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Loss of oral tolerance (LOT) to gluten, driven by dendritic cell (DC) priming of gluten-specific T helper 1 (Th1) cell immune responses, is a hallmark of celiac disease (CeD) and can be triggered by enteric viral infections. Whether certain commensals can moderate virus-mediated LOT remains elusive. Here, using a mouse model of virus-mediated LOT, we discovered that the gut-colonizing protist Tritrichomonas (T.) arnold promotes oral tolerance and protects against reovirus- and murine norovirus-mediated LOT, independent of the microbiota. Protection was not attributable to antiviral host responses or T. arnold-mediated innate type 2 immunity. Mechanistically, T. arnold directly restrained the proinflammatory program in dietary antigen-presenting DCs, subsequently limiting Th1 and promoting regulatory T cell responses. Finally, analysis of fecal microbiomes showed that T. arnold-related Parabasalid strains are underrepresented in human CeD patients. Altogether, these findings will motivate further exploration of oral-tolerance-promoting protists in CeD and other immune-mediated food sensitivities.
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Antígenos , Imunidade Inata , Animais , Camundongos , Humanos , Dieta , Glutens , Células Dendríticas , Tolerância ImunológicaRESUMO
New sublineages of SARS-CoV-2 variants-of-concern (VOCs) continuously emerge with mutations in the spike glycoprotein. In most cases, the sublineage-defining mutations vary between the VOCs. It is unclear whether these differences reflect lineage-specific likelihoods for mutations at each spike position or the stochastic nature of their appearance. Here we show that SARS-CoV-2 lineages have distinct evolutionary spaces (a probabilistic definition of the sequence states that can be occupied by expanding virus subpopulations). This space can be accurately inferred from the patterns of amino acid variability at the whole-protein level. Robust networks of co-variable sites identify the highest-likelihood mutations in new VOC sublineages and predict remarkably well the emergence of subvariants with resistance mutations to COVID-19 therapeutics. Our studies reveal the contribution of low frequency variant patterns at heterologous sites across the protein to accurate prediction of the changes at each position of interest.
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COVID-19 , Farmacorresistência Viral , Evolução Molecular , Mutação , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , SARS-CoV-2/genética , Humanos , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/química , COVID-19/virologia , COVID-19/genética , Farmacorresistência Viral/genética , Biologia Computacional/métodos , Tratamento Farmacológico da COVID-19 , Antivirais/uso terapêuticoRESUMO
The COVID-19 pandemic was one of the deadliest global public health events. In the United States, over 1.1 million individuals have died, and now COVID-19 is the third leading cause of death (CDC, 2023). Vaccine uptake has stalled among different demographics. Vaccine hesitancy, a delay in accepting or refusing vaccines, poses a significant challenge regardless of the availability of safe and effective COVID-19 vaccines. This study aimed to identify disparate COVID-19 vaccine uptake among individuals in Western New York. The primary objective was to identify the factors contributing to lower rates of COVID-19 vaccination within this population.Data were collected from 585 adults recruited from 20 Niagara and Erie Counties sites using a self-administered survey on vaccine hesitancy, vaccination status, and COVID-19-related characteristics. The survey included the adult Vaccine Hesitancy Scale (aVHS) and acquired information on demographic characteristics and COVID-19 impact, knowledge, and information sources. Data were analyzed using descriptive statistics, a chi-squared test, a Wilcoxon rank-sum test, and a logistic regression model.Findings suggest that unvaccinated participants (n = 35) were concerned about vaccine side effects (48.6%). For vaccinated/unboosted participants (n = 52), they (40.0%) reported clinical concerns. After adjusting for gender and age, healthcare provider guidance and family guidance remained significant predictors of vaccination status, while clinical research studies were significant predictors of booster status. Findings from this study suggest public health interventions that target vaccine education and facilitate well-informed decisions about COVID-19 vaccines lead to less vaccine hesitancy.
