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BACKGROUND: Tuberculosis (TB) infectiousness decreases significantly with only a few days of treatment, but delayed diagnosis often leads to late treatment initiation. We conducted a sequential explanatory mixed methods study to understand the barriers and facilitators to prompt diagnosis among people with TB. METHODS: We enrolled 100 adults who started TB treatment in the Carabayllo district of Lima, Peru, between November 2020 and February 2022 and administered a survey about their symptoms and healthcare encounters. We calculated total diagnostic delay as time from symptom onset to diagnosis. We conducted semi-structured interviews of 26 participants who had a range of delays investigating their experience navigating the health system. Interview transcripts were inductively coded for concepts related to diagnostic barriers and facilitators. RESULTS: Overall, 38% of participants sought care first from public facilities and 42% from the private sector. Only 14% reported being diagnosed with TB on their first visit, and participants visited a median of 3 (interquartile range [IQR] health facilities before diagnosis. The median total diagnostic delay was 9 weeks (interquartile range [IQR] 4-22), with a median of 4 weeks (IQR 0-9) before contact with the health system and of 3 weeks (IQR 0-9) after. Barriers to prompt diagnosis included participants attributing their symptoms to an alternative cause or having misconceptions about TB, and leading them to postpone seeking care. Once connected to care, variations in clinical management, health facility resource limitations, and lack of formal referral processes contributed to the need for multiple healthcare visits before obtaining a diagnosis. Facilitators to prompt diagnosis included knowing someone with TB, supportive friends and family, referral documents, and seeing a pulmonologist. CONCLUSIONS: Misinformation about TB among people with TB and providers, poor accessibility of health services, and the need for multiple encounters to obtain diagnostic tests were major factors leading to delays. Extending the hours of operation of public health facilities, improving community awareness and provider training, and creating a formal referral process between the public and private sectors should be priorities in the efforts to combat TB.
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Diagnóstico Tardio , Tuberculose , Humanos , Peru , Adulto , Masculino , Feminino , Diagnóstico Tardio/estatística & dados numéricos , Tuberculose/diagnóstico , Pessoa de Meia-Idade , Acessibilidade aos Serviços de Saúde , Adulto Jovem , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Inquéritos e QuestionáriosRESUMO
Post-translationally modified tau is the primary component of tau neurofibrillary tangles, a pathological hallmark of Alzheimer's disease and other tauopathies. Post-translational modifications (PTMs) within the tau microtubule (MT)-binding domain (MBD), which encompasses two hexapeptide motifs that act as critical nucleating regions for tau aggregation, can potentially modulate tau aggregation as well as interactions with MTs and membranes. Here, we characterize the effects of a recently discovered tau PTM, lysine succinylation, on tau-tubulin interactions and compare these to the effects of two previously reported MBD modifications, lysine acetylation and tyrosine phosphorylation. As generation of site-specific PTMs in proteins is challenging, we used short synthetic peptides to quantify the effects on tubulin binding of three site-specific PTMs located within the PHF6∗ (paired helical filament [PHF] residues 275-280) and PHF6 (residues 306-311) hexapeptide motifs: K280 acetylation, Y310 phosphorylation, and K311 succinylation. We compared these effects to those observed for MBD PTM-mimetic point mutations K280Q, Y310E, and K311E. Finally, we evaluated the effects of these PTM-mimetic mutations on MBD membrane binding and membrane-induced fibril and oligomer formation. We found that all three PTMs perturb tau MT binding, with Y310 phosphorylation exerting the strongest effect. PTM-mimetic mutations partially recapitulated the effects of the PTMs on MT binding and also disrupted tau membrane binding and membrane-induced oligomer and fibril formation. These results imply that these PTMs, including the novel and Alzheimer's disease-specific succinylation of tau K311, may influence both the physiological and pathological interactions of tau and thus represent targets for therapeutic intervention.
