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1.
EMBO Rep ; 25(1): 168-197, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38225354

RESUMO

Cell commitment to tumourigenesis and the onset of uncontrolled growth are critical determinants in cancer development but the early events directing tumour initiating cell (TIC) fate remain unclear. We reveal a single-cell transcriptome profile of brain TICs transitioning into tumour growth using the brain tumour (brat) neural stem cell-based Drosophila model. Prominent changes in metabolic and proteostasis-associated processes including ribogenesis are identified. Increased ribogenesis is a known cell adaptation in established tumours. Here we propose that brain TICs boost ribogenesis prior to tumour growth. In brat-deficient TICs, we show that this dramatic change is mediated by upregulated HEAT-Repeat Containing 1 (HEATR1) to promote ribosomal RNA generation, TIC enlargement and onset of overgrowth. High HEATR1 expression correlates with poor glioma patient survival and patient-derived glioblastoma stem cells rely on HEATR1 for enhanced ribogenesis and tumourigenic potential. Finally, we show that HEATR1 binds the master growth regulator MYC, promotes its nucleolar localisation and appears required for MYC-driven ribogenesis, suggesting a mechanism co-opted in ribogenesis reprogramming during early brain TIC development.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Antígenos de Histocompatibilidade Menor , Proteínas Proto-Oncogênicas c-myc , Proteínas de Ligação a RNA , Animais , Humanos , Encéfalo/metabolismo , Neoplasias Encefálicas/metabolismo , Carcinogênese/patologia , Transformação Celular Neoplásica/patologia , Proteínas de Ligação a DNA/metabolismo , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Glioblastoma/metabolismo , Glioma/patologia , Antígenos de Histocompatibilidade Menor/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo
2.
Proc Natl Acad Sci U S A ; 119(49): e2207754119, 2022 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-36442126

RESUMO

Millions of people across the world live off-grid not by choice but because they live in rural areas, have low income, and have no political clout. Delivering sustainable energy solutions to such a substantial amount of the world's population requires more than a technological fix; it requires leveraging the knowledge of underserved populations working together with a transdisciplinary team to find holistically derived solutions. Our original research has resulted in an innovative Convergence Framework integrating the fields of engineering, social sciences, and communication, and is based on working together with communities and other stakeholders to address the challenges posed by delivering clean energy solutions. In this paper, we discuss the evolution of this Framework and illustrate how this Framework is being operationalized in our on-going research project, cocreating hybrid renewable energy systems for off-grid communities in the Brazilian Amazon. The research shows how this Framework can address clean energy transitions, strengthen emerging industries at local level, and foster Global North-South scholarly collaborations. We do so by the integration of social science and engineering and by focusing on community engagement, energy justice, and governance for underserved communities. Further, this solution-driven Framework leads to the emergence of unique approaches that advance scientific knowledge, while at the same time addressing community needs.


Assuntos
Sistemas Computacionais , Energia Renovável , Humanos , Engenharia , Tecnologia , Altruísmo
3.
J Clin Immunol ; 43(8): 2076-2089, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37740092

RESUMO

Variants of uncertain significance (VUS) in CTLA4 are frequently identified in patients with antibody deficiency or immune dysregulation syndromes including, but not limited to, patients with multi-organ autoimmunity and autoinflammation. However, to ascertain the diagnosis of CTLA4 insufficiency, the functional relevance of each variant needs to be determined. Currently, various assays have been proposed to assess the functionality of CTLA4 VUS, including the analysis of transendocytosis, the biological function of CTLA4 to capture CD80 molecules from antigen presenting cells. Challenges of this assay include weak fluorescence intensity of the internalized ligand, poor reproducibility, and poor performance upon analyzing thawed cells. In addition, the distinction of pathogenic from non-pathogenic variants and from wild-type CTLA4, and the classification of the different VUS according to its level of CTLA4 dysfunction, would be desirable. We developed a novel CD80-expressing cell line for the evaluation of CD80-transendocytosis and compared it to the published transendocytosis assay. Our approach showed lower inter-assay variability and better robustness regardless the type of starting material (fresh or thawed peripheral mononuclear cells). In addition, receiver operating characteristic analysis showed 100% specificity, avoiding false positive results and allowing for a clear distinction between pathogenic and non-pathogenic variants in CTLA4-variant carriers. With our transendocytosis assay, we assessed the pathogenicity of 24 distinct CTLA4 variants from patients submitted to our diagnostic unit. Significantly impaired transendocytosis was demonstrated for 17 CTLA4 variants, whereas seven variants tested normal. In conclusion, our upgraded transendocytosis assay allows a reliable assessment of newly identified variants in CTLA4.


