Similar Datasets
Project description:Accumulation of DNA damage drives β-cell dysfunction, senescence, and death in Type 1 and Type 2 diabetes. While α-cell dysfunction also contributes to disease pathology, they remain remarkably resistant to senescence and cell-death. The mechanisms underlying these differential responses to diabetogenic stress, particularly differences in their DNA damage vulnerability, remain unclear. We demonstrate that replication introduces a window of genomic vulnerability in both α- and β-cells during neonatal growth, with α-cells exhibiting higher replication rates and DNA damage. We show that neonatal β-cells resolve DNA damage more efficiently during mitosis and favor error-free repair, while α-cells compensate for their higher DNA damage vulnerability through increased cellular turnover. Using mouse models of overnutrition and diabetes, we show that β-cells exhibit greater vulnerability to terminal DNA damage and impaired repair capacity under diabetogenic stress, with compensatory replication amplifying this vulnerability. We demonstrate that developmental epigenetic programs shape the differential DNA damage vulnerability of postnatal β- and α-cells. Loss of de novo DNA methyltransferase Dnmt3a in pancreatic progenitors selectively increases the DNA damage vulnerability of β-cells from neonatal growth through adulthood. Our findings uncover novel developmental mechanisms that shape the distinct DNA damage responses of postnatal β- and α-cells during growth and diabetes.
2026-03-06 | GSE315106 | GEO
Project description:Accumulation of DNA damage drives β-cell dysfunction, senescence, and death in Type 1 and Type 2 diabetes. While α-cell dysfunction also contributes to disease pathology, they remain remarkably resistant to senescence and cell-death. The mechanisms underlying these differential responses to diabetogenic stress, particularly differences in their DNA damage vulnerability, remain unclear. We demonstrate that replication introduces a window of genomic vulnerability in both α- and β-cells during neonatal growth, with α-cells exhibiting higher replication rates and DNA damage. We show that neonatal β-cells resolve DNA damage more efficiently during mitosis and favor error-free repair, while α-cells compensate for their higher DNA damage vulnerability through increased cellular turnover. Using mouse models of overnutrition and diabetes, we show that β-cells exhibit greater vulnerability to terminal DNA damage and impaired repair capacity under diabetogenic stress, with compensatory replication amplifying this vulnerability. We demonstrate that developmental epigenetic programs shape the differential DNA damage vulnerability of postnatal β- and α-cells. Loss of de novo DNA methyltransferase Dnmt3a in pancreatic progenitors selectively increases the DNA damage vulnerability of β-cells from neonatal growth through adulthood. Our findings uncover novel developmental mechanisms that shape the distinct DNA damage responses of postnatal β- and α-cells during growth and diabetes.
2026-03-06 | GSE315104 | GEO
Project description:Developmental control of DNA damage responses in α- and β-cells shapes the selective beta-cell susceptibility in diabetes
| PRJNA1406183 | ENA
Project description:Developmental control of DNA damage responses in α- and β-cells shapes the selective beta-cell susceptibility in diabetes [RNA-Seq]
| PRJNA1395002 | ENA
Project description:Developmental control of DNA damage responses in α- and β-cells shapes the selective beta-cell susceptibility in diabetes [scRNA-Seq]
| PRJNA1395009 | ENA
Project description:The stereo correspondence problem poses a challenge to visual neurons because localized receptive fields potentially cause false responses. Neurons in the primary visual cortex (V1) partially resolve this problem by combining excitatory and suppressive responses to encode binocular disparity. We explored the time course of this combination in awake, monkey V1 neurons using subspace mapping of receptive fields. The stimulus was a binocular noise pattern constructed from discrete spatial frequency components. We forward correlated the firing of the V1 neuron with the occurrence of binocular presentations of each spatial frequency component. The forward correlation yielded a complete set of response time courses to every combination of spatial frequency and interocular phase difference. Some combinations produced suppressive responses. Typically, if an interocular phase difference for a given spatial frequency produced strong excitation, we saw suppression in response to the opposite interocular phase difference at lower spatial frequencies. The suppression was delayed relative to the excitation, with a median difference in latency of 7 ms. We found that the suppressive mechanism explains a well-known mismatch of monocular and binocular signals. The suppressive components increased power at low spatial frequencies in disparity tuning, whereas they reduced the monocular response to low spatial frequencies. This long-recognized mismatch of binocular and monocular signals reflects a suppressive mechanism that helps reduce the response to false matches.