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Doença de Alzheimer , Microtúbulos , Emaranhados Neurofibrilares , Processamento de Proteína Pós-Traducional , Proteínas tau , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Humanos , Lisina/metabolismo , Microtúbulos/metabolismo , Emaranhados Neurofibrilares/metabolismo , Fosforilação , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo , Proteínas tau/metabolismoRESUMO
INTRODUCTION: The objective of this study was to assess the durability, short-term and long-term effectiveness, and safety of tofacitinib in ulcerative colitis (UC) in clinical practice. METHODS: This is a retrospective multicenter study including patients with UC who had received the first tofacitinib dose at least 8 weeks before the inclusion. Clinical effectiveness was based on partial Mayo score. RESULTS: A total of 408 patients were included. Of them, 184 (45%) withdrew tofacitinib during follow-up (mean = 18 months). The probability of maintaining tofacitinib was 67% at 6 m, 58% at 12 m, and 49% at 24 m. The main reason for tofacitinib withdrawal was primary nonresponse (44%). Older age at the start of tofacitinib and a higher severity of clinical activity were associated with tofacitinib withdrawal. The proportion of patients in remission was 38% at week 4, 45% at week 8, and 47% at week 16. Having moderate-to-severe vs mild disease activity at baseline and older age at tofacitinib start were associated with a lower and higher likelihood of remission at week 8, respectively. Of 171 patients in remission at week 8, 83 (49%) relapsed. The probability of maintaining response was 66% at 6 m and 54% at 12 m. There were 93 adverse events related to tofacitinib treatment (including 2 pulmonary thromboembolisms [in patients with risk factors] and 2 peripheral vascular thrombosis), and 29 led to tofacitinib discontinuation. DISCUSSION: Tofacitinib is effective in both short-term and long-term in patients with UC. The safety profile is similar to that previously reported.
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Colite Ulcerativa , Humanos , Colite Ulcerativa/tratamento farmacológico , Resultado do Tratamento , Indução de Remissão , Estudos RetrospectivosRESUMO
Selective neuronal vulnerability to protein aggregation is found in many neurodegenerative diseases including Alzheimer's disease (AD). Understanding the molecular origins of this selective vulnerability is, therefore, of fundamental importance. Tau protein aggregates have been found in Wolframin (WFS1)-expressing excitatory neurons in the entorhinal cortex, one of the earliest affected regions in AD. The role of WFS1 in Tauopathies and its levels in tau pathology-associated neurodegeneration, however, is largely unknown. Here we report that WFS1 deficiency is associated with increased tau pathology and neurodegeneration, whereas overexpression of WFS1 reduces those changes. We also find that WFS1 interacts with tau protein and controls the susceptibility to tau pathology. Furthermore, chronic ER stress and autophagy-lysosome pathway (ALP)-associated genes are enriched in WFS1-high excitatory neurons in human AD at early Braak stages. The protein levels of ER stress and autophagy-lysosome pathway (ALP)-associated proteins are changed in tau transgenic mice with WFS1 deficiency, while overexpression of WFS1 reverses those changes. This work demonstrates a possible role for WFS1 in the regulation of tau pathology and neurodegeneration via chronic ER stress and the downstream ALP. Our findings provide insights into mechanisms that underpin selective neuronal vulnerability, and for developing new therapeutics to protect vulnerable neurons in AD.
