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1.
Nat Commun ; 11(1): 4618, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934233

RESUMO

The identification of genes and interventions that slow or reverse aging is hampered by the lack of non-invasive metrics that can predict the life expectancy of pre-clinical models. Frailty Indices (FIs) in mice are composite measures of health that are cost-effective and non-invasive, but whether they can accurately predict health and lifespan is not known. Here, mouse FIs are scored longitudinally until death and machine learning is employed to develop two clocks. A random forest regression is trained on FI components for chronological age to generate the FRIGHT (Frailty Inferred Geriatric Health Timeline) clock, a strong predictor of chronological age. A second model is trained on remaining lifespan to generate the AFRAID (Analysis of Frailty and Death) clock, which accurately predicts life expectancy and the efficacy of a lifespan-extending intervention up to a year in advance. Adoption of these clocks should accelerate the identification of longevity genes and aging interventions.


Assuntos
Envelhecimento/fisiologia , Camundongos/fisiologia , Envelhecimento/genética , Animais , Relógios Biológicos , Feminino , Fragilidade , Humanos , Expectativa de Vida , Aprendizado de Máquina , Masculino , Camundongos/genética , Camundongos/crescimento & desenvolvimento , Camundongos Endogâmicos C57BL
2.
Anim Sci J ; 91(1): e13395, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32484296

RESUMO

This study aimed to investigate the effects of whey protein hydrolysate (WPH) on the growth and immunity of mouse pups in artificial rearing (AR) system. Mouse pups were reared in the AR system with artificial milk including 5% WPH (AR with WPH) or not (AR without WPH), and the remaining pups were reared by their mother (dam) for 14 days after birth. The body weight change and body weight gain rates in the AR with WPH group were significantly higher than those observed in the AR without WPH group and similar to those in the dam group. Moreover the feed and protein efficiencies in the AR with WPH group were significantly higher than those of the AR without WPH group. In addition, the supplement of WPH in the AR system was shown to significantly elevate the number of CD3+ CD8+ , B220+ CD19+ , IA/IE+ CD11c+ , and CD11b+ in the thymocyte and/or splenocyte, and the thymus weight. Furthermore, MALDI-TOF/MS analysis identified the amino acid sequences corresponding to some peptides, and indicated that VRTPEVDDE had the highest relative intensity among the peptides from tested WPH. Therefore, WPH would be required to not only promote growth, but also exert immunomodulatory activities in mouse pups in AR system.


Assuntos
Ração Animal , Criação de Animais Domésticos/métodos , Fenômenos Fisiológicos da Nutrição Animal/efeitos dos fármacos , Dieta/veterinária , Imunomodulação/efeitos dos fármacos , Camundongos/crescimento & desenvolvimento , Camundongos/imunologia , Hidrolisados de Proteína/farmacologia , Proteínas do Soro do Leite , Animais , Antígenos CD/metabolismo , Suplementos Nutricionais , Hidrolisados de Proteína/administração & dosagem , Baço/metabolismo , Timócitos/metabolismo
3.
Curr Biol ; 29(23): 4024-4035.e5, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31708397

RESUMO

Detection of ambient illumination in the developing retina prior to maturation of conventional photoreceptors is mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs) and is critical for driving several physiological processes, including light aversion, pupillary light reflexes, and photoentrainment of circadian rhythms. The strategies by which ipRGCs encode variations in ambient light intensity at these early ages are not known. Using unsupervised clustering of two-photon calcium responses followed by inspection of anatomical features, we found that the population activity of the neonatal retina could be modeled as six functional groups that were composed of mixtures of ipRGC subtypes and non-ipRGC cell types. By combining imaging, whole-cell recording, pharmacology, and anatomical techniques, we found that functional mixing of cell types is mediated in part by gap junction coupling. Together, these data show that both cell-autonomous intrinsic light responses and gap junction coupling among ipRGCs contribute to the proper encoding of light intensity in the developing retina.


