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1.
J Clin Transl Sci ; 7(1): e175, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37745933

RESUMO

Introduction: With persistent incidence, incomplete vaccination rates, confounding respiratory illnesses, and few therapeutic interventions available, COVID-19 continues to be a burden on the pediatric population. During a surge, it is difficult for hospitals to direct limited healthcare resources effectively. While the overwhelming majority of pediatric infections are mild, there have been life-threatening exceptions that illuminated the need to proactively identify pediatric patients at risk of severe COVID-19 and other respiratory infectious diseases. However, a nationwide capability for developing validated computational tools to identify pediatric patients at risk using real-world data does not exist. Methods: HHS ASPR BARDA sought, through the power of competition in a challenge, to create computational models to address two clinically important questions using the National COVID Cohort Collaborative: (1) Of pediatric patients who test positive for COVID-19 in an outpatient setting, who are at risk for hospitalization? (2) Of pediatric patients who test positive for COVID-19 and are hospitalized, who are at risk for needing mechanical ventilation or cardiovascular interventions? Results: This challenge was the first, multi-agency, coordinated computational challenge carried out by the federal government as a response to a public health emergency. Fifty-five computational models were evaluated across both tasks and two winners and three honorable mentions were selected. Conclusion: This challenge serves as a framework for how the government, research communities, and large data repositories can be brought together to source solutions when resources are strapped during a pandemic.

2.
Placenta ; 80: 42-48, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31103066

RESUMO

INTRODUCTION: The placenta is one of the least understood, yet arguably one of the most important organs for human health and development. While there have been numerous research efforts dedicated to understanding the placenta's critical role, these studies and the data they produced remain separated and largely disparate. In order to facilitate placental research, the Eunice Kennedy Shriver National Institute of Child and Human Development (NICHD) released in October 2018 the Placental Atlas Tool (PAT) (https://pat.nichd.nih.gov/), an internet-based platform offering users a centralized placental database of molecular datasets, analytic tools, and images. METHODS: PAT is a cloud-based system developed by the business requirements defined by NICHD leadership and extramural placental researchers. PAT employs a metadata-driven web interface to provide curated placental datasets and images, enriched with structured, descriptive metadata to enhance data discoverability. PAT also incorporates open source molecular data analytical tools to provide a flexible analytics workflow for placental researchers. RESULTS: PAT launched with 426 analyzable molecular placental datasets consisting of over 12,500 samples from 10 distinct species, all systematically annotated and processed for enhanced research utility. 828 placental images, consisting of 7 imaging modalities across 47 species, and nearly 300 annotated linked publications supplement the datasets to facilitate knowledge integration and hypothesis generation across disparate molecular studies. DISCUSSION: PAT will maximize the NICHD's investment in placental research by reinforcing open scientific inquiry, facilitating reuse of datasets, promoting novel research and testing of new hypotheses and analytic methods, and facilitating education of new researchers.


Assuntos
Atlas como Assunto , Bases de Dados Factuais , Placenta , Animais , Feminino , Humanos , Gravidez
3.
J Neurosci ; 37(1): 110-119, 2017 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-28053034