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Vacinas contra COVID-19 , COVID-19 , Hesitação Vacinal , Humanos , Vacinas contra COVID-19/administração & dosagem , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , COVID-19/prevenção & controle , Hesitação Vacinal/estatística & dados numéricos , New York , Adulto Jovem , Idoso , Confiança , Conhecimentos, Atitudes e Prática em Saúde , SARS-CoV-2 , Adolescente , Inquéritos e Questionários , Área Carente de Assistência Médica , Populações Vulneráveis/estatística & dados numéricos , Fonte de InformaçãoRESUMO
The energy band structure provides crucial information on charge transport behaviour in organic semiconductors, such as effective mass, transfer integrals and electron-phonon coupling. Despite the discovery of the valence (the highest occupied molecular orbital (HOMO)) band structure in the 1990s, the conduction band (the lowest unoccupied molecular orbital (LUMO)) has not been experimentally observed. Here we employ angle-resolved low-energy inverse photoelectron spectroscopy to reveal the LUMO band structure of pentacene, a prototypical high-mobility organic semiconductor. The derived transfer integrals and bandwidths from the LUMO are substantially smaller than those predicted by density functional theory calculations. To reproduce this bandwidth reduction, we propose an improved (partially dressed) polaron model that accounts for the electron-intramolecular vibrational interaction with frequency-dependent coupling constants based on Debye relaxation. This model quantitatively reproduces not only the transfer integrals, but also the temperature-dependent HOMO and LUMO bandwidths, and the hole and electron mobilities. The present results demonstrate that electron mobility in high-mobility organic semiconductors is indeed limited by polaron formation.
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FunTree is a new resource that brings together sequence, structure, phylogenetic, chemical and mechanistic information for structurally defined enzyme superfamilies. Gathering together this range of data into a single resource allows the investigation of how novel enzyme functions have evolved within a structurally defined superfamily as well as providing a means to analyse trends across many superfamilies. This is done not only within the context of an enzyme's sequence and structure but also the relationships of their reactions. Developed in tandem with the CATH database, it currently comprises 276 superfamilies covering ~1800 (70%) of sequence assigned enzyme reactions. Central to the resource are phylogenetic trees generated from structurally informed multiple sequence alignments using both domain structural alignments supplemented with domain sequences and whole sequence alignments based on commonality of multi-domain architectures. These trees are decorated with functional annotations such as metabolite similarity as well as annotations from manually curated resources such the catalytic site atlas and MACiE for enzyme mechanisms. The resource is freely available through a web interface: www.ebi.ac.uk/thorton-srv/databases/FunTree.
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Bases de Dados de Proteínas , Enzimas/química , Enzimas/classificação , Evolução Biológica , Enzimas/metabolismo , Filogenia , Estrutura Terciária de Proteína , Alinhamento de Sequência , Análise de Sequência de ProteínaRESUMO
BACKGROUND: Enhanced cell expression of MAdCAM-1 is critical in tissue recruitment of lymphocytes in response to stimuli expressing the α4ß7 integrin. MAdCAM-1 is well characterized in gut mucosa with emerging evidence of hepatic expression. AIMS: (i) Compare quantitative/semi-quantitatively MAdCAM-1 expression in relation to early and advanced liver diseases (ii) Define the fine structure of vascular plexuses/lymphatics in the portal tract on which MAdCAM-1 is expressed. METHODS: Using alkaline phosphatase anti-alkaline phosphatase methodology on paraffin embedded tissue sections (n=28) from cirrhotic individuals who underwent orthotopic liver transplant, we evaluated MAdCAM-1 expression and compared with pre-cirrhotic, fulminant hepatitis B, and non-cirrhotic portal hypertension tissue sections. The positive controls included normal colon tissue with negative controls without primary antibody and isotype-matched purified IgG. We developed a real time PCR to quantify levels of MAdCAM-1 mRNA in our samples. RESULTS: MAdCAM-1 was expressed in 27/28 of the cirrhotic sections, localized primarily to septal areas within (i) endothelium of the peribiliary vascular plexus (PBP) (ii) lymphoid aggregates, with absence from normal, non-cirrhotic portal hypertension and pre-cirrhotic livers. There was significant upregulation of MAdCAM-1 mRNA in cirrhosis (p<0.011), consistent with immunohistochemical analysis. CONCLUSIONS: MAdCAM-1 is up-regulated in cirrhosis with expression on PBP and lymphoid aggregates. MAdCAM-1 is likely to contribute to the localization and recruitment of α4ß7 lymphocytes during the pathogenesis of cirrhosis. MAdCAM-1 could be a useful marker of advanced liver disease. Further studies with respect to the expression of MAdCAM-1 in the presence of reversible and non-reversible stages of liver disease may be of merit.
