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16, 95% CI 1.08-1.24 in 2017). Non-Hispanic black (RR = 1.67, 95% CI 1.47-1.90 in 2013; RR = 1.16, 95% CI 1.00-1.35 in 2017) and Hispanic (RR = 1.30, 95% CI 1.17-1.44 in 2013; RR = 1.22, 95% CI 1.09-1.36 in 2017) mothers with self-payment had a higher risk for infant mortality than those with Medicaid at delivery. Newborns whose mothers have no health insurance would be more vulnerable to infant mortality than Medicaid beneficiaries, and non-white ethnic groups with self-payment would have an elevated risk of infant mortality among other racial and ethnic groups.The Director-General of the World Health Organization has called for global action towards elimination of cervical cancer as a public health problem. Cervical cancer is caused by human papillomavirus (HPV), an infectious agent with no non-human reservoir. One way to achieve this is through very high levels of vaccine coverage that could enable global eradication of vaccine-type HPV. Using the case study of India, we show that HPV eradication can meet all the Dahlem and Strüngmann criteria for feasibility of eradication. It can be achieved with 90% gender-neutral HPV vaccine coverage together with 95% coverage in high-risk groups such as female sex workers. Such a strategy would likely be cost-effective compared to no vaccination. Although it would be more costly in the short-term than achieving cervical cancer elimination alone, it would save costs in the long-term by removing or at least sharply reducing the need for preventive measures.Three-dimensional skin models, also named 3D skin models, human skin equivalents (HSEs), or Human Epidermal Equivalents (HEEs), have been increasingly used for chemical assessments in terms of efficacy and safety. Considering this, we developed an HEE model using immortalized HaCaT cells, aiming to overcome the limitation of primary tissue source. Our 3D model (HaCaT-HEE) exhibited important markers of cell differentiation (CK10, CK14, involucrin, and filaggrin), although the stratum corneum was shown to be modest. Besides, the model showed a good prediction potential considering membrane permeability, sensitivity, specificity, and accuracy in distinguishing irritant and corrosive effects after exposure to selected chemicals recommended by the OECD protocols. We also validated the formazan determination for the MTT method using High-Performance Liquid Chromatography (HPLC). For that, we considered carry over, linearity, reproducibility/robustness, accuracy, precision, selectivity, and matrix effect, according to the Food and Drug Administration (FDA) guideline. Based on our results, we can conclude that our model has an acceptable predictive value for the safety evaluation of compounds after skin exposure, with the great advantage of being constructed using immortalized cells.During mammalian corticogenesis, Notch signaling is essential to maintain neural stem cells called radial glial cells (RGCs) and the cortical architecture. Because the conventional knockout of either Notch1 or Notch2 causes a neuroepithelial loss prior to neurogenesis, their functional relationship in RGCs remain elusive. Here, we investigated the impacts of single knockout of Notch1 and Notch2 genes, and their conditional double knockout (DKO) on mouse corticogenesis. We demonstrated that Notch1 single knockout affected RGC maintenance in early to mid-neurogenesis whereas Notch2 knockout caused no apparent defect. In contrast, Notch2 plays a role in the RGC maintenance as Notch1 does at the late stage. Notch1 and Notch2 DKO resulted in the complete loss of RGCs, suggesting their cooperative function. We found that Notch activity in RGCs depends on the Notch gene dosage irrespective of Notch1 or Notch2 at late neurogenic stage, and that Notch1 and Notch2 have a similar activity, most likely due to a drastic increase in Notch2 transcription. Our results revealed that Notch1 has an essential role in establishing the RGC pool during the early stage, whereas Notch1 and Notch2 subsequently exhibit a comparable function for RGC maintenance and neurogenesis in the late neurogenic period in the mouse telencephalon.Developmental neurite pruning is a process by which neurons selectively eliminate unnecessary processes of axons and/or dendrites without cell death, which shapes the mature wiring of nervous systems. In this sense, developmental neurite pruning requires spatiotemporally precise control of local degradation of cellular components including cytoskeletons and membranes. The Drosophila nervous system undergoes large-scale remodeling, including axon/dendrite pruning, during metamorphosis. In addition to this unique phenomenon in the nervous system, powerful genetic tools make the Drosophila nervous system a sophisticated model to investigate spatiotemporal regulation of neural remodeling. This article reviews recent advances to our understanding of the molecular and cellular mechanisms of developmental axon/dendrite pruning, mainly focusing on studies in Drosophila sensory neurons and mushroom body neurons.The cerebral cortex has complex yet perfectly wired neuronal circuits that are important for high-level brain functions such as perception and cognition. The rodent's somatosensory system is widely used for understanding the mechanisms of circuit formation during early developmental periods. In this review, we summarize the developmental processes of circuit formation in layer 4 of the somatosensory cortex, and we describe the molecules involved in layer 4 circuit formation and neuronal activity-dependent mechanisms of circuit formation. We also introduce the dynamic mechanisms of circuit formation in layer 4 revealed by intravital two-photon imaging technologies, which include time-lapse imaging