Assuntos
Junções Comunicantes/metabolismo , Camundongos/fisiologia , Células Fotorreceptoras de Vertebrados/metabolismo , Retina/crescimento & desenvolvimento , Células Ganglionares da Retina/fisiologia , Animais , Feminino , Masculino , Camundongos/crescimento & desenvolvimento
4.
Curr Biol ; 29(21): 3588-3599.e4, 2019 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-31630949

RESUMO

The topographic map in layer 4 of somatosensory cortex is usually specified early postnatally and stable thereafter. Genital cortex, however, undergoes a sex-hormone- and sexual-touch-dependent pubertal expansion. Here, we image pubertal development of genital cortex in Scnn1a-Tg3-Cre mice, where transgene expression has been shown to be restricted to layer 4 neurons with primary sensory cortex identity. Interestingly, during puberty, the number of Scnn1a+ neurons roughly doubled within genital cortex. The increase of Scnn1a+ neurons was gradual and rapidly advanced by initial sexual experience. Neurons that gained Scnn1a expression comprised stellate and pyramidal neurons in layer 4. Unlike during neonatal development, pyramids did not retract their apical dendrites during puberty. Calcium imaging revealed stronger genital-touch responses in Scnn1a+ neurons in males versus females and a developmental increase in responsiveness in females. The first sexual interaction is a unique physical experience that often creates long-lasting memories. We suggest such experience uniquely alters somatosensory body maps.


Assuntos
Camundongos/fisiologia , Comportamento Sexual Animal , Maturidade Sexual , Córtex Somatossensorial/fisiologia , Animais , Cálcio , Feminino , Masculino , Camundongos/crescimento & desenvolvimento , Microscopia de Fluorescência por Excitação Multifotônica
5.
PLoS One ; 14(8): e0220879, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31404099

RESUMO

A common feature of preclinical animal experiments is repeated measurement of the outcome, e.g., body weight measured in mice pups weekly for 20 weeks. Separate time point analysis or repeated measures analysis approaches can be used to analyze such data. Each approach requires assumptions about the underlying data and violations of these assumptions have implications for estimation of precision, and type I and type II error rates. Given the ethical responsibilities to maximize valid results obtained from animals used in research, our objective was to evaluate approaches to reporting repeated measures design used by investigators and to assess how assumptions about variation in the outcome over time impact type I and II error rates and precision of estimates. We assessed the reporting of repeated measures designs of 58 studies in preclinical animal experiments. We used simulation modelling to evaluate three approaches to statistical analysis of repeated measurement data. In particular, we assessed the impact of (a) repeated measure analysis assuming that the outcome had non-constant variation at all time points (heterogeneous variance) (b) repeated measure analysis assuming constant variation in the outcome (homogeneous variance), (c) separate ANOVA at individual time point in repeated measures designs. The evaluation of the three model fitting was based on comparing the p-values distributions, the type I and type II error rates and by implication, the shrinkage or inflation of standard error estimates from 1000 simulated dataset. Of 58 studies with repeated measures design, three provided a rationale for repeated measurement and 23 studies reported using a repeated-measures analysis approach. Of the 35 studies that did not use repeated-measures analysis, fourteen studies used only two time points to calculate weight change which potentially means collected data was not fully utilized. Other studies reported only select time points (n = 12) raising the issue of selective reporting. Simulation studies showed that an incorrect assumption about the variance structure resulted in modified error rates and precision estimates. The reporting of the validity of assumptions for repeated measurement data is very poor. The homogeneous variation assumption, which is often invalid for body weight measurements, should be confirmed prior to conducting the repeated-measures analysis using homogeneous covariance structure and adjusting the analysis using corrections or model specifications if this is not met.


Assuntos
Experimentação Animal , Experimentação Animal/normas , Experimentação Animal/estatística & dados numéricos , Animais , Animais Recém-Nascidos/crescimento & desenvolvimento , Peso Corporal , Confiabilidade dos Dados , Interpretação Estatística de Dados , Camundongos/crescimento & desenvolvimento , Modelos Estatísticos , Reprodutibilidade dos Testes , Fatores de Tempo
6.
Epilepsia ; 60(7): 1424-1437, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31158310