Assuntos
Células Apresentadoras de Antígenos , Autoimunidade , Humanos , Antígeno CTLA-4/genética , Citometria de Fluxo , Reprodutibilidade dos Testes
4.
BMC Public Health ; 23(1): 575, 2023 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-36978071

RESUMO

BACKGROUND: It is critical to assess implementation fidelity of evidence-based interventions and factors moderating fidelity, to understand the reasons for their success or failure. However, fidelity and fidelity moderators are seldom systematically reported. The study objective was to conduct a concurrent implementation fidelity evaluation and examine fidelity moderators of CHORD (Community Health Outreach to Reduce Diabetes), a pragmatic, cluster-randomized, controlled trial to test the impact of a Community Health Workers (CHW)-led health coaching intervention to prevent incident type 2 Diabetes Mellitus in New York (NY). METHODS: We applied the Conceptual Framework for Implementation Fidelity to assess implementation fidelity and factors moderating it across the four core intervention components: patient goal setting, education topic coaching, primary care (PC) visits, and referrals to address social determinants of health (SDH), using descriptive statistics and regression models. PC patients with prediabetes receiving care from safety-net patient-centered medical homes (PCMHs) at either, VA NY Harbor or at Bellevue Hospital (BH) were eligible to be randomized into the CHW-led CHORD intervention or usual care. Among 559 patients randomized and enrolled in the intervention group, 79.4% completed the intake survey and were included in the analytic sample for fidelity assessment. Fidelity was measured as coverage, content adherence and frequency of each core component, and the moderators assessed were implementation site and patient activation measure. RESULTS: Content adherence was high for three components with nearly 80.0% of patients setting ≥ 1 goal, having ≥ 1 PC visit and receiving ≥ 1 education session. Only 45.0% patients received ≥ 1 SDH referral. After adjusting for patient gender, language, race, ethnicity, and age, the implementation site moderated adherence to goal setting (77.4% BH vs. 87.7% VA), educational coaching (78.9% BH vs. 88.3% VA), number of successful CHW-patient encounters (6 BH vs 4 VA) and percent of patients receiving all four components (41.1% BH vs. 25.7% VA). CONCLUSIONS: The fidelity to the four CHORD intervention components differed between the two implementation sites, demonstrating the challenges in implementing complex evidence-based interventions in different settings. Our findings underscore the importance of measuring implementation fidelity in contextualizing the outcomes of randomized trials of complex multi-site behavioral interventions. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov on 30/12/2016 and the registration number is NCT03006666 .


Assuntos
Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/prevenção & controle , Cidade de Nova Iorque , Terapia Comportamental , Hospitais , Atenção Primária à Saúde
5.
Int J Mol Sci ; 24(16)2023 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-37628979

