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Project description:Epithelial surfaces form critical barriers to the outside world and are continuously renewed by adult stem cells1. Whereas dynamics of epithelial stem cells during homeostasis are increasingly well understood, how stem cells are redirected from a tissue-maintenance program to initiate repair after injury remains unclear. Here we examined infection by Heligmosomoides polygyrus, a co-evolved pathosymbiont of mice, to assess the epithelial response to disruption of the mucosal barrier. H. polygyrus disrupts tissue integrity by penetrating the duodenal mucosa, where it develops while surrounded by a multicellular granulomatous infiltrate2. Crypts overlying larvae-associated granulomas did not express intestinal stem cell markers, including Lgr53, in spite of continued epithelial proliferation. Granuloma-associated Lgr5- crypt epithelium activated an interferon-gamma (IFN-γ)-dependent transcriptional program, highlighted by Sca-1 expression, and IFN-γ-producing immune cells were found in granulomas. A similar epithelial response accompanied systemic activation of immune cells, intestinal irradiation, or ablation of Lgr5+ intestinal stem cells. When cultured in vitro, granuloma-associated crypt cells formed spheroids similar to those formed by fetal epithelium, and a sub-population of H. polygyrus-induced cells activated a fetal-like transcriptional program, demonstrating that adult intestinal tissues can repurpose aspects of fetal development. Therefore, re-initiation of the developmental program represents a fundamental mechanism by which the intestinal crypt can remodel itself to sustain function after injury.
| S-EPMC6042247 | biostudies-literature
Project description:BackgroundStaphylococcus aureus can infect and adapt to multiple host species. However, our understanding of the genetic and evolutionary drivers of its generalist lifestyle remains inadequate. This is particularly important when considering local populations of S. aureus, where close physical proximity between bacterial lineages and between host species may facilitate frequent and repeated interactions between them. Here, we aim to elucidate the genomic differences between human- and animal-derived S. aureus from 437 isolates sampled from disease cases in the northeast region of the United States.ResultsMulti-locus sequence typing revealed the existence of 75 previously recognized sequence types (ST). Our population genomic analyses revealed heterogeneity in the accessory genome content of three dominant S. aureus lineages (ST5, ST8, ST30). Genes related to antimicrobial resistance, virulence, and plasmid types were differentially distributed among isolates according to host (human versus non-human) and among the three major STs. Across the entire population, we identified a total of 1,912 recombination events that occurred in 765 genes. The frequency and impact of homologous recombination were comparable between human- and animal-derived isolates. Low-frequency STs were major donors of recombined DNA, regardless of the identity of their host. The most frequently recombined genes (clfB, aroA, sraP) function in host infection and virulence, which were also frequently shared between the rare lineages.ConclusionsTaken together, these results show that frequent but variable patterns of recombination among co-circulating S. aureus lineages, including the low-frequency lineages, that traverse host barriers shape the structure of local gene pool and the reservoir of host-associated genetic variants. Our study provides important insights to the genetic and evolutionary factors that contribute to the ability of S. aureus to colonize and cause disease in multiple host species. Our study highlights the importance of continuous surveillance of S. aureus circulating in different ecological host niches and the need to systematically sample from them. These findings will inform development of effective measures to control S. aureus colonization, infection, and transmission across the One Health continuum.
| S-EPMC10463932 | biostudies-literature
Project description:Ubiquitination is a post-translational modification initiated by the E1 enzyme UBA1, which transfers ubiquitin to ~35 E2 ubiquitin-conjugating enzymes. While UBA1 loss is cell lethal, it remains unknown how partial reduction in UBA1 activity is endured. Here, we utilize deep-coverage mass spectrometry to define the E1-E2 interactome and to determine the proteins that are modulated by knockdown of UBA1 and of each E2 in human cells. These analyses define the UBA1/E2-sensitive proteome and the E2 specificity in protein modulation. Interestingly, profound adaptations in peroxisomes and other organelles are triggered by decreased ubiquitination. While the cargo receptor PEX5 depends on its mono-ubiquitination for binding to peroxisomal proteins and importing them into peroxisomes, we find that UBA1/E2 knockdown induces the compensatory upregulation of other PEX proteins necessary for PEX5 docking to the peroxisomal membrane. Altogether, this study defines a homeostatic mechanism that sustains peroxisomal protein import in cells with decreased ubiquitination capacity.
