The developing brain is highly sensitive to methylmercury (MeHg). Still, the initial changes in cell proliferation that may contribute to long-term MeHg effects are largely undefined. Our previous studies with growth factors indicate that acute alterations of G1/S phase transition can permanently affect cell numbers and organ size. Therefore, we determined whether an environmental toxicant could also impact brain development with rapid (6-7h) effects on DNA synthesis and cell cycle machinery in neuronal precursors. In vivo studies in newborn rat hippocampus and cerebellum, two regions of postnatal neurogenesis, were followed by in vitro analysis of two precursor models, cortical and cerebellar cells, focusing on the proteins that regulate G1/S transition. In postnatal day 7 (P7) pups, a single subcutaneous injection of MeHg (3μg/g) acutely (7h) decreased DNA synthesis in the hippocampus by 40% and produced long-term (2 weeks) reductions in total cell number, estimated by DNA quantification. Surprisingly, cerebellar granule cells were resistant to MeHg effects in vivo at comparable tissue concentrations, suggesting region-specific differences in precursor populations. In vitro, MeHg altered proliferation and cell viability, with DNA synthesis selectively inhibited at an early timepoint (6h) corresponding to our in vivo observations. Considering that G1/ S regulators are targets of exogenous signals, we used a well-defined cortical cell model to examine MeHg effects on relevant cyclin dependent kinases (CDK) and CDK inhibitors. At 6h, MeHg decreased by 75% levels of cyclin E, a cell cycle regulator with roles in proliferation and apoptosis, without altering p57, p27, or CDK2 nor levels of activated caspase 3. In aggregate, our observations identify the G1/S transition as an early target of MeHg toxicity and raise the possibility that cyclin E degradation contributes to both decreased proliferation and eventual cell death.

Generation of distinct cell types and numbers in developing cerebral cortex is subject to regulation by extracellular factors that positively or negatively control precursor proliferation. Although signals stimulating proliferation are well described, factors halting cell cycle progression are less well defined. At the molecular level, production and association of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors (CKIs) regulate cycle progression. We now report that the endogenous peptide, pituitary adenylate cyclase activating polypeptide (PACAP), negatively regulates the cell cycle by inhibiting p57Kip2-dependent CDK2 activity in embryonic cortex. Protein levels of CDK2 and members of the CIP/KIP family of CKIs (p27Kip1, p57Kip2) were detected in developing rat cortex from embryonic day 13.5 through postnatal day 2. With advancing development, CDK2 protein levels decreased, whereas CKI expression increased, suggesting that stimulatory and inhibitory cycle proteins control cell cycle exit. Using a well defined, nonsynchronized, 8 hr precursor culture, PACAP decreased the fraction of cells crossing the G1/S boundary, inhibiting DNA synthesis by 35%. CDK2 kinase activity was inhibited 75% by PACAP, whereas kinase protein and its regulatory cyclin E subunit were unaffected. Moreover, decreased kinase activity was accompanied by a twofold increase in levels of p57Kip2 protein, but not p21Cip1 or p27Kip1, suggesting that p57Kip2 mediates PACAP anti-mitogenic effects. Indeed, immunoprecipitation of CDK2 complex revealed increased p57Kip2 association with the kinase and concomitant reduction in free inhibitor after PACAP exposure, suggesting that p57Kip2 interactions directly regulate CDK2 activity. These observations establish a mechanism whereby anti-mitogenic signals actively induce cell cycle withdrawal in developing cortex.

Automatically predicting age group and gender from face images acquired in unconstrained conditions is an important and challenging task in many real-world applications. Nevertheless, the conventional methods with manually-designed features on in-the-wild benchmarks are unsatisfactory because of incompetency to tackle large variations in unconstrained images. This difficulty is alleviated to some degree through Convolutional Neural Networks (CNN) for its powerful feature representation. In this paper, we propose a new CNN based method for age group and gender estimation leveraging Residual Networks of Residual Networks (RoR), which exhibits better optimization ability for age group and gender classification than other CNN architectures. Moreover, two modest mechanisms based on observation of the characteristics of age group are presented to further improve the performance of age estimation. In order to further improve the performance and alleviate overfitting problem, RoR model is pre-trained on ImageNet firstly, and then it is fune-tuned on the IMDB-WIKI-101 data set for further learning the features of face images, finally, it is used to fine-tune on Adience data set. Our experiments illustrate the effectiveness of RoR method for age and gender estimation in the wild, where it achieves better performance than other CNN methods. Finally, the RoR-152+IMDB-WIKI-101 with two mechanisms achieves new state-of-the-art results on Adience benchmark.

Cell adhesion and morphology are affected by the mechanical properties of the extracellular matrix. Using polyacrylamide gels as cell substrates, the cellular response to substrate compliance was investigated in pure neuronal, pure astroglial, or mixed co-cultures. Substrates used spanned a large range of stiffnesses including that of brain tissue. In both pure and mixed cultures, immature (vimentin+) astroglia adhered best to stiffest gels. Mature (GFAP+) astrocyte adhesion peaked on intermediate stiffness, while pure GFAP+ astroglial adhesion displayed no intermediate preference and increased with stiffness. Neurite length was constant with stiffness; however, primary dendrite number was lowest on intermediate gels. Pure neuronal cultures were more adherent to hard gels, while mixed cultures had no stiffness preference. Furthermore, we investigated the role of stiffness in the modulation of the neurotoxic effect of glutamate. Exposure to two glutamate concentrations (500 and 1000 M) of cultured spinal cord neurons induced cell death. The damage elicited by 500 m glutamate to neurons in a mixed culture of spinal cord cells is most severe on soft 300 Pa gels. The neurotoxic effect of glutamate on neurons cultured on hard gels where astrocytes are present was strongly attenuated compared with that observed on soft gels, where there is a relatively low number of astrocytes. Our data suggest that mechanical stiffness of the substrate affects the response of both neurons and astroglia, and this response is varied by interaction between the two cell types.

BackgroundThe health-related quality of life (HRQoL) of the elderly population of Yi ethnic minority, which is the seventh largest nationality in China, has been rarely reported. This study was designed to explore the HRQoL of the elderly Yi ethnicity and association between their HRQOL and functional abilities.MethodsA total of 291 Yi ethnic residents were randomly recruited from 12 rural counties in Yunnan province and divided into different age groups. Local residents in Yunnan province and the elderly from Hangzhou were enrolled as controls. The MOS 36-Item Short Form Health Survey (SF-36), activities of daily living (ADL), instrumental activities of daily living (IADL) scales were utilized to evaluate the HRQoL and functional ability. One-way ANOVA was used to statistically compare the ADL and IADL among different age groups. The influential variables on HRQOL were analyzed by multiple linear regression analysis. Pearson correlation analysis was used to analyze the association among HRQoL, ADL and IADL.ResultsThe HRQoL of the elderly Yi minority was significantly lower than those of local residents in Yunnan province and the elderly counterparts in Hangzhou. The IADL ability of the elderly Yi minority was low, whereas they could perform most items of ADL. ADL, IADL, and education level were positively associated with HRQoL, whereas age, chronic diseases, and the frequency of medication use were negatively correlated with HRQoL.ConclusionThe HRQoL and functional capacity of the elderly Yi ethnic minority were lower compared with their counterparts in Yunnan province and Hangzhou. The low level of IADL indicated that the elderly Yi participants had a high risk of cognitive impairment. Much attention should be diverted to influential factors of the HRQoL.Electronic supplementary materialThe online version of this article (doi:10.1186/s12877-017-0455-y) contains supplementary material, which is available to authorized users.

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