RESUMO

Marine ecosystems are among the richest in terms of biodiversity, and at present, still remain largely unknown today. In the molecular biology era, several analyses have been conducted to unravel the biological processes in this ecosystem. These systems have provided biotechnological solutions to current problems, including the treatment of diseases, as well as for the development of new biotechnological tools with applications in biomedicine and/or agri-food. In addition, in the context of climate change and global warming, these studies become even more necessary for the development of molecular tools that allow a reliable follow-up of this situation to anticipate alterations and responses of bioindicator species and to create a database to prevent and predict the environmental and climatic changes before the damage is irreversible. Proteomics approaches have revealed their potential use to obtain the set of biological effectors that lead to the real biological station on a specific stage, the proteins. In addition, proteomics-based algorithms have allowed the discovery of proteins with new potential biotechnological applications from proteome data through "applied proteomics". In this project, the first proteome analysis of the sea anemone, Anemonia sulcata, and its symbiont has been developed. These organisms present a wide distribution sea ecosystem. In Spain, it is accepted as a fishing and aquaculture species. Moreover, Anemonia sulcate has a symbiotic relation with autotroph Dinoflagellates, Symbiodinium spp., that allows the study of its relation at the molecular level. For the first characterization of A. sulcata proteome, three independent biological replicates were used, and proteins were extracted and analyzed by LC-MS/MS, allowing the quantification of 325 proteins, 81 from Symbiodinium spp. proteins and 244 from A. sulcata proteins. These proteins were subjected to gene ontology categorization by Cellular Component, Molecular Function and Biological Process. These analyzes have allowed the identification of biomarkers of gene expression as potential powerful emerging diagnostic tools to identify and characterize the molecular drivers of climate change stresses and improve monitoring techniques. In addition, through the application of novel algorithms for the detection of bioactive compounds based on the analysis of molecules of marine origin, the proteome has allowed the identification of proteins with potential applications in the fields of biomedicine and agri-food.


Assuntos
Dinoflagellida , Anêmonas-do-Mar , Animais , Proteômica , Ecossistema , Mudança Climática , Proteoma , Cromatografia Líquida , Espectrometria de Massas em Tandem , Biomarcadores
6.
Int J Mol Sci ; 24(3)2023 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-36768752

RESUMO

Recombination is an evolutionary strategy to quickly acquire new viral properties inherited from the parental lineages. The systematic survey of the SARS-CoV-2 genome sequences of the Andalusian genomic surveillance strategy has allowed the detection of an unexpectedly high number of co-infections, which constitute the ideal scenario for the emergence of new recombinants. Whole genome sequence of SARS-CoV-2 has been carried out as part of the genomic surveillance programme. Sample sources included the main hospitals in the Andalusia region. In addition to the increase of co-infections and known recombinants, three novel SARS-CoV-2 delta-omicron and omicron-omicron recombinant variants with two break points have been detected. Our observations document an epidemiological scenario in which co-infection and recombination are detected more frequently. Finally, we describe a family case in which co-infection is followed by the detection of a recombinant made from the two co-infecting variants. This increased number of recombinants raises the risk of emergence of recombinant variants with increased transmissibility and pathogenicity.


Assuntos
COVID-19 , Coinfecção , Humanos , Coinfecção/epidemiologia , COVID-19/epidemiologia , SARS-CoV-2/genética , Evolução Biológica , Genômica
7.
Rev Esp Enferm Dig ; 115(3): 154-155, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36043551

RESUMO

Gallstone ileus is a rare complication of cholecystoduodenal fistula. Gastric ischemia due to intestinal obstruction is an extremely rare event that, if not diagnosed in time, can have a fatal outcome. We present the case of a patient with intestinal occlusion due to a gallstone obstructing the middle jejunum in which gastric ischemia was diagnosed intraoperatively due to the distension caused by the intestinal obstruction.


Assuntos
Cálculos Biliares , Íleus , Fístula Intestinal , Obstrução Intestinal , Humanos , Cálculos Biliares/complicações , Cálculos Biliares/diagnóstico por imagem , Cálculos Biliares/cirurgia , Obstrução Intestinal/diagnóstico por imagem , Obstrução Intestinal/etiologia , Obstrução Intestinal/cirurgia , Fístula Intestinal/complicações , Colecistectomia/efeitos adversos , Íleus/diagnóstico por imagem , Íleus/etiologia , Íleus/cirurgia
8.
Pediatr Allergy Immunol ; 33(12): e13886, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36564875

RESUMO

One of the causes of inborn errors of immunity is immune dysregulation. The inability of the immune system to regulate the extent of its activity has several deleterious effects, including autoimmunity, recurrent infections, and malignancy. In recent years, many proteins in the CD28 family - CD28, ICOS, CTLA-4, PD-1, and BTLA - have come into the focus of several research areas for their consequential role in the upregulation or downregulation of the immune response. In this review, we will discuss the structure and function of these proteins, as well as provide an overview of the clinical picture of patients with genetic defects.