RESUMO

In vertebrate olfactory sensory neurons (OSNs), Ca2+ plays key roles in both mediating and regulating the olfactory response. Ca2+ enters OSN cilia during the response through the olfactory cyclic nucleotide-gated (CNG) channel and stimulates a depolarizing chloride current by opening the olfactory Ca2+-activated chloride channel to amplify the response. Ca2+ also exerts negative regulation on the olfactory transduction cascade, through mechanisms that include reducing the CNG current by desensitizing the CNG channel via Ca2+/calmodulin (CaM), to reduce the response. Ca2+ is removed from the cilia primarily by the K+-dependent Na+/Ca2+ exchanger 4 (NCKX4), and the removal of Ca2+ leads to closure of the chloride channel and response termination. In this study, we investigate how two mechanisms conventionally considered negative regulatory mechanisms of olfactory transduction, Ca2+ removal by NCKX4, and desensitization of the CNG channel by Ca2+/CaM, interact to regulate the olfactory response. We performed electro-olfactogram (EOG) recordings on the double-mutant mice, NCKX4-/-;CNGB1ΔCaM, which are simultaneously lacking NCKX4 (NCKX4-/-) and Ca2+/CaM-mediated CNG channel desensitization (CNGB1ΔCaM). Despite exhibiting alterations in various response attributes, including termination kinetics and adaption properties, OSNs in either NCKX4-/- mice or CNGB1ΔCaM mice show normal resting sensitivity, as determined by their unchanged EOG response amplitude. We found that OSNs in NCKX4-/-;CNGB1ΔCaM mice displayed markedly reduced EOG amplitude accompanied by alterations in other response attributes. This study suggests that what are conventionally considered negative regulatory mechanisms of olfactory transduction also play a role in setting the resting sensitivity in OSNs. SIGNIFICANCE STATEMENT: Sensory receptor cells maintain high sensitivity at rest. Although the mechanisms responsible for setting the resting sensitivity of sensory receptor cells are not well understood, it has generally been assumed that the sensitivity is set primarily by how effectively the components in the activation cascade of sensory transduction can be stimulated. Our findings in mouse olfactory sensory neurons suggest that mechanisms that are primarily responsible for terminating the olfactory response are also critical for proper resting sensitivity.


Assuntos
Antiporters/fisiologia , Canais de Cátion Regulados por Nucleotídeos Cíclicos/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Neurônios Receptores Olfatórios/fisiologia , Olfato/genética , Animais , Antiporters/genética , Cálcio/metabolismo , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Feminino , Masculino , Camundongos , Camundongos Knockout , Mutação/genética , Proteínas do Tecido Nervoso/genética , Mucosa Olfatória/inervação , Mucosa Olfatória/fisiologia , Transdução de Sinais/genética
4.
Am J Hum Genet ; 92(2): 307-12, 2013 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-23375655

RESUMO

A combination of autozygosity mapping and exome sequencing identified a null mutation in SLC24A4 in a family with hypomineralized amelogenesis imperfect a (AI), a condition in which tooth enamel formation fails. SLC24A4 encodes a calcium transporter upregulated in ameloblasts during the maturation stage of amelogenesis. Screening of further AI families identified a missense mutation in the ion-binding site of SLC24A4 expected to severely diminish or abolish the ion transport function of the protein. Furthermore, examination of previously generated Slc24a4 null mice identified a severe defect in tooth enamel that reflects impaired amelogenesis. These findings support a key role for SLC24A4 in calcium transport during enamel formation.


Assuntos
Amelogênese Imperfeita/genética , Antiporters/genética , Mutação/genética , Trocador de Sódio e Cálcio/genética , Sequência de Aminoácidos , Animais , Antiporters/química , Sequência de Bases , Família , Feminino , Humanos , Incisivo/ultraestrutura , Masculino , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Linhagem , Fenótipo
5.
J Neurosci ; 32(42): 14557-62, 2012 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-23077041

RESUMO

Feedback inhibition of adenylyl cyclase III (ACIII) via Ca(2+)-induced phosphorylation has long been hypothesized to contribute to response termination and adaptation of olfactory sensory neurons (OSNs). To directly determine the functional significance of this feedback mechanism for olfaction in vivo, we genetically mutated serine(1076) of ACIII, the only residue responsible for Ca(2+)-induced phosphorylation and inhibition of ACIII (Wei et al., 1996, 1998), to alanine in mice. Immunohistochemistry and Western blot analysis showed that the mutation affects neither the cilial localization nor the expression level of ACIII in OSNs. Electroolfactogram analysis showed no differences in the responses between wild-type and mutant mice to single-pulse odorant stimulations or in several stimulation paradigms for adaptation. These results suggest that phosphorylation of ACIII on serine(1076) plays a far less important role in olfactory response attenuation than previously thought.


Assuntos
Adenilil Ciclases/metabolismo , Nervo Olfatório/enzimologia , Serina/genética , Olfato/genética , Adenilil Ciclases/genética , Sequência de Aminoácidos , Animais , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Dados de Sequência Molecular , Nervo Olfatório/metabolismo , Fosforilação/genética
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