RESUMO

OBJECTIVE: Glutamate-gated N-methyl-d-aspartate receptors (NMDARs) are instrumental to brain development and functioning. Defects in the GRIN2A gene, encoding the GluN2A subunit of NMDARs, cause slow-wave sleep (SWS)-related disorders of the epilepsy-aphasia spectrum (EAS). The as-yet poorly understood developmental sequence of early EAS-related phenotypes, and the role of GluN2A-containing NMDARs in the development of SWS and associated electroencephalographic (EEG) activity patterns, were investigated in Grin2a knockout (KO) mice. METHODS: Early social communication was investigated by ultrasonic vocalization (USV) recordings; the relationship of electrical activity of the cerebral cortex with SWS was studied using deep local field potential or chronic EEG recordings at various postnatal stages. RESULTS: Grin2a KO pups displayed altered USV and increased occurrence of high-voltage spindles. The pattern of slow-wave activity induced by low-dose isoflurane was altered in Grin2a KO mice in the 3rd postnatal week and at 1 month of age. These alterations included strong suppression of the delta oscillation power and an increase in the occurrence of the spike-wave bursts. The proportion of SWS and the sleep quality were transiently reduced in Grin2a KO mice aged 1 month but recovered by the age of 2 months. Grin2a KO mice also displayed spontaneous spike-wave discharges, which occurred nearly exclusively during SWS, at 1 and 2 months of age. SIGNIFICANCE: The impaired vocal communication, the spike-wave discharges occurring almost exclusively in SWS, and the age-dependent alteration of SWS that were all seen in Grin2a KO mice matched the sleep-related and age-dependent manifestations seen in children with EAS, hence validating the Grin2a KO as a reliable model of EAS disorders. Our data also show that GluN2A-containing NMDARs are involved in slow-wave activity, and that the period of postnatal brain development (postnatal day 30) when several anomalies peaked might be critical for GluN2A-dependent, sleep-related physiological and pathological processes.


Assuntos
Receptores de N-Metil-D-Aspartato/fisiologia , Sono de Ondas Lentas/fisiologia , Sono/fisiologia , Vocalização Animal , Animais , Animais Recém-Nascidos/fisiologia , Eletroencefalografia , Feminino , Masculino , Camundongos/crescimento & desenvolvimento , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de N-Metil-D-Aspartato/metabolismo , Vocalização Animal/fisiologia
7.
Integr Comp Biol ; 59(5): 1369-1381, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31199435

RESUMO

Allometry refers to the ways in which organismal shape is associated with size. It is a special case of integration, or the tendency for traits to covary, in that variation in size is ubiquitous and evolutionarily important. Allometric variation is so commonly observed that it is routinely removed from morphometric analyses or invoked as an explanation for evolutionary change. In this case, familiarity is mistaken for understanding because rarely do we know the mechanisms by which shape correlates with size or understand their significance. As with other forms of integration, allometric variation is generated by variation in developmental processes that affect multiple traits, resulting in patterns of covariation. Given this perspective, we can dissect the genetic and developmental determinants of allometric variation. Our work on the developmental and genetic basis for allometric variation in craniofacial shape in mice and humans has revealed that allometric variation is highly polygenic. Different measures of size are associated with distinct but overlapping patterns of allometric variation. These patterns converge in part on a common genetic basis. Finally, environmental modulation of size often generates variation along allometric trajectories, but the timing of genetic and environmental perturbations can produce deviations from allometric patterns when traits are differentially sensitive over developmental time. These results question the validity of viewing allometry as a singular phenomenon distinct from morphological integration more generally.


Assuntos
Evolução Biológica , Tamanho Corporal , Camundongos/crescimento & desenvolvimento , Fenótipo , Crânio/crescimento & desenvolvimento , Animais , Humanos , Camundongos/anatomia & histologia , Camundongos/genética , Crânio/anatomia & histologia
8.
Philos Trans R Soc Lond B Biol Sci ; 374(1770): 20180116, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30966886

RESUMO

Animal models have been indispensable in elucidating the potential causative mechanisms underlying the effects of maternal diet on offspring health. Of these, the mouse has been widely used to model maternal overnutrition and/or maternal obesity and to study its effects across one or more generations. This review discusses recent findings from mouse models, which resemble the human situation, i.e. overnutrition/obesity across pregnancy and lactation. It also highlights the importance of embryo transfer models in identifying critical developmental period(s) during which specific metabolic changes are programmed in the offspring. The mouse is also an excellent tool for maternal intervention studies aimed at elucidating the longer-term effects on the offspring and for defining possible maternal factors underling the programming of metabolic adversity in offspring. While knowledge of the mouse genome and the molecular tools available have allowed great progress to be made in the field, it is clear that we need to define if the effects on the offspring are mediated by maternal obesity per se or if specific components of the maternal metabolic environment are more important. We can then begin to identify at-risk offspring and to design more effective interventions for the mother and/or her child. This article is part of the theme issue 'Developing differences: early-life effects and evolutionary medicine'.