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Doença de Alzheimer , Tauopatias , Doença de Alzheimer/patologia , Animais , Lisossomos/metabolismo , Camundongos , Camundongos Transgênicos , Neurônios/patologia , Agregados Proteicos , Tauopatias/patologiaRESUMO
BACKGROUND: The COVID-19 pandemic disrupted TB services worldwide, leading to diagnostic delays. There have been few published reports describing how the pandemic affected people's pathway to diagnosis from their own perspectives. We sought to evaluate the impact on the pandemic on people's experiences obtaining a TB diagnosis. METHODS: We performed a mixed-methods study, enrolling newly diagnosed TB patients from 12 health centers in Lima, Peru. We used structured surveys to quantify diagnostic delay, defined as the time between symptom onset and diagnosis, and in-depth interviews to understand the ways in which the pandemic affected the pathway to care. We compared diagnostic delay between patients enrolled during the first year of the pandemic to those diagnosed after using a Wilcoxon rank-sum test. We used an inductive content analysis approach to analyze interview content related to the pandemic. RESULTS: We enrolled 51 patients during November 2020-April 2021 (during the first year of the pandemic) and 49 patients during October 2021-February 2022. Median diagnostic delay was longer for patients diagnosed during the first year of the pandemic (median 15 [IQR 5-26] weeks compared to 6 [IQR 3-18] weeks, p = 0.027). Qualitative analysis of 26 interviews revealed that the pandemic affected participants' care-seeking behavior and their ability to access to TB diagnostic services, particularly for those diagnosed in the first year of the pandemic. Many participants initially had their symptoms attributed to COVID-19, resulting in delayed TB evaluation and additional costs for COVID-19 treatment. CONCLUSIONS: The COVID-19 pandemic impacted multiple steps in the pathway to care for TB patients in Lima, causing delays in TB diagnosis. These findings demonstrate how the shifting of health care resources to prioritize COVID-19 can lead to collateral damage for people with TB and other conditions.
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COVID-19 , Tuberculose , Humanos , COVID-19/diagnóstico , Diagnóstico Tardio , Pandemias , Peru/epidemiologia , Estudos Transversais , Tuberculose/diagnóstico , Tuberculose/epidemiologia , Tuberculose/terapia , Tratamento Farmacológico da COVID-19RESUMO
Naegleria fowleri is a free-living amoeba, which is able to infect humans through the nasal mucosa causing a disease in the central nervous system known as primary amoebic meningoencephalitis (PAM). Polymorphonuclear cells (PMNs) play a critical role in the early phase of N fowleri infection. Recently, a new biological defence mechanism called neutrophil extracellular traps (NETs) has been attracting attention. These structures represent an important strategy to immobilize and kill invading microorganisms. In this work, we evaluate the capacity of N fowleri to induce the NETs release by PMNs cells in mice in vitro and in vivo. In vitro: Neutrophils from bone marrow were cocultured with N fowleri trophozoites. In vivo: we employed a mouse model of PAM. We evaluated DNA, histone and myeloperoxidase (MPO) and the formation of NETs by confocal microscopy. Our results showed N fowleri induce both NETs and MPO release by PMNs cells in mice after trophozoite exposure, which increased through time, in vitro and in vivo. These results demonstrate that NETs are somehow associated with the amoebas. We suggest PMNs release their traps trying to avoid N fowleri attachment at the apical side of the nasal epithelium.
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Armadilhas Extracelulares , Naegleria fowleri/imunologia , Neutrófilos/imunologia , Amebíase , Animais , Células Cultivadas , Infecções Protozoárias do Sistema Nervoso Central/imunologia , Técnicas de Cocultura , DNA de Protozoário/análise , Histonas/análise , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Confocal , Mucosa Nasal/imunologia , Peroxidase/análise , Trofozoítos/imunologiaRESUMO
INTRODUCTION: The stereotypical progression of Alzheimer's disease (AD) pathology is not fully understood. The selective impact of AD on distinct regions has led the field to question if innate vulnerability exists. This study aims to determine if the causative factors of regional vulnerability are dependent on cell-autonomous or transneuronal (non-cell autonomous) processes. METHODS: Using mathematical and statistical models, we analyzed the contribution of cell-autonomous and non-cell autonomous factors to predictive linear models of AD pathology. RESULTS: Results indicate gene expression as a weak contributor to predictive linear models of AD. Instead, the network diffusion model acts as a strong predictor of observed AD atrophy and hypometabolism. DISCUSSION: We propose a convenient methodology for identifying genes and their role in determining AD topography, in comparison with network spread. Results reinforce the role of transneuronal network spread on disease progression and suggest that innate gene expression plays a secondary role in seeding and subsequent disease progression.