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Imunoglobulinas/metabolismo , Cirrose Hepática/metabolismo , Fígado/metabolismo , Mucoproteínas/metabolismo , Adulto , Moléculas de Adesão Celular , Colo/metabolismo , Endotélio Linfático/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Fígado/irrigação sanguínea , Tecido Linfoide/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Adulto JovemRESUMO
Background: Improving maternal and child health, one of the key UN Sustainable Development Goals (SDGs), is a major challenge in sub-Saharan Africa. Exclusive breast-feeding contributes significantly to child survival and development, but many mothers in Africa do not exclusively breastfeed their infants. This paper reports a study in Mulago hospital in Kampala. The study aims to identify factors influencing mothers' choices of infant feeding practices. Methods: Mixed methods were used. Respondents included 362 lactating mothers and health workers. Participants were who came for treatment were selected using simple random sampling. EpiInfor and SPSS were used for analysing the data and presented as descriptive study. Results: Results indicate that socio-demographic factors including age and education level influence mothers' ability and willingness to breastfeed exclusively for the first six months. Awareness about breast-feeding was mainly obtained from health centres, leaving mothers unable to attend these centres to miss out on vital information about exclusive breast-feeding. Around 43% of health workers were unaware of the country's Young and Infant Feeding Policy Guidelines. Conclusions: To increase the rate of exclusive breast-feeding in Uganda, it is important that community health is strengthened, and health workers are trained on national breast-feeding policies.
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Aleitamento Materno , Lactação , Humanos , Lactente , Feminino , Criança , Estudos Transversais , Uganda , HospitaisRESUMO
Selecting the right immunosuppressant to ensure rejection-free outcomes poses unique challenges in pediatric liver transplant (LT) recipients. A molecular predictor can comprehensively address these challenges. Currently, there are no well-validated blood-based biomarkers for pediatric LT recipients before or after LT. Here, we discover and validate separate pre- and post-LT transcriptomic signatures of rejection. Using an integrative machine learning approach, we combine transcriptomics data with the reference high-quality human protein interactome to identify network module signatures, which underlie rejection. Unlike gene signatures, our approach is inherently multivariate and more robust to replication and captures the structure of the underlying network, encapsulating additive effects. We also identify, in an individual-specific manner, signatures that can be targeted by current anti-rejection drugs and other drugs that can be repurposed. Our approach can enable personalized adjustment of drug regimens for the dominant targetable pathways before and after LT in children.
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Transplante de Fígado , Criança , Humanos , Imunossupressores/uso terapêuticoRESUMO
Mutations in the spike glycoprotein of SARS-CoV-2 allow the virus to probe the sequence space in search of higher-fitness states. New sublineages of SARS-CoV-2 variants-of-concern (VOCs) continuously emerge with such mutations. Interestingly, the sites of mutation in these sublineages vary between the VOCs. Whether such differences reflect the random nature of mutation appearance or distinct evolutionary spaces of spike in the VOCs is unclear. Here we show that each position of spike has a lineage-specific likelihood for mutations to appear and dominate descendent sublineages. This likelihood can be accurately estimated from the lineage-specific mutational profile of spike at a protein-wide level. The mutability environment of each position, including adjacent sites on the protein structure and neighboring sites on the network of comutability, accurately forecast changes in descendent sublineages. Mapping of imminent changes within the VOCs can contribute to the design of immunogens and therapeutics that address future forms of SARS-CoV-2.