Assuntos
Herança Materna/fisiologia , Camundongos/fisiologia , Estado Nutricional/fisiologia , Hipernutrição/fisiopatologia , Animais , Feminino , Lactação , Camundongos/embriologia , Camundongos/crescimento & desenvolvimento , Gravidez
9.
Curr Biol ; 29(7): 1149-1160.e4, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30905607

RESUMO

The existence of axons extending from one retina to the other has been reported during perinatal development in different vertebrates. However, it has been thought that these axons are either a labeling artifact or misprojections. Here, we show unequivocally that a small subset of retinal ganglion cells (RGCs) project to the opposite retina and that the guidance receptor Unc5c, expressed in the retinal region where the retinal-retinal (R-R) RGCs are located, is necessary and sufficient to guide axons to the opposite retina. In addition, Netrin1, an Unc5c ligand, is expressed in the ventral diencephalon in a pattern that is consistent with impeding the growth of Unc5c-positive retinal axons into the brain. We also have generated a mathematical model to explore the formation of retinotopic maps in the presence and absence of a functional connection between both eyes. This model predicts that an R-R connection is required for the bilateral coordination of axonal refinement in species where refinement depends upon spontaneous retinal waves. Consistent with this idea, the retinal expression of Unc5c correlates with the existence and size of an R-R projection in different species and with the extent of axonal refinement in visual targets. These findings demonstrate that active guidance drives the formation of the R-R projection and suggest an important role for these projections in visual mapping to ensure congruent bilateral refinement.


Assuntos
Galinhas/crescimento & desenvolvimento , Furões/crescimento & desenvolvimento , Receptores de Netrina/genética , Retina/fisiologia , Células Ganglionares da Retina/fisiologia , Vias Visuais/crescimento & desenvolvimento , Peixe-Zebra/crescimento & desenvolvimento , Animais , Camundongos/crescimento & desenvolvimento , Receptores de Netrina/metabolismo
10.
Mol Cell Biol ; 39(6)2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30642949

RESUMO

The physiological functions of the atypical mitogen-activated protein kinase extracellular signal-regulated kinase 3 (ERK3) remain poorly characterized. Previous analysis of mice with a targeted insertion of the lacZ reporter in the Mapk6 locus (Mapk6lacZ ) showed that inactivation of ERK3 in Mapk6lacZ mice leads to perinatal lethality associated with intrauterine growth restriction, defective lung maturation, and neuromuscular anomalies. To further explore the role of ERK3 in physiology and disease, we generated novel mouse models expressing a catalytically inactive (Mapk6KD ) or conditional (Mapk6Δ ) allele of ERK3. Surprisingly, we found that mice devoid of ERK3 kinase activity or expression survive the perinatal period without any observable lung or neuromuscular phenotype. ERK3 mutant mice reached adulthood, were fertile, and showed no apparent health problem. However, analysis of growth curves revealed that ERK3 kinase activity is necessary for optimal postnatal growth. To gain insight into the genetic basis underlying the discrepancy in phenotypes of different Mapk6 mutant mouse models, we analyzed the regulation of genes flanking the Mapk6 locus by quantitative PCR. We found that the expression of several Mapk6 neighboring genes is deregulated in Mapk6lacZ mice but not in Mapk6KD or Mapk6Δ mutant mice. Our genetic analysis suggests that off-target effects of the targeting construct on local gene expression are responsible for the perinatal lethality phenotype of Mapk6lacZ mutant mice.


Assuntos
Camundongos/crescimento & desenvolvimento , Proteína Quinase 6 Ativada por Mitógeno/metabolismo , Animais , Modelos Animais de Doenças , Embrião de Mamíferos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo
11.
Heredity (Edinb) ; 122(2): 150-171, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29795180

RESUMO

North Africa is now recognized as a major area for the emergence and dispersal of anatomically modern humans from at least 315 kya. The Mediterranean Basin is thus particularly suited to study the role of climate versus human-mediated changes on the evolutionary history of species. The Algerian mouse (Mus spretus Lataste) is an endemic species from this basin, with its distribution restricted to North Africa (from Libya to Morocco), Iberian Peninsula and South of France. A rich paleontological record of M. spretus exists in North Africa, suggesting hypotheses concerning colonization pathways, and the demographic and morphologic history of this species. Here we combined genetic (3 mitochondrial DNA loci and 18 microsatellites) and climatic niche modeling data to infer the evolutionary history of the Algerian mouse. We collected 646 new individuals in 51 localities. Our results are consistent with an anthropogenic translocation of the Algerian mouse from North Africa to the Iberian Peninsula via Neolithic navigators, probably from the Tingitane Peninsula. Once arrived in Spain, suitable climatic conditions would then have favored the dispersion of the Algerian mice to France. The morphological differentiation observed between Spanish, French and North African populations could be explained by a founder effect and possibly local adaptation. This article helps to better understand the role of climate versus human-mediated changes on the evolutionary history of mammal species in the Mediterranean Basin.