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Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Encéfalo/patologia , Regulação da Expressão Gênica , Idoso , Idoso de 80 Anos ou mais , Atrofia/patologia , Progressão da Doença , Feminino , Redes Reguladoras de Genes , Predisposição Genética para Doença , Humanos , Imageamento por Ressonância Magnética , Masculino , Modelos Estatísticos , Valor Preditivo dos TestesRESUMO
OBJECTIVE: To describe the experience of percutaneous transhepatic cholangiography (PTC) with biliary dilatation and drainage after pediatric liver transplantation and to determine the long-term outcome of this procedure. METHODS: Retrospective study from 2001 to 2013. Follow-up after treatment was also undertaken. A survival analysis was performed in patients in whom the procedure and eventual removal of the catheter were successful. RESULTS: In all, 196 children received liver transplants; 40 of them (20 boys and 20 girls; median age of 4 years) were treated using PTC due to biliary complications. Sixty-one PTC procedures were performed in 40 liver transplant recipients. Technically successful PTC was achieved in 87.5% of the patients. The probability of a patient not developing unfavorable outcomes 1, 5, and 10 years after treatment was 88.9%, 83.0%, and 74.1%.
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Doenças Biliares/complicações , Doenças Biliares/cirurgia , Procedimentos Cirúrgicos do Sistema Biliar/métodos , Constrição Patológica/cirurgia , Rejeição de Enxerto/prevenção & controle , Transplante de Fígado , Anastomose Cirúrgica , Cateterismo , Criança , Pré-Escolar , Colangiografia , Constrição Patológica/complicações , Drenagem , Feminino , Seguimentos , Sobrevivência de Enxerto , Humanos , Lactente , Masculino , Prognóstico , Estudos Retrospectivos , Fatores de RiscoRESUMO
In order to investigate the involvement of sulfated groups in the Trypanosoma cruzi host-parasite relationship, we studied the interaction between the major cysteine proteinase of T. cruzi, cruzipain (Cz), a sulfate-containing sialylated molecule and the sialic acid-binding immunoglobulin like lectin-E (Siglec-E). To this aim, ELISA, indirect immunofluorescence assays and flow cytometry, using mouse Siglec-E-Fc fusion molecules and glycoproteins of parasites, were performed. Competition assays verified that the lectins, Maackia amurensis II (Mal II) and Siglec-E-Fc, compete for the same binding sites. Taking into account that Mal II binding remains unaltered by sulfation, we established this lectin as sialylation degree control. Proteins of an enriched microsomal fraction showed the highest binding to Siglec-E as compared with those from the other parasite subcellular fractions. ELISA assays and the affinity purification of Cz by a Siglec-E column confirmed the interaction between both molecules. The significant decrease in binding of Siglec-E-Fc to Cz and to its C-terminal domain (C-T) after desulfation of these molecules suggests that sulfates contribute to the interaction between Siglec-E-Fc and these glycoproteins. Competitive ELISA assays confirmed the involvement of sulfated epitopes in the affinity between Siglec-E and Cz, probably modified by natural protein environment. Interestingly, data from flow cytometry of untreated and chlorate-treated parasites suggested that sulfates are not primary receptors, but enhance the binding of Siglec-E to trypomastigotic forms. Altogether, our findings support the notion that sulfate-containing sialylated glycoproteins interact with Siglec-E, an ortholog protein of human Siglec-9, and might modulate the immune response of the host, favoring parasitemia and persistence of the parasite.
