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1.
Genome Med ; 16(1): 75, 2024 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-38822427

RESUMO

BACKGROUND: Congenital hypopituitarism (CH) and its associated syndromes, septo-optic dysplasia (SOD) and holoprosencephaly (HPE), are midline defects that cause significant morbidity for affected people. Variants in 67 genes are associated with CH, but a vast majority of CH cases lack a genetic diagnosis. Whole exome and whole genome sequencing of CH patients identifies sequence variants in genes known to cause CH, and in new candidate genes, but many of these are variants of uncertain significance (VUS). METHODS: The International Mouse Phenotyping Consortium (IMPC) is an effort to establish gene function by knocking-out all genes in the mouse genome and generating corresponding phenotype data. We used mouse embryonic imaging data generated by the Deciphering Mechanisms of Developmental Disorders (DMDD) project to screen 209 embryonic lethal and sub-viable knockout mouse lines for pituitary malformations. RESULTS: Of the 209 knockout mouse lines, we identified 51 that have embryonic pituitary malformations. These genes not only represent new candidates for CH, but also reveal new molecular pathways not previously associated with pituitary organogenesis. We used this list of candidate genes to mine whole exome sequencing data of a cohort of patients with CH, and we identified variants in two unrelated cases for two genes, MORC2 and SETD5, with CH and other syndromic features. CONCLUSIONS: The screening and analysis of IMPC phenotyping data provide proof-of-principle that recessive lethal mouse mutants generated by the knockout mouse project are an excellent source of candidate genes for congenital hypopituitarism in children.


Assuntos
Hipopituitarismo , Camundongos Knockout , Hipófise , Hipopituitarismo/genética , Animais , Humanos , Hipófise/metabolismo , Hipófise/anormalidades , Hipófise/patologia , Camundongos , Fenótipo , Feminino , Masculino , Modelos Animais de Doenças , Sequenciamento do Exoma , Displasia Septo-Óptica/genética
2.
Elife ; 122023 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-38113081

RESUMO

Neurons coordinate their activity to produce an astonishing variety of motor behaviors. Our present understanding of motor control has grown rapidly thanks to new methods for recording and analyzing populations of many individual neurons over time. In contrast, current methods for recording the nervous system's actual motor output - the activation of muscle fibers by motor neurons - typically cannot detect the individual electrical events produced by muscle fibers during natural behaviors and scale poorly across species and muscle groups. Here we present a novel class of electrode devices ('Myomatrix arrays') that record muscle activity at unprecedented resolution across muscles and behaviors. High-density, flexible electrode arrays allow for stable recordings from the muscle fibers activated by a single motor neuron, called a 'motor unit,' during natural behaviors in many species, including mice, rats, primates, songbirds, frogs, and insects. This technology therefore allows the nervous system's motor output to be monitored in unprecedented detail during complex behaviors across species and muscle morphologies. We anticipate that this technology will allow rapid advances in understanding the neural control of behavior and identifying pathologies of the motor system.


Assuntos
Neurônios Motores , Primatas , Ratos , Camundongos , Animais , Neurônios Motores/fisiologia , Eletrodos , Fibras Musculares Esqueléticas
3.
bioRxiv ; 2023 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36865176

RESUMO

Neurons coordinate their activity to produce an astonishing variety of motor behaviors. Our present understanding of motor control has grown rapidly thanks to new methods for recording and analyzing populations of many individual neurons over time. In contrast, current methods for recording the nervous system's actual motor output - the activation of muscle fibers by motor neurons - typically cannot detect the individual electrical events produced by muscle fibers during natural behaviors and scale poorly across species and muscle groups. Here we present a novel class of electrode devices ("Myomatrix arrays") that record muscle activity at unprecedented resolution across muscles and behaviors. High-density, flexible electrode arrays allow for stable recordings from the muscle fibers activated by a single motor neuron, called a "motor unit", during natural behaviors in many species, including mice, rats, primates, songbirds, frogs, and insects. This technology therefore allows the nervous system's motor output to be monitored in unprecedented detail during complex behaviors across species and muscle morphologies. We anticipate that this technology will allow rapid advances in understanding the neural control of behavior and in identifying pathologies of the motor system.

4.
AAPS PharmSciTech ; 13(2): 661-73, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22552929

RESUMO

A stability-indicating high-performance liquid chromatography method to quantify 2-(2,4-difluorophenyl)-4,5,6,7-tetrafluoroisoindoline-1,3-dione (NSC-726796) and its three main degradation products was developed. This method was used to investigate its degradation kinetics and mechanism. The reaction follows first-order kinetics and appears to be base catalyzed with the maximum stability at pH 1. The products were identified as 2-(2,4-difluorophenylcarbamoyl)-3,4,5,6-tetrafluorobenzoic acid (NSC-749820), 2,4-difluoroaniline, and tetrafluorophthalic acid. The parent drug, NSC-726796, was also found to react with methanol and ethanol. NSC-726796 demonstrates antiangiogenic activity, however, when its degradant NSC749820 does not show antiangiogenic activity.


Assuntos
Inibidores da Angiogênese/química , Ftalimidas/química , Inibidores da Angiogênese/farmacologia , Compostos de Anilina/química , Animais , Varredura Diferencial de Calorimetria , Química Farmacêutica , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Etanol/química , Concentração de Íons de Hidrogênio , Hidrólise , Cinética , Metanol/química , Neovascularização Fisiológica/efeitos dos fármacos , Ácidos Ftálicos/química , Ftalimidas/farmacologia , Ratos , Reprodutibilidade dos Testes , Solventes/química , Tecnologia Farmacêutica/métodos , Temperatura , Técnicas de Cultura de Tecidos
5.
AAPS PharmSciTech ; 11(1): 247-52, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20151336

RESUMO

In vivo, the DNA methyltransferase inhibitor, 5-fluoro-2'-deoxycytidine (FdCyd, NSC-48006), is rapidly converted to its unwanted metabolites. Tetrahydrouridine (THU, NSC-112907), a cytidine deaminase inhibitor can block the first metabolic step in FdCyd catabolism. Clinical studies have shown that co-administration with THU can inhibit the metabolism of FdCyd. The National Cancer Institute is particularly interested in a 1:5 FdCyd/THU formulation. The purpose of this study was to investigate the in vitro pH stability of FdCyd and THU individually and in combination. A stability-indicating high-performance liquid chromatography method for the quantification of both compounds and their degradants was developed using a ZIC(R)-HILIC column. The effect of THU and FdCyd on the in vitro degradation of each other was studied as a function of pH from 1.0 to 7.4 in aqueous solutions at 37 degrees C. The degradation of FdCyd appears to be first-order and acid-catalyzed. THU equilibrates with at least one of its degradants. The combination of FdCyd and THU in solution does not affect the stability of either compound. The stability and compatibility of FdCyd and THU in the solid state at increased relative humidity and at various temperatures are also evaluated.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Tetra-Hidrouridina , Animais , Cromatografia Líquida de Alta Pressão , Desoxicitidina/análogos & derivados , Desoxicitidina/metabolismo , Cinética , Camundongos , Temperatura , Tetra-Hidrouridina/química , Tetra-Hidrouridina/metabolismo , Tetra-Hidrouridina/farmacologia , Água
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