Assuntos
Migração Animal , Camundongos/crescimento & desenvolvimento , África do Norte , Animais , Clima , DNA Mitocondrial/genética , Europa (Continente) , Camundongos/classificação , Camundongos/genética , Camundongos/fisiologia , Repetições de Microssatélites , Filogenia , Espanha
12.
Microb Pathog ; 128: 153-161, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30583023

RESUMO

The purpose of this study was to evaluate the effects of Bacillus subtilis 18 (BS-18) isolated from free-ranging Tibetan yaks in high altitude regions of Tibet (3600 m) on growth performance and gut microbial community in mice. In this study, mice (15-day-old) were used as an animal model and raised under standard conditions. A total of 20 KM mice were divided equally into two groups: control group (feed and drink freely), experimental group (feed and drink freely + 1 × 109 CFU/day BS-18). The intestines (duodenum, jejunum, ileum, cecum) and organs (liver, spleen, kidney) were collected from all the mice at day 18 for high throughput sequencing and HE staining. During the whole experiment, the mice treated by BS-18 displayed no abnormal behavior or macroscopic lesions on dissection. Meanwhile, there were no pathological changes observed using HE staining compared with the control group. The results show that BS-18 isolated from Tibetan yaks was safe and could increase average daily gain (ADG) and reduce feed conversion ratio (FCR). Furthermore, supplementation with BS-18 could improve the mucosal morphology and the ratio of villi to crypt cells (P < 0.05 or P < 0.01). The high-throughput sequencing results showed that the abundance and diversity of duodenum and jejunum in the experimental group were higher than control group. Lactobacillus in experimental group had higher abundance than control group. In addition, the quantity of Candidatus arthromitu was increased after BS-18 intake, which is associated with immune system activity. Acinetobacter induced brain abscess and bronchopneumonia were reduced in the experimental group. In conclusion, this study demonstrated that BS-18 isolated from Tibetan yaks was safe, beneficial and had the potential to serve as a probiotic.


Assuntos
Bacillus subtilis/isolamento & purificação , Bacillus subtilis/fisiologia , Bovinos/microbiologia , Microbioma Gastrointestinal , Probióticos/uso terapêutico , Ração Animal , Animais , Bacillus subtilis/genética , Biodiversidade , Abscesso Encefálico/microbiologia , Abscesso Encefálico/terapia , Broncopneumonia/terapia , Dieta , Modelos Animais de Doenças , Feminino , Microbioma Gastrointestinal/genética , Ensaios de Triagem em Larga Escala , Mucosa Intestinal/crescimento & desenvolvimento , Mucosa Intestinal/microbiologia , Intestinos/microbiologia , Rim/patologia , Lactobacillus , Masculino , Camundongos/crescimento & desenvolvimento , Camundongos/microbiologia , Baço/patologia , Tibet
13.
Neurobiol Learn Mem ; 165: 106962, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30502397

RESUMO

Rett Syndrome (RTT) is a genetic disorder that is caused by mutations in the x-linked gene coding for methyl-CpG-biding-protein 2 (MECP2) and that mainly affects females. Male and female transgenic mouse models of RTT have been studied extensively, and we have learned a great deal regarding RTT neuropathology and how MeCP2 deficiency may be influencing brain function and maturation. In this manuscript we review what is known concerning structural and coinciding functional and behavioral deficits in RTT and in mouse models of MeCP2 deficiency. We also introduce our own corroborating data regarding behavioral phenotype and morphological alterations in volume of the cortex and striatum and the density of neurons, aberrations in experience-dependent plasticity within the barrel cortex and the impact of MeCP2 loss on glial structure. We conclude that regional structural changes in genetic models of RTT show great similarity to the alterations in brain structure of patients with RTT. These region-specific modifications often coincide with phenotype onset and contribute to larger issues of circuit connectivity, progression, and severity. Although the alterations seen in mouse models of RTT appear to be primarily due to cell-autonomous effects, there are also non-cell autonomous mechanisms including those caused by MeCP2-deficient glia that negatively impact healthy neuronal function. Collectively, this body of work has provided a solid foundation on which to continue to build our understanding of the role of MeCP2 on neuronal and glial structure and function, its greater impact on neural development, and potential new therapeutic avenues.