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Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos B/metabolismo , Antígenos de Protozoários/metabolismo , Cisteína Endopeptidases/metabolismo , Interações Hospedeiro-Patógeno , Fatores Imunológicos/metabolismo , Sulfatos/metabolismo , Trypanosoma cruzi/imunologia , Animais , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Técnica Indireta de Fluorescência para Anticorpo , Camundongos , Ligação Proteica , Proteínas de Protozoários , CoelhosRESUMO
Composition-gradient multi-angle static light scattering (CG-MALS) is an emerging technique for the determination of intermolecular interactions via the second virial coefficient B22. With CG-MALS, detailed studies of the second virial coefficient can be carried out more accurately and effectively than with traditional methods. In addition, automated mixing, delivery and measurement enable high speed, continuous, fluctuation-free sample delivery and accurate results. Using CG-MALS we measure the second virial coefficient of bovine serum albumin (BSA) in aqueous solutions at various values of pH and ionic strength of a univalent salt (NaCl). The systematic variation of the second virial coefficient as a function of pH and NaCl strength reveals the net charge change and the isoelectric point of BSA under different solution conditions. The magnitude of the second virial coefficient decreases to 1.13 x 10(-5) ml*mol/g(2) near the isoelectric point of pH 4.6 and 25 mM NaCl. These results illuminate the role of fundamental long-range electrostatic and van der Waals forces in protein-protein interactions, specifically their dependence on pH and ionic strength.
Assuntos
Luz , Concentração Osmolar , Espalhamento de Radiação , Soroalbumina Bovina/metabolismo , Animais , Bovinos , Hidrodinâmica , Ligação Proteica/efeitos dos fármacos , Soroalbumina Bovina/química , Cloreto de Sódio/farmacologia , Eletricidade EstáticaRESUMO
Alzheimer's Disease (AD) pathology has been increasingly explored through single-cell and single-nucleus RNA-sequencing (scRNA-seq & snRNA-seq) and spatial transcriptomics (ST). However, the surge in data demands a comprehensive, user-friendly repository. Addressing this, we introduce a single-cell and spatial RNA-seq database for Alzheimer's disease (ssREAD). It offers a broader spectrum of AD-related datasets, an optimized analytical pipeline, and improved usability. The database encompasses 1,053 samples (277 integrated datasets) from 67 AD-related scRNA-seq & snRNA-seq studies, totaling 7,332,202 cells. Additionally, it archives 381 ST datasets from 18 human and mouse brain studies. Each dataset is annotated with details such as species, gender, brain region, disease/control status, age, and AD Braak stages. ssREAD also provides an analysis suite for cell clustering, identification of differentially expressed and spatially variable genes, cell-type-specific marker genes and regulons, and spot deconvolution for integrative analysis. ssREAD is freely available at https://bmblx.bmi.osumc.edu/ssread/ .
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Doença de Alzheimer , RNA-Seq , Análise de Célula Única , Doença de Alzheimer/genética , Humanos , Análise de Célula Única/métodos , Animais , Camundongos , RNA-Seq/métodos , Encéfalo/metabolismo , Encéfalo/patologia , Bases de Dados Genéticas , Transcriptoma , Análise de Sequência de RNA/métodos , Perfilação da Expressão Gênica/métodos , MasculinoRESUMO
In Latin America, little is known about the involvement of private health-care providers in tuberculosis (TB) detection and management. We sought to gain a better understanding of current and potential roles of the private sector in delivering TB services in Peru. We conducted a mixed-methods study in North Lima, Peru. The quantitative component comprised a patient pathway analysis assessing the alignment of TB services with patient care-seeking behavior. The qualitative component comprised in-depth interviews with 18 private health-care providers and 5 key informants. We estimated that 77% of patients sought care initially at a facility with TB diagnostic capacity and 59% at a facility with TB treatment capacity. Among private facilities, 43% offered smear microscopy, 13% offered radiography, and none provided TB treatment. Among public-sector facilities, 100% offered smear microscopy, 26% offered radiography, and 99% provided TB treatment. Private providers believed they offered shorter wait times and a faster diagnosis, but they struggled with a lack of referral systems and communication with the public sector. Nonrecognition of private-sector tests by the public sector led to duplicate testing of referred patients. Although expressing willingness to collaborate with public-sector programs for diagnosis and referral, private providers had limited interest in treating TB. This study highlights the role of private providers in Peru as an entry point for TB care. Public-private collaboration is necessary to harness the potential of the private sector as an ally for early diagnosis.