Assuntos
Antígenos CD28 , Tolerância Imunológica , Humanos , Antígenos CD28/genética , Antígenos CD28/metabolismo , Autoimunidade
9.
J Clin Immunol ; 41(8): 1804-1838, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34390440

RESUMO

Hyper-IgE syndromes and chronic mucocutaneous candidiasis constitute rare primary immunodeficiency syndromes with an overlapping clinical phenotype. In recent years, a growing number of underlying genetic defects have been identified. To characterize the underlying genetic defects in a large international cohort of 275 patients, of whom 211 had been clinically diagnosed with hyper-IgE syndrome and 64 with chronic mucocutaneous candidiasis, targeted panel sequencing was performed, relying on Agilent HaloPlex and Illumina MiSeq technologies. The targeted panel sequencing approach allowed us to identify 87 (32 novel and 55 previously described) mutations in 78 patients, which generated a diagnostic success rate of 28.4%. Specifically, mutations in DOCK8 (26 patients), STAT3 (21), STAT1 (15), CARD9 (6), AIRE (3), IL17RA (2), SPINK5 (3), ZNF341 (2), CARMIL2/RLTPR (1), IL12RB1 (1), and WAS (1) have been detected. The most common clinical findings in this cohort were elevated IgE (81.5%), eczema (71.7%), and eosinophilia (62.9%). Regarding infections, 54.7% of patients had a history of radiologically proven pneumonia, and 28.3% have had other serious infections. History of fungal infection was noted in 53% of cases and skin abscesses in 52.9%. Skeletal or dental abnormalities were observed in 46.2% of patients with a characteristic face being the most commonly reported feature (23.1%), followed by retained primary teeth in 18.9% of patients. Targeted panel sequencing provides a cost-effective first-line genetic screening method which allows for the identification of mutations also in patients with atypical clinical presentations and should be routinely implemented in referral centers.


Assuntos
Candidíase Mucocutânea Crônica/genética , Síndrome de Job/genética , Adolescente , Adulto , Candidíase Mucocutânea Crônica/sangue , Criança , Pré-Escolar , Estudos de Coortes , Eczema/genética , Eosinofilia/genética , Feminino , Humanos , Imunoglobulina E/sangue , Lactente , Síndrome de Job/sangue , Masculino , Pessoa de Meia-Idade , Mutação , Adulto Jovem
10.
Am J Obstet Gynecol ; 225(2): 138-152, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33812809

RESUMO

The postpartum period represents a critical window of opportunity to improve maternal short- and long-term health, including optimizing postpartum recovery, providing effective contraception, caring for mood disorders, managing weight, supporting lactation, initiating preventive care, and promoting cardiometabolic health. However, inadequate postpartum care, especially for individuals facing social and structural barriers, is common in the United States and contributes to suboptimal health outcomes with lasting consequences. Patient navigation is a patient-centered intervention that uses trained personnel to identify financial, cultural, logistical, and educational obstacles to effective healthcare and to mitigate these barriers to facilitate comprehensive and timely access to needed health services. Given the emerging evidence suggesting that patient navigation may be a promising method to improve health among postpartum individuals, our team developed a postpartum patient navigator training guide to be used in the Navigating New Motherhood 2 and other obstetrical navigation programs. Navigating New Motherhood 2 is a randomized trial exploring whether patient navigation by a trained, lay postpartum navigator for individuals with a low income can improve health and patient-reported outcomes during and after the postpartum period. Hiring and training patient navigators without health professional degrees are integral components of initiating a navigation program. However, patient navigator training is highly variable, and no guideline regarding key elements in such a training program exists for obstetrics specifically. Thus, this paper aimed to describe the core principles, content, and rationale for each element in a comprehensive postpartum patient navigator training program. Training should be centered around the following 6 core elements: (1) principles of patient navigation; (2) knowledge of pregnancy and postpartum care; (3) health education and health promotion principles; (4) cultural sensitivity and health equity; (5) care coordination and community resources; and (6) electronic medical record systems. These core elements can serve as a basis for the development of adaptable curricula for several institutions and contexts. In addition, we offer recommendations for the implementation of a navigator training program. A curriculum with built-in flexibility to meet community and institutional needs may promote the effective and sustainable use of patient navigation in the postpartum context.