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Combating fungal pathogens poses metabolic challenges for neutrophils, key innate cells in anti-Candida albicans immunity, yet how host-pathogen interactions cause remodeling of the neutrophil metabolism is unclear. We show that neutrophils mediate renal immunity to disseminated candidiasis by upregulating glucose uptake via selective expression of glucose transporter 1 (Glut1). Mechanistically, dectin-1-mediated recognition of ß-glucan leads to activation of PKCδ, which triggers phosphorylation, localization, and early glucose transport by a pool of pre-formed Glut1 in neutrophils. These events are followed by increased Glut1 gene transcription, leading to more sustained Glut1 accumulation, which is also dependent on the ß-glucan/dectin-1/CARD9 axis. Card9-deficient neutrophils show diminished glucose incorporation in candidiasis. Neutrophil-specific Glut1-ablated mice exhibit increased mortality in candidiasis caused by compromised neutrophil phagocytosis, reactive oxygen species (ROS), and neutrophil extracellular trap (NET) formation. In human neutrophils, ß-glucan triggers metabolic remodeling and enhances candidacidal function. Our data show that the host-pathogen interface increases glycolytic activity in neutrophils by regulating Glut1 expression, localization, and function.
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Candidíase , Transportador de Glucose Tipo 1 , Neutrófilos , beta-Glucanas , Animais , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Candida albicans , Candidíase/imunologia , Glucose/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Camundongos , Neutrófilos/imunologia , beta-Glucanas/metabolismoRESUMO
While there have been extensive analyses characterizing cellular and humoral responses across the severity spectrum in COVID-19, outcome predictors within severe COVID-19 remain less comprehensively elucidated. Furthermore, properties of antibodies (Abs) directed against viral antigens beyond spike and their associations with disease outcomes remain poorly defined. We perform deep molecular profiling of Abs directed against a wide range of antigenic specificities in severe COVID-19 patients. The profiles included canonical (spike [S], receptor-binding domain [RBD], and nucleocapsid [N]) and non-canonical (orf3a, orf8, nsp3, nsp13, and membrane [M]) antigenic specificities. Notably, multivariate Ab profiles directed against canonical or non-canonical antigens are equally discriminative of survival in severe COVID-19. Intriguingly, pre-pandemic healthy controls have cross-reactive Abs directed against nsp13, a protein conserved across coronaviruses. Consistent with these findings, a model built on Ab profiles for endemic coronavirus antigens also predicts COVID-19 outcome. Our results suggest the importance of studying Abs targeting non-canonical severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and endemic coronavirus antigens in COVID-19.
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COVID-19 , Anticorpos Antivirais , Humanos , Pandemias , SARS-CoV-2 , Glicoproteína da Espícula de CoronavírusRESUMO
The interfaces of a perovskite solar cell significantly influence the charge processes in the cell, which contributes to the device performance with direct implication for surface potential, electronic structure, and chemical reactivity. The properties of the interface are strongly affected by the surface termination. In this work, the combination of ultraviolet photoelectron spectroscopy (UPS) and metastable-atom electron spectroscopy is demonstrated, to examine the surface termination of a solution-processed CH3NH3PbI3 perovskite film. The results show that the surface of the CH3NH3PbI3 perovskite film is terminated with a layer consisting of CH3NH3 and I. The interface energy level alignment for both occupied and unoccupied levels between CH3NH3PbI3 and C60 is also examined using UPS and low-energy inverse photoelectron spectroscopy. It turns out that an ideal energy level alignment is established for the electron collection and hole block at the perovskite and C60 interface.