| S-EPMC10646096 | biostudies-literature
Project description:Adult neurogenesis in the dentate gyrus of the hippocampus is highly regulated by environmental influences, and functionally implicated in behavioural responses to stress and antidepressants1-4. However, how adult-born neurons regulate dentate gyrus information processing to protect from stress-induced anxiety-like behaviour is unknown. Here we show in mice that neurogenesis confers resilience to chronic stress by inhibiting the activity of mature granule cells in the ventral dentate gyrus (vDG), a subregion that is implicated in mood regulation. We found that chemogenetic inhibition of adult-born neurons in the vDG promotes susceptibility to social defeat stress, whereas increasing neurogenesis confers resilience to chronic stress. By using in vivo calcium imaging to record neuronal activity from large cell populations in the vDG, we show that increased neurogenesis results in a decrease in the activity of stress-responsive cells that are active preferentially during attacks or while mice explore anxiogenic environments. These effects on dentate gyrus activity are necessary and sufficient for stress resilience, as direct silencing of the vDG confers resilience whereas excitation promotes susceptibility. Our results suggest that the activity of the vDG may be a key factor in determining individual levels of vulnerability to stress and related psychiatric disorders.
| S-EPMC6118212 | biostudies-literature
Project description:Polyamines (PAs) constitute a group of low molecular weight aliphatic amines that have been implicated as key players in growth and development processes, as well as in the response to biotic and abiotic stresses. Transgenic plants overexpressing PA-biosynthetic genes show increased tolerance to abiotic stress. Therein, abscisic acid (ABA) is the hormone involved in plant responses to environmental stresses such as drought or high salinity. An increase in the level of free spermine (Spm) in transgenic Arabidopsis plants resulted in increased levels of endogenous ABA and promoted, in a Spm-dependent way, transcription of different ABA inducible genes. This phenotype was only partially reversed by blocking ABA biosynthesis, indicating an ABA independent response mediated by Spm. Moreover, the phenotype was reproduced by adding Spm to Col0 wild-type Arabidopsis plants. In contrast, Spm-deficient mutants showed a lower tolerance to salt stress. These results indicate that Spm plays a key role in modulating plant stress responses.
| S-EPMC6684778 | biostudies-literature
Project description:BackgroundAdolescent brains are sensitive to stressors. However, under certain circumstances, developmental stress can promote an adaptive phenotype, allowing individuals to cope better with adverse situations in adulthood, thereby contributing to resilience.MethodsSprague Dawley rats (50 males, 48 females) were subjected to adolescent chronic variable stress (adol CVS) for 2 weeks at postnatal day 45. At postnatal day 85, a group was subjected to single prolonged stress (SPS). After a week, animals were evaluated in an auditory-cued fear conditioning paradigm, and neuronal recruitment during reinstatement was assessed by Fos expression. Patch clamp electrophysiology (17-35 cells/group) was performed in male rats to examine physiological changes associated with resilience.ResultsAdol CVS blocked fear potentiation evoked by SPS. We observed that SPS impaired extinction (males) and enhanced reinstatement (both sexes) of the conditioned freezing response. Prior adol CVS prevented both effects. SPS effects were associated with a reduction of infralimbic (IL) cortex neuronal recruitment after reinstatement in males and increased engagement of the central amygdala in females, both also prevented by adol CVS, suggesting different neurocircuits involved in generating resilience between sexes. We explored the mechanism behind reduced IL recruitment in males by studying the intrinsic excitability of IL pyramidal neurons. SPS reduced excitability of IL neurons, and prior adol CVS prevented this effect.ConclusionsOur data indicate that adolescent stress can impart resilience to the effects of traumatic stress on neuroplasticity and behavior. Our data provide a mechanistic link behind developmental stress-induced behavioral resilience and prefrontal (IL) cortical excitability in males.