Assuntos
Pessoal Técnico de Saúde/educação , Currículo , Navegação de Pacientes , Cuidado Pós-Natal/métodos , Fatores de Risco Cardiometabólico , Anticoncepção , Assistência à Saúde Culturalmente Competente , Registros Eletrônicos de Saúde , Feminino , Equidade em Saúde , Promoção da Saúde , Humanos , Lactação , Obstetrícia , Guias de Prática Clínica como Assunto , Gravidez , Medicina Preventiva , Sistemas de Apoio Psicossocial , Comportamento de Redução do Risco
11.
Phys Chem Chem Phys ; 23(14): 8200-8221, 2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33875989

RESUMO

The expansion of lithium-ion batteries from consumer electronics to larger-scale transport and energy storage applications has made understanding the many mechanisms responsible for battery degradation increasingly important. The literature in this complex topic has grown considerably; this perspective aims to distil current knowledge into a succinct form, as a reference and a guide to understanding battery degradation. Unlike other reviews, this work emphasises the coupling between the different mechanisms and the different physical and chemical approaches used to trigger, identify and monitor various mechanisms, as well as the various computational models that attempt to simulate these interactions. Degradation is separated into three levels: the actual mechanisms themselves, the observable consequences at cell level called modes and the operational effects such as capacity or power fade. Five principal and thirteen secondary mechanisms were found that are generally considered to be the cause of degradation during normal operation, which all give rise to five observable modes. A flowchart illustrates the different feedback loops that couple the various forms of degradation, whilst a table is presented to highlight the experimental conditions that are most likely to trigger specific degradation mechanisms. Together, they provide a powerful guide to designing experiments or models for investigating battery degradation.

13.
Proc Natl Acad Sci U S A ; 115(6): E1147-E1156, 2018 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-29351990

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is characterized by the presence of abundant desmoplastic stroma primarily composed of cancer-associated fibroblasts (CAFs). It is generally accepted that CAFs stimulate tumor progression and might be implicated in drug resistance and immunosuppression. Here, we have compared the transcriptional profile of PDGFRα+ CAFs isolated from genetically engineered mouse PDAC tumors with that of normal pancreatic fibroblasts to identify genes potentially implicated in their protumorigenic properties. We report that the most differentially expressed gene, Saa3, a member of the serum amyloid A (SAA) apolipoprotein family, is a key mediator of the protumorigenic activity of PDGFRα+ CAFs. Whereas Saa3-competent CAFs stimulate the growth of tumor cells in an orthotopic model, Saa3-null CAFs inhibit tumor growth. Saa3 also plays a role in the cross talk between CAFs and tumor cells. Ablation of Saa3 in pancreatic tumor cells makes them insensitive to the inhibitory effect of Saa3-null CAFs. As a consequence, germline ablation of Saa3 does not prevent PDAC development in mice. The protumorigenic activity of Saa3 in CAFs is mediated by Mpp6, a member of the palmitoylated membrane protein subfamily of the peripheral membrane-associated guanylate kinases (MAGUK). Finally, we interrogated whether these observations could be translated to a human scenario. Indeed, SAA1, the ortholog of murine Saa3, is overexpressed in human CAFs. Moreover, high levels of SAA1 in the stromal component correlate with worse survival. These findings support the concept that selective inhibition of SAA1 in CAFs may provide potential therapeutic benefit to PDAC patients.