Assuntos
Encéfalo/crescimento & desenvolvimento , Síndrome de Rett/etiologia , Animais , Gânglios da Base/patologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Hipocampo/patologia , Humanos , Proteína 2 de Ligação a Metil-CpG/metabolismo , Camundongos/crescimento & desenvolvimento , Transtornos Motores/etiologia , Transtornos Motores/fisiopatologia , Plasticidade Neuronal , Síndrome de Rett/fisiopatologia , Síndrome de Rett/psicologia
14.
Biochim Biophys Acta Mol Basis Dis ; 1865(1): 56-62, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30343141

RESUMO

Translocator protein (TSPO) is a high-affinity cholesterol- and drug-binding mitochondrial protein. Nuclear receptor subfamily 5 group A member 1 or steroidogenic factor 1 (Nr5a1)-Cre mice were previously used to generate steroidogenic cell-specific Tspo gene conditional knockout (cKO) mice. TSPO-depleted homozygotes showed no response to adrenocorticotropic hormone (ACTH) in stimulating adrenal cortex corticosterone production but showed increased epinephrine synthesis in the medulla. No other phenotype was observed under normal growth conditions. During these studies, we noted that pairing two cKO mice resulted in the generation of small pups. These pups showed low growth rate at weaning, which has been linked to the development of type 2 diabetes (T2D) in adulthood. Experimental verification of T2D symptoms via blood testing of the adult mice, including glycated hemoglobin and insulin C-peptide measurements, showed that these Tspo cKO mice exhibited sustained hyperglycemia, a sign of prediabetes, likely due to the augmentation of hepatic glucose production mediated by the increased epinephrine. We also observed increased expression of the S100a8 gene, which is upregulated after chronic glucose stimulation. Taken together, the observed prediabetes phenotype and lack of response to ACTH indicate that Tspo cKO mice (Nr5a1-Cre+/-, Tspofl/fl) could provide a useful model to study the link between diabetes and stress.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Integrases/metabolismo , Estado Pré-Diabético/metabolismo , Receptores de GABA/metabolismo , Fator Esteroidogênico 1/metabolismo , Estresse Fisiológico , Animais , Glicemia , Calgranulina A/genética , Calgranulina A/metabolismo , Colesterol/sangue , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Glucose/metabolismo , Humanos , Hiperglicemia , Fígado/metabolismo , Masculino , Camundongos/crescimento & desenvolvimento , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Mitocondriais , Receptores de GABA/genética
15.
Medisan ; 22(9)nov.-dic. 2018. tab, ilus
Artigo em Espanhol | LILACS | ID: biblio-976174

RESUMO

Se realizó un estudio descriptivo, observacional y transversal en 160 cortes histológicos de la fascia dentada del hipocampo de ratones BALB/c y ratas Wistar blancas, en el Laboratorio de Investigaciones Biomédicas de la Universidad de Ciencias Médicas de Santiago de Cuba, de septiembre de 2013 a igual mes de 2014, con vistas a determinar las transformaciones histológicas que ocurren en dicha fascia en el segundo y sexto días posnatales. La observación microscópica de estos cortes se realizó empleando del software Image J. La extensión de la fascia al sexto día de vida llegó a ser mayor en los ratones; los máximos incrementos del grosor en ambos tipos de roedores se encontraron en el hilus, y el estrato granuloso fue de menor crecimiento en las ratas. La celularidad en los roedores presentó mayores proporciones en las tres regiones del hilus al segundo día, pero disminuyó en el sexto día, mientras que las zonas relacionadas con el hilus mantuvieron una mayor cantidad de células; sin embargo, el número celular disminuyó en ambas regiones moleculares de la fascia de las ratas.


A descriptive, observational and cross-sectional study was carried out in 160 histological cuts of the hippocampus fascia dentata from mice BALB/c and rats white Wistar, in the Laboratory of Biomedical Investigations from Santiago de Cuba Medical University, from September, 2013 to the same month in 2014, with the aim of determining the histological transformations that take place in this fascia in the second and sixth posnatal days. The microscopic observation of these cuts was carried out using the software Image J. The extension of the fascia at the sixth day of life was larger in the mice; the maximum increases of thickness in both types of rodents were in the hilus, and the granular stratum was of smaller growth in rats. The celularity in the rodents presented larger proportions in the three regions from the hilus at the second day, but it decreased at the sixth day, while the areas related to the hilus maintained a greater quantity of cells; however, the cellular number diminished in both molecular regions of the rats fascia.