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Setor Privado , Tuberculose , Humanos , Peru/epidemiologia , Tuberculose/diagnóstico , Tuberculose/tratamento farmacológico , Tuberculose/terapia , Setor Público , Pessoal de Saúde , Aceitação pelo Paciente de Cuidados de SaúdeRESUMO
Providing equitable informal science, technology, engineering, and mathematics (STEM) learning opportunities to young children from diverse backgrounds may be a way to increase access and interest in STEM and can help to address the broader goal of increasing representation. Importantly, these learning experiences must be meaningful and engage everyday cultural practices. Guided by a strengths-based approach, the current study examines how oral stories as a cultural resource can be harnessed to support Latine children's engagement in a tinkering activity. The project explores whether and how setting an at-home tinkering activity within a story context engenders rich parent-child conversations that provide engineering learning opportunities for young children. Fifty-two Latine parents and children (Mage = 7.69 years; 23 girls; 90.4% Mexican heritage) were randomly assigned to either hear a story as a frame for a hands-on tinkering activity or to engage in the same tinkering activity without the story. After families finished tinkering, a researcher elicited the children's reflections about their tinkering experience. Approximately 2 weeks after the activity, children were asked to share their tinkering reflections with a second researcher. Parents and children in the story condition talked more about engineering during tinkering, and these children also talked more about engineering during both reflections than did children in the no-story condition. These findings suggest that integrating oral storytelling into tinkering activities is a promising future direction for the creation of more equitable informal engineering learning opportunities for Latine children and families. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
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Aprendizagem , Pais , Feminino , Humanos , Pré-Escolar , Criança , Engenharia , Comunicação , TecnologiaRESUMO
In Latin America, little is known about the involvement of private healthcare providers in TB detection and management. We sought to gain a better understanding of current and potential roles of the private sector in delivering TB services in Peru. We conducted a mixed-methods study in Lima, Peru. The quantitative component comprised a patient pathway analysis assessing the alignment of TB services with patient care-seeking behavior. The qualitative component comprised in-depth interviews with 18 private healthcare providers and 5 key informants. We estimated that 77% of patients initially sought care at a facility with TB diagnostic capacity and 59% at a facility with TB treatment capacity. The lack of TB services at initial care-seeking location was driven by the 41% of patients estimated to seek care first at a private facility. Among private facilities, 43% offered smear microscopy, 13% offered radiography, and none provided TB treatment. Among public sector facilities, 100% offered smear microscopy, 26% offered radiography, and 99% provided TB treatment. Interviews revealed that private providers believed that they offered shorter wait times and a quicker diagnosis, but they struggled with a lack of follow-up systems and communication barriers with the public sector. While expressing willingness to collaborate with public sector programs for diagnosis and referral, private providers had limited interest in treating TB. This study highlights the role of private providers in Peru as an entry point for TB care. Public-private collaboration is necessary to harness the potential of the private sector as an ally for early diagnosis.
RESUMO
Mobile screening units can help close tuberculosis case detection gaps. Placing screening units where people at high risk for undiagnosed tuberculosis preferentially spend time could make screening more resource-effective. We conducted a case-control study in Lima, Peru to identify locations where people with tuberculosis were more likely to spend time than community controls. We surveyed participants about activity locations over the past 6 months. We used density-based clustering to assess how patient and control activity locations differed, and logistic regression to compare location-based exposures. We included 109 tuberculosis patients and 79 controls. In density-based clustering analysis, the two groups had similar patterns of living locations, but their work locations clustered in distinct areas. Both groups were similarly likely to use public transit, but patients predominantly used buses and were less likely to use rapid transit (adjusted odds ratio [aOR] 0.31, 95% confidence interval [CI] 0.10-0.96) or taxis (aOR 0.42, 95% CI 0.21-0.85). Patients were more likely to have spent time in prison (aOR 11.55, 95% CI 1.48-90.13). Placing mobile screening units at bus terminals serving locations where tuberculosis patients have worked and within and around prisons could help reach people with undiagnosed tuberculosis.