| S-EPMC10140393 | biostudies-literature
Project description:The increased vulnerability to stress-induced neuropsychiatric disorders in women, including anxiety disorders, does not emerge until pubertal onset, suggesting a role for ovarian hormones in organizing sex-specific vulnerability to anxiety. Parvalbumin (PV) interneurons in the prefrontal cortex are a potential target for these ovarian hormones. PV+ interneurons undergo maturation during the adolescent period and have been shown to be sensitive to stress and to mediate stress-induced anxiety in female mice. To test the idea that ovarian hormones at puberty are necessary for the acquisition of sensitivity to stress, hypothetically driving the response of PV+ interneurons to stress, we performed ovariectomy or sham surgery before pubertal onset in female mice. These mice then were exposed to four weeks of unpredictable chronic mild stress in adulthood. We then assessed anxiety-like behavior and PV/FosB colocalization in the medial PFC. Additionally, we assessed stress-induced anxiety-like behavior in female mice following ovariectomy in adulthood to determine if puberty is a sensitive period for ovarian hormones in mediating vulnerability to stress. We found that prepubertal ovariectomy protects against the development of anxiety-like behavior in adulthood, an effect not found following ovariectomy in adulthood. This effect may be independent of ovarian hormones on prefrontal PV+ interneurons response to stress.
| S-EPMC9898172 | biostudies-literature
Project description:Ubiquitination is a post-translational modification that regulates protein function and turnover. E2 ubiquitin-conjugating enzymes are key for ubiquitination but it remains uncharted what fraction of the proteome is E2-modulated. Here, we utilized deep-coverage TMT mass spectrometry to determine how protein abundance is modulated by E2s. Analysis of human cells with ~25% reduction in ubiquitination and with individual E2 knockdown indicates that 48% of the proteome is modulated by partial E2 loss, and that this rewires organelle and metabolic functions by reducing the turnover of E2-sensitive targets. In particular, several peroxins are upregulated by UBA1/E2 RNAi, and this promotes peroxisomal protein import and rewires cellular metabolism. Altogether, this study provides a framework for understanding how moderate reduction in E2 function rewires the proteome and cellular function.
2023-10-18 | GSE222110 | GEO
Project description:Cells possess several conserved adaptive mechanisms to respond to stress. Stress signaling is initiated to reestablish cellular homeostasis, but its effects on the tissue or systemic levels are far less understood. We report that the secreted luminal domain of the endoplasmic reticulum (ER) stress transducer CREB3L2 (which we name TAILS [transmissible activator of increased cell livability under stress]) is an endogenous, cell non-autonomous activator of neuronal resilience. In response to oxidative insults, neurons secrete TAILS, which potentiates hedgehog signaling through direct interaction with Sonic hedgehog (SHH) and its receptor PTCH1, leading to improved antioxidant signaling and mitochondrial function in neighboring neurons. In an in vivo model of ischemic brain injury, administration of TAILS enables survival of CNS neurons and fully preserves cognitive function in behavioral tests. Our findings reveal an SHH-mediated, cell non-autonomous branch of cellular stress signaling that confers resilience to oxidative stress in the mature brain, providing protection from ischemic neurodegeneration.
| S-EPMC9623505 | biostudies-literature
Project description:Chronic stress represents a vulnerability factor for anxiety and depressive disorders and has been widely used to model aspects of these disorders in rodents. Disinhibition of somatostatin (SST)-positive GABAergic interneurons in mice by deletion of γ2 GABAA receptors selectively from these cells (SSTCre:γ2f/f mice) has been shown to result in behavioral and biochemical changes that mimic the responses to antidepressant doses of ketamine. Here we explored the extent to which SSTCre:γ2f/f mice exhibit resilience to unpredictable chronic mild stress (UCMS). We found that male SSTCre:γ2f/f mice are resilient to UCMS-induced (i) reductions in weight gain, (ii) reductions in SST-immuno-positive cells in medial prefrontal cortex (mPFC), (iii) increases in phosphorylation of eukaryotic elongation factor 2 (eEF2) in mPFC, and (iv) increased anxiety in a novelty suppressed feeding test. Female SSTCre:γ2f/f mice were resilient to UCMS-induced reductions in SST-immuno-positive cells indistinguishably from males. However, in contrast to males, they showed no UCMS effects on weight gain independent of genotype. Moreover, in mPFC of female γ2f/f control mice, UCMS resulted in paradoxically reduced p-EF2 levels without stress effects in the SSTCre:γ2f/f mutants. Lastly, female SSTCre:γ2f/f mice showed increased rather than reduced UCMS induced anxiety compared to γ2f/f controls. Thus, disinhibition of SST interneurons results in behavioral resilience to UCMS selectively in male mice, along with cellular resilience of SST neurons to UCMS independent of sex. Thus, mechanisms underlying vulnerability and resilience to stress are sex specific and map to mPFC rather than hippocampus but appear unrelated to changes in expression of SST as a marker of corresponding interneurons.
| S-EPMC7739040 | biostudies-literature