 107 EBV peptide reactivities were heritable and at least two Epstein-Barr nuclear antigen 2 (EBNA-2) reactivities were associated with variants in the MHC class II locus. We identified an EBV serosignature that predicted viral load in peripheral blood mononuclear cells and was associated with variants in the MHC class I locus. Our study illustrates the utility of epitope profiling to investigate the genetics of pathogen immunity, reports heritable features of the antibody response to viruses, and identifies specific HLA loci important for EBV epitope selection.
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Anticorpos Antivirais/metabolismo , Epitopos/metabolismo , Infecções por Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Genótipo , Herpesvirus Humano 4/fisiologia , Epitopos Imunodominantes/metabolismo , Proteínas Virais/metabolismo , Adolescente , Adulto , Idoso , Estudos de Coortes , Mapeamento de Epitopos , Epitopos/genética , Infecções por Vírus Epstein-Barr/imunologia , Antígenos Nucleares do Vírus Epstein-Barr/genética , Feminino , Antígenos HLA/genética , Antígenos HLA/metabolismo , Humanos , Imunidade Humoral , Epitopos Imunodominantes/genética , Masculino , Pessoa de Meia-Idade , Peptídeos/genética , Polimorfismo de Nucleotídeo Único , Característica Quantitativa Herdável , Estudos Soroepidemiológicos , Carga Viral , Proteínas Virais/genética , Adulto JovemRESUMO
PURPOSE: Obesity in youth increases the risk for type 2 diabetes (T2D) and elevated abdominal adipose tissue and organ fat may be particularly deleterious. The purpose of this study was to examine associations among measures of adiposity including total, visceral, and organ fat (hepatic and pancreatic) and whether these measures were independently associated with glycemia in Latino youth at risk for diabetes. METHODS: Latino adolescents (47 boys and 32 girls, 13.7 ± 1.4 years) with obesity (BMIz 2.3 ± 0.3) were assessed for total fat by DXA and visceral and organ fat by 3 T magnetic resonance imaging. Glycemic indicators included HbA1c, fasting glucose (FG), and 2-h glucose (2-HrG) following an oral glucose tolerance test. Pearson correlations and stepwise linear regression analyses controlling for age and sex were used to examine independent associations between adiposity and glycemia. RESULTS: Total fat was associated with visceral (r = 0.66, p = 0.001) and hepatic fat (r = 0.34, p < 0.01) while visceral fat was associated with hepatic (r = 0.42, p < 0.001) and pancreatic fat (r = 0.36, p < 0.001). In stepwise linear regression analysis, hepatic and pancreatic fat were significant predictors of FG, explaining 4.7% and 5.2% of the variance, respectively (total R2 = 0.14, p = 0.02). Hepatic fat was the only significant predictor of 2-HrG explaining 9.9% of the variance in the model (total R2 = 0.12, p = 0.03). No measure of adiposity was retained as a significant predictor of HbA1c. CONCLUSION: Hepatic and pancreatic fat were the only adiposity measures independently associated with glycemia but the small amount of variance explained underscores the need for additional T2D biomarkers in high risk youth.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Adiposidade , Adolescente , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/etiologia , Feminino , Hispânico ou Latino , Humanos , Gordura Intra-Abdominal/metabolismo , MasculinoRESUMO
Molecular doping is a key process to increase the density of charge carriers in organic semiconductors. Doping-induced charges in polymer semiconductors result in the formation of polarons and/or bipolarons due to the strong electron-vibron coupling in conjugated organic materials. Identifying the nature of charge carriers in doped polymers is essential to optimize the doping process for applications. In this work, we use Raman spectroscopy to investigate the formation of charge carriers in molecularly doped poly(3-hexylthiophene-2,5-diyl) (P3HT) for increasing dopant concentration, with the organic salt dimesityl borinium tetrakis(penta-fluorophenyl)borate (Mes2B+ [B(C6F5)4]-) and the Lewis acid tris(pentafluorophenyl)borane [B(C6F5)3]. While the Raman signatures of neutral P3HT and singly charged P3HT segments (polarons) are known, the Raman spectra of doubly charged P3HT segments (bipolarons) are not yet sufficiently understood. Combining Raman spectroscopy measurements on doped P3HT thin films with first-principles calculations on oligomer models, we explain the evolution of the Raman spectra from neutral P3HT to increasingly doped P3HT featuring polarons and eventually bipolarons at high doping levels. We identify and explain the origin of the spectral features related to bipolarons by tracing the Raman signature of the symmetric collective vibrations along the polymer backbone, which - compared to neutral P3HT - redshifts for polarons and blueshifts for bipolarons. This is explained by a planarization of the singly charged P3HT segments with polarons and rather high order in thin films, while the doubly charged segments with bipolarons are located in comparably disordered regions of the P3HT film due to the high dopant concentration. Furthermore, we identify additional Raman peaks associated with vibrations in the quinoid doubly charged segments of the polymer. Our results offer the opportunity for readily identifying the nature of charge carriers in molecularly doped P3HT while taking advantage of the simplicity, versatility, and non-destructive nature of Raman spectroscopy.