Assuntos
Animais , Masculino , Feminino , Recém-Nascido , Camundongos , Ratos , Ratos Wistar/anatomia & histologia , Giro Denteado/crescimento & desenvolvimento , Camundongos/anatomia & histologia , Ratos Wistar/crescimento & desenvolvimento , Giro Denteado/anatomia & histologia , Camundongos/crescimento & desenvolvimento
16.
J Am Heart Assoc ; 7(20): e010378, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30371266

RESUMO

Background The molecular mechanisms mediating postnatal loss of cardiac regeneration in mammals are not fully understood. We aimed to provide an integrated resource of mRNA , protein, and metabolite changes in the neonatal heart for identification of metabolism-related mechanisms associated with cardiac regeneration. Methods and Results Mouse ventricular tissue samples taken on postnatal day 1 (P01), P04, P09, and P23 were analyzed with RNA sequencing and global proteomics and metabolomics. Gene ontology analysis, KEGG pathway analysis, and fuzzy c-means clustering were used to identify up- or downregulated biological processes and metabolic pathways on all 3 levels, and Ingenuity pathway analysis (Qiagen) was used to identify upstream regulators. Differential expression was observed for 8547 mRNA s and for 1199 of 2285 quantified proteins. Furthermore, 151 metabolites with significant changes were identified. Differentially regulated metabolic pathways include branched chain amino acid degradation (upregulated at P23), fatty acid metabolism (upregulated at P04 and P09; downregulated at P23) as well as the HMGCS ( HMG -CoA [hydroxymethylglutaryl-coenzyme A] synthase)-mediated mevalonate pathway and ketogenesis (transiently activated). Pharmacological inhibition of HMGCS in primary neonatal cardiomyocytes reduced the percentage of BrdU-positive cardiomyocytes, providing evidence that the mevalonate and ketogenesis routes may participate in regulating the cardiomyocyte cell cycle. Conclusions This study is the first systems-level resource combining data from genomewide transcriptomics with global quantitative proteomics and untargeted metabolomics analyses in the mouse heart throughout the early postnatal period. These integrated data of molecular changes associated with the loss of cardiac regeneration may open up new possibilities for the development of regenerative therapies.


Assuntos
Coração/crescimento & desenvolvimento , Camundongos/crescimento & desenvolvimento , Aminoácidos de Cadeia Ramificada/metabolismo , Animais , Animais Recém-Nascidos/crescimento & desenvolvimento , Ácidos Graxos/metabolismo , Expressão Gênica/fisiologia , Coração/embriologia , Ventrículos do Coração , Corpos Cetônicos/biossíntese , Metabolômica , Ácido Mevalônico/metabolismo , Proteômica , RNA Mensageiro/genética , RNA Mensageiro/fisiologia , Transcriptoma/fisiologia
17.
Curr Opin Neurobiol ; 53: 210-219, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30342228

RESUMO

The rodent whiskers are topographically mapped in brainstem sensory nuclei as neuronal modules known as barrelettes. Little is known about how the facial whisker pattern is copied into a brainstem barrelette topographic pattern, which serves as a template for the establishment of thalamic barreloid and, in turn, cortical barrel maps, and how precisely is the whisker pattern mapped in the brainstem during prenatal development. Here, we review recent insights advancing our understanding of the intrinsic and extrinsic patterning mechanisms contributing to establish topographical equivalence between the facial whisker pattern and the mouse brainstem during prenatal development and their relative importance.


Assuntos
Tronco Encefálico/crescimento & desenvolvimento , Desenvolvimento Fetal/fisiologia , Camundongos/crescimento & desenvolvimento , Células Receptoras Sensoriais/fisiologia , Gânglio Trigeminal/crescimento & desenvolvimento , Vibrissas/inervação , Animais
18.
Proc Biol Sci ; 285(1882)2018 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-30051823

RESUMO

Males are known to adjust their expenditure on testes growth and sperm production in response to sperm competition risk. Genital morphology can also contribute to competitive fertilization success but whether male genital morphology can respond plastically to the sperm competition environment has received little attention. Here, we exposed male house mice to two different sperm competition environments during their sexual development and quantified phenotypic plasticity in baculum morphology. The sperm competition environment generated plasticity in body growth. Males maturing under sperm competition risk were larger and heavier than males maturing under no sperm competition risk. We used a landmark-based geometric morphometric approach to measure baculum size and shape. Independent of variation in body size, males maintained under risk of sperm competition had a relatively thicker and more distally extended baculum bulb compared with males maintained under no sperm competition risk. Plasticity in baculum shape paralleled evolutionary responses to selection from sperm competition reported in previous studies of house mice. Our findings provide experimental evidence of socially mediated phenotypic plasticity in male genitalia.