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Reliable, fast, and affordable diagnosis for tuberculosis (TB) remains a challenge to reduce disease incidence in resource-poor countries. Tests based on nucleotide sequences that are signature to Mycobacterium tuberculosis have the potential to make a positive impact on case detection rates, which can eventually help control TB. Using extensive comparative bioinformatics approach, we mined the genome for M. tuberculosis-specific genes and identified four genes so-called signature sequence (SS). With <25% homology with other known genes/proteins of mycobacterial/nonmycobacterial origin in various databases, these SS genes are ideal targets for species-specific identification. Sputum from suspected patients was liquefied using novel complete liquefying reagent, and DNA was isolated. Samples from patients (n = 417), reporting to TB clinics at two different hospitals, which met our inclusion criteria, were collected for this study. A small number (n = 143) was used for initial standardization, and the remaining patient samples (n = 274) were evaluated by SS and compared with smear microscopy, GeneXpert, culture, and clinical outcome. An overwhelming sensitivity of 97.0%, significantly higher than GeneXpert (95.0%), was seen. SS could pick all smear-negative, but culture-positive samples, along with other culture-negative samples; some of the latter were declared clinically positive. Our results yielded superior sensitivity and specificity through conventional PCR.
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Técnicas de Diagnóstico Molecular/métodos , Mycobacterium tuberculosis/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/genética , Sequência de Bases/genética , Biologia Computacional/métodos , DNA Bacteriano/genética , DNA Bacteriano/isolamento & purificação , Genes Bacterianos , Humanos , Projetos Piloto , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Escarro/microbiologia , Tuberculose Pulmonar/microbiologiaRESUMO
Enzymes, as biological catalysts, form the basis of all forms of life. How these proteins have evolved their functions remains a fundamental question in biology. Over 100 years of detailed biochemistry studies, combined with the large volumes of sequence and protein structural data now available, means that we are able to perform large-scale analyses to address this question. Using a range of computational tools and resources, we have compiled information on all experimentally annotated changes in enzyme function within 379 structurally defined protein domain superfamilies, linking the changes observed in functions during evolution to changes in reaction chemistry. Many superfamilies show changes in function at some level, although one function often dominates one superfamily. We use quantitative measures of changes in reaction chemistry to reveal the various types of chemical changes occurring during evolution and to exemplify these by detailed examples. Additionally, we use structural information of the enzymes active site to examine how different superfamilies have changed their catalytic machinery during evolution. Some superfamilies have changed the reactions they perform without changing catalytic machinery. In others, large changes of enzyme function, in terms of both overall chemistry and substrate specificity, have been brought about by significant changes in catalytic machinery. Interestingly, in some superfamilies, relatives perform similar functions but with different catalytic machineries. This analysis highlights characteristics of functional evolution across a wide range of superfamilies, providing insights that will be useful in predicting the function of uncharacterised sequences and the design of new synthetic enzymes.
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Evolução Molecular , Hidrolases/genética , Hidrolases/metabolismo , Domínio Catalítico , Biologia Computacional , Hidrolases/química , Modelos MolecularesRESUMO
Many crucial biochemical reactions in the cell require not only enzymes for catalysis but also organic cofactors or metal ions. Here, we analyse the physicochemical properties, chemical structures and functions of organic cofactors. Based on a thorough analysis of the literature complemented by our quantitative characterisation and classification, we found that most of these molecules are constructed from nucleotide and amino-acid-type building blocks, as well as some recurring cofactor-specific chemical scaffolds. We show that, as expected, organic cofactors are on average significantly more polar and slightly larger than other metabolites in the cell, yet they cover the full spectrum of physicochemical properties found in the metabolome. Furthermore, we have identified intrinsic groupings among the cofactors, based on their molecular properties, structures and functions, that represent a new way of considering cofactors. Although some classes of cofactors, as defined by their physicochemical properties, exhibit clear structural communalities, cofactors with similar structures can have diverse functional and physicochemical profiles. Finally, we show that the molecular functions of the cofactors not only may duplicate reactions performed by inorganic metal cofactors and amino acids, the cell's other catalytic tools, but also provide novel chemistries for catalysis.