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Spontaneous clearance of acute hepatitis C virus (HCV) infection is associated with single nucleotide polymorphisms (SNPs) on the MHC class II. We fine-mapped the MHC region in European (n = 1,600; 594 HCV clearance/1,006 HCV persistence) and African (n = 1,869; 340 HCV clearance/1,529 HCV persistence) ancestry individuals and evaluated HCV peptide binding affinity of classical alleles. In both populations, HLA-DQß1Leu26 (p valueMeta = 1.24 × 10-14) located in pocket 4 was negatively associated with HCV spontaneous clearance and HLA-DQß1Pro55 (p valueMeta = 8.23 × 10-11) located in the peptide binding region was positively associated, independently of HLA-DQß1Leu26. These two amino acids are not in linkage disequilibrium (r2 < 0.1) and explain the SNPs and classical allele associations represented by rs2647011, rs9274711, HLA-DQB1∗03:01, and HLA-DRB1∗01:01. Additionally, HCV persistence classical alleles tagged by HLA-DQß1Leu26 had fewer HCV binding epitopes and lower predicted binding affinities compared to clearance alleles (geometric mean of combined IC50 nM of persistence versus clearance; 2,321 nM versus 761.7 nM, p value = 1.35 × 10-38). In summary, MHC class II fine-mapping revealed key amino acids in HLA-DQß1 explaining allelic and SNP associations with HCV outcomes. This mechanistic advance in understanding of natural recovery and immunogenetics of HCV might set the stage for much needed enhancement and design of vaccine to promote spontaneous clearance of HCV infection.
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Cadeias beta de HLA-DQ/genética , Hepacivirus/patogenicidade , Hepatite C/genética , Interações Hospedeiro-Patógeno/genética , Polimorfismo de Nucleotídeo Único , Doença Aguda , Alelos , Substituição de Aminoácidos , População Negra , Feminino , Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Cadeias beta de HLA-DQ/imunologia , Hepacivirus/crescimento & desenvolvimento , Hepacivirus/imunologia , Hepatite C/etnologia , Hepatite C/imunologia , Hepatite C/virologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Leucina/imunologia , Leucina/metabolismo , Masculino , Prolina/imunologia , Prolina/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Remissão Espontânea , População BrancaRESUMO
BACKGROUND: The application of advanced imaging in pediatric research trials introduces the challenge of how to effectively handle and communicate incidental and reportable findings. This challenge is amplified in underserved populations that experience disparities in access to healthcare as recommendations for follow-up care may be difficult to coordinate. Therefore, the purpose of the present report is to describe the process for identifying and communicating findings from a research MRI to low-income Latino children and families. METHODS: Latino adolescents (n = 86) aged 12-16 years old with obesity and prediabetes underwent a research MRI (3 Tesla Philips Ingenia®) as part of a randomized controlled diabetes prevention trial. The research MRIs were performed at baseline and 6 months to assess changes in whole-abdominal fat distribution and organ fat in response to the intervention. An institutional pathway was developed for identifying and reporting findings to participants and families. The pathway was developed through a collaborative process with hospital administration, research compliance, radiology, and the research team. All research images were reviewed by a board-certified pediatric radiologist who conveyed findings to the study pediatrician for determination of clinical actionability and reportability to children and families. Pediatric sub-specialists were consulted as necessary and a primary care practitioner (PCP) from a free community health clinic agreed to receive referrals for uninsured participants. RESULTS: A total of 139 images (86 pre- and 53 post-intervention) were reviewed with 31 findings identified and 23 deemed clinically actionable and reportable. The only reportable finding was severely elevated liver fat (> 10%, n = 14) with the most common and concerning incidental findings being horseshoe kidney (n = 1) and lung lesion (n = 1). The remainder (n = 7) were less serious. Of youth with a reportable or incidental finding, 18 had a PCP but only 7 scheduled a follow-up appointment. Seven participants without a PCP were referred to a safety-net clinic for follow-up. CONCLUSIONS: With the increased utilization of high-resolution imaging in pediatric research, additional standardization is needed on what, when, and how to return incidental and reportable findings to participants, particularly among historically underrepresented populations that may be underserved in the community. TRIAL REGISTRATION: Preventing Diabetes in Latino Youth, NCT02615353.
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Diabetes Mellitus , Estado Pré-Diabético , Adolescente , Criança , Hispânico ou Latino , Humanos , Imageamento por Ressonância Magnética , ObesidadeRESUMO
Purpose: The purpose of this study was to present our hypothesis that aging alters metabolic function in ocular tissues. We tested the hypothesis by measuring metabolism in aged murine tissues alongside retinal responses to light. Methods: Scotopic and photopic electroretinogram (ERG) responses in young (3-6 months) and aged (23-26 months) C57Bl/6J mice were recorded. Metabolic flux in retina and eyecup explants was quantified using U-13C-glucose or U-13C-glutamine with gas chromatography-mass spectrometry (GC-MS), O2 consumption rate (OCR) in a perifusion apparatus, and quantifying adenosine triphosphatase (ATP) with a bioluminescence assay. Results: Scotopic and photopic ERG responses were reduced in aged mice. Glucose metabolism, glutamine metabolism, OCR, and ATP pools in retinal explants were mostly unaffected in aged mice. In eyecups, glutamine usage in the Krebs Cycle decreased while glucose metabolism, OCR, and ATP pools remained stable. Conclusions: Our examination of metabolism showed negligible impact of age on retina and an impairment of glutamine anaplerosis in eyecups. The metabolic stability of these tissues ex vivo suggests age-related metabolic alterations may not be intrinsic. Future experiments should focus on determining whether external factors including nutrient supply, oxygen availability, or structural changes influence ocular metabolism in vivo.