Assuntos
Fibroblastos Associados a Câncer/patologia , Carcinoma Ductal Pancreático/patologia , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Proteína Amiloide A Sérica/metabolismo , Proteína Amiloide A Sérica/fisiologia , Células Estromais/patologia , Animais , Fibroblastos Associados a Câncer/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Movimento Celular , Proliferação de Células , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pâncreas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteína Amiloide A Sérica/genética , Células Estromais/metabolismo , Microambiente Tumoral
14.
Neural Plast ; 2021: 3468795, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603440

RESUMO

Synaptic activity mediates information storage and memory consolidation in the brain and requires a fast de novo synthesis of mRNAs in the nucleus and proteins in synapses. Intracellular localization of a protein can be achieved by mRNA trafficking and localized translation. Activity-regulated cytoskeleton-associated protein (Arc) is a master regulator of synaptic plasticity and plays an important role in controlling large signaling networks implicated in learning, memory consolidation, and behavior. Transcription of the Arc gene may be induced by a short behavioral event, resulting in synaptic activation. Arc mRNA is exported into the cytoplasm and can be trafficked into the dendrite of an activated synapse where it is docked and translated. The structure of Arc is similar to the viral GAG (group-specific antigen) protein, and phylogenic analysis suggests that Arc may originate from the family of Ty3/Gypsy retrotransposons. Therefore, Arc might evolve through "domestication" of retroviruses. Arc can form a capsid-like structure that encapsulates a retrovirus-like sentence in the 3'-UTR (untranslated region) of Arc mRNA. Such complex can be loaded into extracellular vesicles and transported to other neurons or muscle cells carrying not only genetic information but also regulatory signals within neuronal networks. Therefore, Arc mRNA inter- and intramolecular trafficking is essential for the modulation of synaptic activity required for memory consolidation and cognitive functions. Recent studies with single-molecule imaging in live neurons confirmed and extended the role of Arc mRNA trafficking in synaptic plasticity.


Assuntos
Proteínas do Citoesqueleto/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , RNA Mensageiro/metabolismo , Sinapses/metabolismo , Animais , Proteínas do Citoesqueleto/genética , Humanos , Proteínas do Tecido Nervoso/genética , Sistema Nervoso/metabolismo , RNA Mensageiro/genética
15.
Int J Mol Sci ; 22(17)2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34502262

RESUMO

Intestinal microfold cells (M cells) are a dynamic lineage of epithelial cells that initiate mucosal immunity in the intestine. They are responsible for the uptake and transcytosis of microorganisms, pathogens, and other antigens in the gastrointestinal tract. A mature M cell expresses a receptor Gp2 which binds to pathogens and aids in the uptake. Due to the rarity of these cells in the intestine, their development and differentiation remain yet to be fully understood. We recently demonstrated that polycomb repressive complex 2 (PRC2) is an epigenetic regulator of M cell development, and 12 novel transcription factors including Atoh8 were revealed to be regulated by the PRC2. Here, we show that Atoh8 acts as a regulator of M cell differentiation; the absence of Atoh8 led to a significant increase in the number of Gp2+ mature M cells and other M cell-associated markers such as Spi-B and Sox8. In vitro organoid analysis of RankL treated organoid showed an increase of mature marker GP2 expression and other M cell-associated markers. Atoh8 null mice showed an increase in transcytosis capacity of luminal antigens. An increase in M cell population has been previously reported to be detrimental to mucosal immunity because some pathogens like orally acquired prions have been able to exploit the transcytosis capacity of M cells to infect the host; mice with an increased population of M cells are also susceptible to Salmonella infections. Our study here demonstrates that PRC2 regulated Atoh8 is one of the factors that regulate the population density of intestinal M cell in the Peyer's patch.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular/genética , Células Epiteliais/metabolismo , Mucosa Intestinal/metabolismo , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Animais , Linfócitos B/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular/imunologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Imunidade nas Mucosas/genética , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Camundongos , Camundongos Knockout , Nódulos Linfáticos Agregados/efeitos dos fármacos , Nódulos Linfáticos Agregados/metabolismo , Cultura Primária de Células , Ligante RANK/farmacologia , Receptor Ativador de Fator Nuclear kappa-B/farmacologia , Linfócitos T/metabolismo , Transcitose/genética
16.
J Clin Immunol ; 40(6): 820-832, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32506362