| S-EPMC4044366 | biostudies-literature
Project description:The mTOR pathway integrates both extracellular and intracellular signals and serves as a central regulator of cell metabolism, growth, survival, and stress responses. Neurotropic viruses, such as herpes simplex virus-1 (HSV-1), also rely on cellular AKT-mTORC1 signaling to achieve viral latency. Here, we define a novel genotoxic response whereby spatially separated signals initiated by extracellular neurotrophic factors and nuclear DNA damage are integrated by the AKT-mTORC1 pathway. We demonstrate that endogenous DNA double-strand breaks (DSBs) mediated by Topoisomerase 2β-DNA cleavage complex (TOP2βcc) intermediates are required to achieve AKT-mTORC1 signaling and maintain HSV-1 latency in neurons. Suppression of host DNA-repair pathways that remove TOP2βcc trigger HSV-1 reactivation. Moreover, perturbation of AKT phosphorylation dynamics by downregulating the PHLPP1 phosphatase led to AKT mis-localization and disruption of DSB-induced HSV-1 reactivation. Thus, the cellular genome integrity and environmental inputs are consolidated and co-opted by a latent virus to balance lifelong infection with transmission.
| S-EPMC6499694 | biostudies-literature
Project description:Developmental sensory experience is critical to the tuning of sensory systems and can shape perceptual abilities and their neural substrates. Neuromodulators, including catecholamines, contribute to sensory plasticity in both older and younger individuals and provide a mechanism for translating sensory experience into changes in brain and behavior. Less well known, however, is whether developmental sensory experience has lasting effects on the neuromodulatory neurons themselves. Here, we used female zebra finches to investigate the degree to which developmental auditory experience can have lasting effects on the density and sensory responsiveness of catecholamine-synthesizing neuron populations. We found that hearing courtship, but not non-courtship, song increased expression of the activity-dependent immediate early gene cFOS in dopamine neurons of the caudal ventral tegmental area (VTA) and this increase was dependent on whether females heard adult song during development. Developmental song exposure also affected the density of dopamine producing neurons in the rostral VTA. In contrast, song-evoked responses in noradrenergic neurons of the Locus Coeruleus were not affected by either developmental song exposure or the social context of the stimulus. These data highlight the lasting effects that developmental auditory experience can have in shaping both the density and sensory responsiveness of dopamine neuron populations.
| S-EPMC6079043 | biostudies-literature
Project description:Lung cancer sequencing efforts have uncovered mutational signatures that are attributed to exposure to the cigarette smoke carcinogen benzo[a]pyrene. Benzo[a]pyrene metabolizes in cells to benzo[a]pyrene diol epoxide (BPDE) and reacts with guanine nucleotides to form bulky BPDE adducts. These DNA adducts block transcription and replication, compromising cell function and survival, and are repaired in human cells by the nucleotide excision repair pathway. Here, we applied high-resolution genomic assays to measure BPDE-induced damage formation and mutagenesis in human cells. We integrated the new damage and mutagenesis data with previous repair, DNA methylation, RNA expression, DNA replication, and chromatin component measurements in the same cell lines, along with lung cancer mutagenesis data. BPDE damage formation is significantly enhanced by DNA methylation and in accessible chromatin regions, including transcribed and early-replicating regions. Binding of transcription factors is associated primarily with reduced, but also enhanced damage formation, depending on the factor. While DNA methylation does not appear to influence repair efficiency, this repair was significantly elevated in accessible chromatin regions, which accumulated fewer mutations. Thus, when damage and repair drive mutagenesis in opposing directions, the final mutational patterns appear to be dictated by the efficiency of repair rather than the frequency of underlying damages.
| S-EPMC11811737 | biostudies-literature
Project description:We report a simple method for the highly regio- and stereoselective hydrolysis of α,β-epoxyalcohols. Treatment of enantiopure epoxyalcohols derived from Sharpless epoxidation with TBAF/H(2)O resulted in exclusive ring opening at the normally disfavored α-position, providing access to arabino- or lyxo-configured triols with full preservation of stereochemical purity. The method was applied in syntheses of 5-deoxy-l-arabinose (26) and a family of bicyclic acetals based on the insect pheromone hydroxybrevicomin (4).
| S-EPMC2937070 | biostudies-literature