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Tuberculose , Estudos de Casos e Controles , Humanos , Programas de Rastreamento , Prisões , Meios de Transporte , Tuberculose/diagnóstico , Tuberculose/epidemiologiaRESUMO
Abnormalities in brain glucose metabolism and accumulation of abnormal protein deposits called plaques and tangles are neuropathological hallmarks of Alzheimer's disease (AD), but their relationship to disease pathogenesis and to each other remains unclear. Here we show that succinylation, a metabolism-associated post-translational protein modification (PTM), provides a potential link between abnormal metabolism and AD pathology. We quantified the lysine succinylomes and proteomes from brains of individuals with AD, and healthy controls. In AD, succinylation of multiple mitochondrial proteins declined, and succinylation of small number of cytosolic proteins increased. The largest increases occurred at critical sites of amyloid precursor protein (APP) and microtubule-associated tau. We show that in vitro, succinylation of APP disrupted its normal proteolytic processing thereby promoting Aß accumulation and plaque formation and that succinylation of tau promoted its aggregation to tangles and impaired microtubule assembly. In transgenic mouse models of AD, elevated succinylation associated with soluble and insoluble APP derivatives and tau. These findings indicate that a metabolism-linked PTM may be associated with AD.
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Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Placa Amiloide/metabolismo , Processamento de Proteína Pós-Traducional , Ácido Succínico/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Sequência de Aminoácidos , Precursor de Proteína beta-Amiloide/genética , Animais , Autopsia , Encéfalo/metabolismo , Encéfalo/patologia , Estudos de Casos e Controles , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Camundongos , Camundongos Transgênicos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Placa Amiloide/genética , Placa Amiloide/patologia , Agregados Proteicos , Proteólise , Proteoma/genética , Proteoma/metabolismo , Proteínas tau/genéticaRESUMO
Human middle temporal gyrus (MTG) is a vulnerable brain region in early Alzheimer's disease (AD), but little is known about the molecular mechanisms underlying this regional vulnerability. Here we utilize the 10 × Visium platform to define the spatial transcriptomic profile in both AD and control (CT) MTG. We identify unique marker genes for cortical layers and the white matter, and layer-specific differentially expressed genes (DEGs) in human AD compared to CT. Deconvolution of the Visium spots showcases the significant difference in particular cell types among cortical layers and the white matter. Gene co-expression analyses reveal eight gene modules, four of which have significantly altered co-expression patterns in the presence of AD pathology. The co-expression patterns of hub genes and enriched pathways in the presence of AD pathology indicate an important role of cell-cell-communications among microglia, oligodendrocytes, astrocytes, and neurons, which may contribute to the cellular and regional vulnerability in early AD. Using single-molecule fluorescent in situ hybridization, we validated the cell-type-specific expression of three novel DEGs (e.g., KIF5A, PAQR6, and SLC1A3) and eleven previously reported DEGs associated with AD pathology (i.e., amyloid beta plaques and intraneuronal neurofibrillary tangles or neuropil threads) at the single cell level. Our results may contribute to the understanding of the complex architecture and neuronal and glial response to AD pathology of this vulnerable brain region.