RESUMO

LPS-responsive beige-like anchor (LRBA) deficiency is an autosomal recessive primary immunodeficiency disorder, OMIM (#614700). LRBA deficiency patients suffer from variable manifestations including recurrent infections, immune dysregulation, autoimmunity, cytopenias, and enteropathy. This study describes different clinical phenotypes and immunological characteristics of 18 LRBA deficiency patients diagnosed from Egypt. T and B lymphocyte subpopulations, LRBA, and cytotoxic T lymphocyte-associated protein 4 (CTLA4) expression were evaluated in resting and stimulated T cells using flow cytometry. Next-generation sequencing was used to identify mutations in the LRBA gene. LRBA deficiency patients had significantly lower B cells and increased percentage of memory T cells. CTLA4 levels were lower in LRBA-deficient T regulatory cells in comparison to healthy donors at resting conditions and significantly increased upon stimulation of T cells. We identified 11 novel mutations in LRBA gene ranging from large deletions to point mutations. Finally, we were able to differentiate LRBA-deficient patients from healthy control and common variable immunodeficiency patients using a simple flow cytometry test performed on whole blood and without need to prior stimulation. LRBA deficiency has heterogeneous phenotypes with poor phenotype-genotype correlation since the same mutation may manifest differently even within the same family. Low LRBA expression, low numbers of B cells, increased numbers of memory T cells, and defective CTLA4 expression (which increase to normal level upon T cell stimulation) are useful laboratory tests to establish the diagnosis of LRBA deficiency. Screening of the siblings of affected patients is very important as patients may be asymptomatic at the beginning of the disease course.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/deficiência , Estudos de Associação Genética , Predisposição Genética para Doença , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Fenótipo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Biomarcadores , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Criança , Pré-Escolar , Egito , Feminino , Expressão Gênica , Genes Recessivos , Estudos de Associação Genética/métodos , Humanos , Imunoglobulinas/sangue , Imunoglobulinas/imunologia , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/metabolismo , Imunofenotipagem , Lactente , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Mutação , Curva ROC
17.
Crit Rev Food Sci Nutr ; 60(10): 1738-1746, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30924346

RESUMO

The link between diet and human health status has been repeatedly proved by strong scientific evidence, and developed societies demand food products with an added value beyond the satisfaction of hunger and the provision of nutrients. Functional foods, food supplements and nutraceuticals are at the interface between nutrition and pharma and opens the doors for seeking new therapeutic alternatives for the prevention of nutrition-related diseases. The present review is aimed at clarifying the differences between functional foods, food supplements and nutraceuticals as well as describing its regulatory framework in Europe, United States and Japan. Specific harmonized regulation for these products is needed. Functional foods, food supplements and nutraceuticals exert health-promoting properties and could be considered as potential candidates in the management of chronic diseases in combination with prescribed medication. Further research is essential for establishing which nutrition-pharma combinations are most favorable and suitable for each chronic disease.


Assuntos
Suplementos Nutricionais , Alimento Funcional , Dieta , Europa (Continente) , Regulamentação Governamental , Humanos , Japão , Estados Unidos
18.
Crit Rev Food Sci Nutr ; 60(9): 1515-1522, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30896289

RESUMO

The beneficial effect of fresh tomatoes or processed tomato products on platelet aggregation depends on the presence of bioactive compounds in these products, in sufficient quantities, to produce a relevant physiological effect, when consumed as part of a normal diet. This work is focused on reviewing the development on tomato products bioactive compounds, particularly with reference to its potential biological activity with beneficial effect on the prevention of platelet aggregation.The most relevant studies found show that all bioactive compounds found in Water-soluble tomato concentrate are in tomato fruit and other tomato products, and there is enough evidence of their beneficial effects. According to the European Food Safety Authority requirements, further intervention studies (human clinical trials) using valid markers should be performed in order to demonstrate the beneficial effects of tomato products as consumer products (paste, puree, sauce or juice) on platelet aggregation. Our PubMed review results support the development of promising nutritional strategies involving tomatoes and tomato products to tackle cardiovascular disease as antiplatelet aggregation.