of neuronal morphology and calcium imaging of neuronal activity in newborn mice.Environmental factors in early life interact with genetics to exert a long-lasting and broad influence on health and disease. There has been a marked growth in the number of environmental factors studied in association with neurodevelopmental disorders. Colonization of the gut microbiota in the offspring uses the maternal resident flora as a primary source of bacteria during perinatal periods. Several lines of evidence have shown that various environmental factors including the mode of delivery, exposure to antibiotics, infection, stress, diet, quality of breast milk, and type of infant-feeding during the perinatal periods can perturb the gut microbiota colonization in the offspring, finally leading to disturbances in brain development. This study proposes that the gut microbiota seeded primarily by maternal microbiota, and the postnatal colonization of the microbiota in the offspring can be critical action points of environmental factors when deciphering the mechanisms of actions of environmental factors in brain development. This research reviews the inheritance and colonization of the microbiota during early life and the potential actions of the environmental factors influencing brain development in the offspring by modulating the vertical transmission of gut microbiota.The pathological form of a-synuclein (a-syn) is transmitted through neural circuits in the brains of Parkinson disease (PD) patients and amplifies misfolded a-syn, further forming intracellular deposits. However, the details of a-syn pre-formed fibrils (PFFs) transmission in vivo have not been fully elucidated. By inoculating Quantum dots (QD)-labeled a-syn PFFs (QD-a-syn PFFs) into the unilateral striatum, we detected QD-a-syn PFFs in brain homogenates obtained from the ipsilateral and contralateral sides of the inoculated site and further obtained QD-a-syn PFFs enriched-particles with fluorescence-activated organelle sorting. Proteomic analysis suggested that QD-a-syn PFFs-enriched particles in the contralateral side were associated with component proteins of synapse. In contrast, QD-a-syn PFFs-enriched particles in the ipsilateral side were associated with proteins belonging to ER components. Immunostaining of brain sections confirmed that QD-a-syn PFFs in the contralateral side were co-localized with synaptic vesicle marker proteins in the cortex and striatum. Additionally, QD-a-syn PFFs in the ipsilateral side were more co-localized with ER marker proteins compared to the contralateral side. These results correspond to proteomic analysis. This study provides potential candidates for the subcellular localization of a-syn PFFs in vivo during the dissemination phase of seeds. These subcellular compartments could be involved in the transmission of seeds.Pioglitazone (PGZ), a PPARγ agonist, has been used for diabetic patients as an insulin-sensitizing agent. NVP-CGM097 order Recent studies have demonstrated that PGZ increases adiponectin (APN) levels and provides vascular protection in ischemic conditions. This study was designed to assess the neuroprotective effects of PGZ against cerebral ischemia-reperfusion injury via an APN-related mechanism. Type 2 diabetic leptin-deficient mice (db/db) were administered PGZ for 1 week, and plasma insulin and APN levels were measured. These mice received a middle cerebral artery occlusion and reperfusion injury, and they were evaluated for the infarct volume and by immunohistochemistry and western blotting analysis at several time points after ischemia. PGZ-administered db/db mice showed improved insulin sensitivity, and the hemorrhagic rate and infarct volume were decreased (P less then 0.05). In the PGZ-administered group, plasma APN levels increased compared with the vehicle group. In the db/db group, PGZ administration significantly suppressed inflammatory reactions and oxidative stress after reperfusion (P less then 0.05). PGZ may be applicable for acute cerebral ischemia treatment in metabolic syndrome patients as well as antidiabetic agents.Aging is a complex process that can be characterized by functional and cognitive decline in an individual. Aging can be assessed based on the functional capacity of vital organs and their intricate interactions with one another. Thus, the nature of aging can be described by focusing on a specific organ and an individual itself. However, to fully understand the complexity of aging, one must investigate not only a single tissue or biological process but also its complex interplay and interdependencies with other biological processes. Here, using RNA-seq, we monitored changes in the transcriptome during aging in four tissues (including brain, blood, skin and liver) in mice at 9 months, 15 months, and 24 months, with a final evaluation at the very old age of 30 months. We identified several genes and processes that were differentially regulated during aging in both tissue-dependent and tissue-independent manners. Most importantly, we found that the electron transport chain (ETC) of mitochondria was similarly affected at the transcriptome level in the four tissues during the aging process. We also identified the liver as the tissue showing the largest variety of differentially expressed genes (DEGs) over time. Lcn2 (Lipocalin-2) was found to be similarly regulated among all tissues, and its effect on longevity and survival was validated using its orthologue in Caenorhabditis elegans. Our study demonstrated that the molecular processes of aging are relatively subtle in their progress, and the aging process of every tissue depends on the tissue's specialized function and environment. Hence, individual gene or process alone cannot be described as the key of aging in the whole organism.