Assuntos
Genitália Masculina/anatomia & histologia , Camundongos/crescimento & desenvolvimento , Comportamento Sexual Animal , Espermatozoides/fisiologia , Animais , Tamanho Corporal , Masculino , Camundongos/anatomia & histologia , Fenótipo , Maturidade Sexual
19.
PLoS Genet ; 14(5): e1007412, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29799838

RESUMO

The N6-methyladenosine (m6A) modification is the most prevalent internal RNA modification in eukaryotes. The majority of m6A sites are found in the last exon and 3' UTRs. Here we show that the nuclear m6A reader YTHDC1 is essential for embryo viability and germline development in mouse. Specifically, YTHDC1 is required for spermatogonial development in males and for oocyte growth and maturation in females; Ythdc1-deficient oocytes are blocked at the primary follicle stage. Strikingly, loss of YTHDC1 leads to extensive alternative polyadenylation in oocytes, altering 3' UTR length. Furthermore, YTHDC1 deficiency causes massive alternative splicing defects in oocytes. The majority of splicing defects in mutant oocytes are rescued by introducing wild-type, but not m6A-binding-deficient, YTHDC1. YTHDC1 is associated with the pre-mRNA 3' end processing factors CPSF6, SRSF3, and SRSF7. Thus, YTHDC1 plays a critical role in processing of pre-mRNA transcripts in the oocyte nucleus and may have similar non-redundant roles throughout fetal development.


Assuntos
Processamento Alternativo/genética , Camundongos/crescimento & desenvolvimento , Proteínas do Tecido Nervoso/genética , Oócitos/crescimento & desenvolvimento , Poliadenilação/genética , Fatores de Processamento de RNA/genética , Regiões 3' não Traduzidas/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , Animais , Núcleo Celular/metabolismo , Fator de Especificidade de Clivagem e Poliadenilação/metabolismo , Desenvolvimento Embrionário/genética , Éxons/genética , Feminino , Masculino , Camundongos/genética , Camundongos Transgênicos , Mutação , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/metabolismo , Oócitos/metabolismo , Precursores de RNA/genética , Fatores de Processamento de RNA/deficiência , Fatores de Processamento de RNA/metabolismo , RNA Mensageiro/genética , Fatores de Processamento de Serina-Arginina/metabolismo , Espermatogônias/crescimento & desenvolvimento , Espermatogônias/metabolismo
20.
J Agric Food Chem ; 66(11): 2925-2933, 2018 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-29470912

RESUMO

Natural halloysite (Al2Si2O5(OH)4· nH2O) nanotubes (HNT) are clay materials with hollow tubular structure and are widely applied in many fields. Many in vitro studies indicate that HNTs exhibit a high level of biocompatibility; however, the in vivo toxicity of HNTs remains unclear. In this study, the biodistribution and pulmonary toxicity of the purified HNTs in mice were investigated after intragastric administration for 30 days. HNTs have high stability in biological conditions. Oral administration of HNTs caused significant Al accumulation predominantly in the lung with relative slight effects on Si biodistribution. Oral administration of HNTs stimulated the growth of the mice at low dose (5 mg/kg BW) with no pulmonary toxicity but inhibited the mouse growth and resulted in oxidative stress and inflammation in lung at high dose (50 mg/kg BW). In addition, oral HNTs at high dose could be absorbed from the gastrointestinal tract and deposited in lung and could also induce pulmonary fibrosis.


Assuntos
Silicatos de Alumínio/metabolismo , Silicatos de Alumínio/toxicidade , Alumínio/toxicidade , Pulmão/efeitos dos fármacos , Camundongos/metabolismo , Nanotubos/toxicidade , Alumínio/metabolismo , Animais , Argila , Pulmão/metabolismo , Masculino , Camundongos/crescimento & desenvolvimento , Estresse Oxidativo , Distribuição Tecidual
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