Assuntos
Doenças Cardiovasculares/dietoterapia , Agregação Plaquetária , Solanum lycopersicum/química , Frutas/química , Humanos
19.
Exp Dermatol ; 28(11): 1298-1308, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31487753

RESUMO

BACKGROUND: Atopic dermatitis (AD) is a complex skin disease involving causative effects from both intrinsic and extrinsic sources. Murine models of the disease often fall short in one of these components and, as a result, do not fully encapsulate these disease mechanisms. OBJECTIVE: We aimed to determine whether the protease-activated receptor 2 over-expressor mouse (PAR2OE) with topical house dust mite (HDM) application is a more comprehensive and clinically representative AD model. METHODS: Following HDM extract application to PAR2OE mice and controls, AD clinical scoring, itching behaviour, skin morphology and structure, barrier function, immune cell infiltration and inflammatory markers were assessed. Skin morphology was analysed using haematoxylin and eosin staining, and barrier function was assessed by transepidermal water loss measurements. Immune infiltrate was characterised by histological and immunofluorescence staining. Finally, an assessment of AD-related gene expression was performed using quantitative RT-PCR. RESULTS: PAR2OE mice treated with HDM displays all the characteristic clinical symptoms including erythema, dryness and oedema, skin morphology, itch and inflammation typically seen in patients with AD. There is a significant influx of mast cells (P < .01) and eosinophils (P < .0001) into the dermis of these mice. Furthermore, the PAR2OE + HDM mice exhibit similar expression patterns of key differentially expressed genes as seen in human AD. CONCLUSION: The PAR2OE + HDM mouse presents with a classic AD pathophysiology and is a valuable model in terms of reproducibility and overall disease representation to study the condition and potential therapeutic approaches.


Assuntos
Dermatite Atópica/etiologia , Modelos Animais de Doenças , Pyroglyphidae/imunologia , Receptor PAR-2/fisiologia , Animais , Dermatite Atópica/patologia , Pele/imunologia , Pele/patologia
20.
Allergy ; 74(4): 753-766, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30394557

RESUMO

BACKGROUND: When an immune cell migrates from the bloodstream to a site of chronic inflammation, it experiences a profound decrease in microenvironmental oxygen levels leading to a state of cellular hypoxia. The hypoxia-inducible factor-1α (HIF-1α) promotes an adaptive transcriptional response to hypoxia and as such is a major regulator of immune cell survival and function. HIF hydroxylases are the family of oxygen-sensing enzymes primarily responsible for conferring oxygen dependence upon the HIF pathway. METHODS: Using a mouse model of allergic contact dermatitis (ACD), we tested the effects of treatment with the pharmacologic hydroxylase inhibitor DMOG, which mimics hypoxia, on disease development. RESULTS: Re-exposure of sensitized mice to 2,4-dinitrofluorobenzene (DNFB) elicited inflammation, edema, chemokine synthesis (including CXCL1 and CCL5) and the recruitment of neutrophils and eosinophils. Intraperitoneal or topical application of the pharmacologic hydroxylase inhibitors dymethyloxalylglycine (DMOG) or JNJ1935 attenuated this inflammatory response. Reduced inflammation was associated with diminished recruitment of neutrophils and eosinophils but not lymphocytes. Finally, hydroxylase inhibition reduced cytokine-induced chemokine production in cultured primary keratinocytes through attenuation of the JNK pathway. CONCLUSION: These data demonstrate that hydroxylase inhibition attenuates the recruitment of neutrophils to inflamed skin through reduction of chemokine production and increased neutrophilic apoptosis. Thus, pharmacologic inhibition of HIF hydroxylases may be an effective new therapeutic approach in allergic skin inflammation.


Assuntos
Aminoácidos Dicarboxílicos/uso terapêutico , Dermatite Alérgica de Contato/prevenção & controle , Oxigenases de Função Mista/antagonistas & inibidores , Aminoácidos Dicarboxílicos/farmacologia , Animais , Movimento Celular/efeitos dos fármacos , Citocinas/metabolismo , Eosinófilos/citologia , Humanos , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia , Inflamação/tratamento farmacológico , Camundongos , Neutrófilos/citologia
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