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Doença de Alzheimer , Lobo Temporal , Transcriptoma , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Hibridização in Situ Fluorescente , Cinesinas/genética , Cinesinas/metabolismo , Lobo Temporal/metabolismoRESUMO
Polyaniline (PANI) composites have gained momentum as supercapacitive materials due to their high energy density and power density. However, some drawbacks in their performance remain, such as the low stability after hundreds of charge-discharge cycles and limitations in the synthesis scalability. Herein, we report for the first time PANI-Graphitic oxidized carbon nitride composites as potential supercapacitor material. The biomimetic polymerization of aniline assisted by hematin, supported by phosphorous and oxygen-modified carbon nitrides (g-POCN and g-OCN, respectively), achieved up to 89% yield. The obtained PAI/g-POCN and PANI/g-OCN show enhanced electrochemical properties, such as conductivity of up to 0.0375 S/cm, specific capacitances (Cs) of up to 294 F/g (at high current densities, 5 A/g) and a stable operation after 500 charge-discharge cycles (at 3 A/g). In contrast, the biomimetic synthesis of Free PANI, assisted by stabilized hematin in cosolvents, exhibited lower performance properties (65%). Due to their structural differences, the electrochemical properties of Free PANI (conductivity of 0.0045 S/cm and Cs of up to 82 F/g at 5 A/g) were lower than those of nanostructured PANI/g-POCN and g-OCN supports, which provide stability and improve the properties of biomimetically synthesized PANI. This work reveals the biomimetic synthesis of PANI, assisted by hematin supported by modified carbon nitrides, as a promising strategy to produce nanostructured supercapacitors with high performance.
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Using a design-based research approach, we studied ways to advance opportunities for children and families to engage in engineering design practices in an informal educational setting. 213 families with 5-11-year-old children were observed as they visited a tinkering exhibit at a children's museum during one of three iterations of a program posing an engineering design challenge. Children's narrative reflections about their experience were recorded immediately after tinkering. Across iterations of the program, changes to the exhibit design and facilitation provided by museum staff corresponded to increased families' engagement in key engineering practices. In the latter two cycles of the program, families engaged in the most testing, and in turn, redesigning. Further, in the latter cycles, the more children engaged in testing and retesting during tinkering, the more their narratives contained engineering-related content. The results advance understanding and the evidence base for educational practices that can promote engineering learning opportunities for children.
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BACKGROUND: Active disease during conception and pregnancy in women with inflammatory bowel disease (IBD) increases the risk of pregnancy complications and adverse neonatal outcomes. The use of IBD treatments during pregnancy should be weighed against their adverse effects on the neonate, but longer-term safety data and data on serious infection rates and malignancies postnatally are lacking, particularly for newer drugs, such as tofacitinib, vedolizumab and ustekinumab. METHODS: This ongoing, prospective registry study being conducted at 70 centres in Spain is enrolling pregnant women who are ⩾18 years, are at any point in pregnancy up to the end of the second trimester and have a diagnosis of Crohn's disease, ulcerative colitis or unclassified IBD. Patients will receive treatment decided independently by their IBD specialist. Each incident gestation will be followed up through pregnancy and the first 4 years postnatally. Three cohorts will be compared: biologicals exposed, immunomodulatory exposed and non-exposed. The primary endpoint is the risk of severe infection in newborns postnatally up to 4 years of age; other endpoints include serious adverse events (SAEs) such as pregnancy and delivery complications, neonatal SAEs, development [Ages and Stages Questionnaire-3 (ASQ3)], and malignancy incidence, up to 4 years of age. IBD specialists will collect maternal data (baseline/end of each trimester/1 month post-delivery), neonatal birth data, and the SAE and ASQ3 data in children exposed during pregnancy, reported every 3 months by the mother. Statistical analysis will include summary statistics for quantitative variables, comparisons of qualitative variables with significance set at p < 0.025 and a binary logistic regression model to determine the risk factors for severe infections. RESULTS: Enrolment began in September 2019 and study completion is expected in September 2028. CONCLUSIONS: This prospective, controlled study will provide evidence on the long-term safety profile in children after intrauterine and lactation exposure to biological and immunomodulatory IBD treatments, including data on postnatal severe infections, development and malignancies. CLINICALTRIALSGOV IDENTIFIER: NCT03894228.