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The arginine-vasopressin (AVP)-containing hypothalamic magnocellular neurosecretory neurons (VPMNNs) are known for their role in hydro-electrolytic balance control via their projections to the neurohypophysis. Recently, projections from these same neurons to hippocampus, habenula and other brain regions in which vasopressin infusion modulates contingent social and emotionally-affected behaviors, have been reported. Here, we present evidence that VPMNN collaterals also project to the amygdaloid complex, and establish synaptic connections with neurons in central amygdala (CeA). The density of AVP innervation in amygdala was substantially increased in adult rats that had experienced neonatal maternal separation (MS), consistent with our previous observations that MS enhances VPMNN number in the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus. In the CeA, V1a AVP receptor mRNA was only observed in GABAergic neurons, demonstrated by complete co-localization of V1a transcripts in neurons expressing Gad1 and Gad2 transcripts in CeA using the RNAscope method. V1b and V2 receptor mRNAs were not detected, using the same method. Water-deprivation (WD) for 24 h, which increased the metabolic activity of VPMNNs, also increased anxiety-like behavior measured using the elevated plus maze (EPM) test, and this effect was mimicked by bilateral microinfusion of AVP into the CeA. Anxious behavior induced by either WD or AVP infusion was reversed by CeA infusion of V1a antagonist. VPMNNs are thus a newly discovered source of CeA inhibitory circuit modulation, through which both early-life and adult stress coping signals are conveyed from the hypothalamus to the amygdala.

Plant disease epidemics are responsible for millions of tons of yield loss from crops annually. To provide sufficient nutritious food, feed, fiber, and fuel for a growing world human population on a non‐expanding land resource, yield loss caused by plant pathogens must be minimized. The Northern Great Plains (NGP) region of the United States is a major crop‐producing region, but crop production in this region is threatened by climate variability, new pathogen or pathogen race development, limited in‐field management practices, pathogen synergism, and fungicide resistance in some fungal pathogens. To sustain stable food, feed, fiber, and fuel production from plants, concerted efforts from all stakeholders must be harnessed to develop new varieties that are resistant to plant pathogens and less sensitive to climate variability, promote use of integrated disease management (that incorporates resistant/tolerant varieties, plant disease prediction, and accurate disease diagnosis and assessment), and enhance early detection capabilities of new pathogens/races. Here, we review the current and near‐future likely plant disease epidemic concerns in the NGP of the United States and propose some actions to prevent or lessen the extent of the next plant disease epidemic development. Core Ideas Worldwide, plant disease epidemics have been devastating, leading to loss of human life. Risk factors such as changing global climate and new pathogen races threaten food production. Awareness and concerted efforts to address these factors are needed to reverse the course.

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder characterized by cerebellar ataxia and retinopathy. SCA7 is caused by a CAG expansion in the ATXN7 gene, which results in an extended polyglutamine (polyQ) tract in the encoded protein, the ataxin-7. PolyQ expanded ataxin-7 elicits neurodegeneration in cerebellar Purkinje cells, however, its impact on the SCA7-associated retinopathy remains to be addressed. Since Müller glial cells play an essential role in retinal homeostasis, we generate an inducible model for SCA7, based on the glial Müller MIO-M1 cell line. The SCA7 pathogenesis has been explained by a protein gain-of-function mechanism, however, the contribution of the mutant RNA to the disease cannot be excluded. In this direction, we found nuclear and cytoplasmic foci containing mutant RNA accompanied by subtle alternative splicing defects in MIO-M1 cells. RNA foci were also observed in cells from different lineages, including peripheral mononuclear leukocytes derived from SCA7 patient, suggesting that this molecular mark could be used as a blood biomarker for SCA7. Collectively, our data showed that our glial cell model exhibits the molecular features of SCA7, which makes it a suitable model to study the RNA toxicity mechanisms, as well as to explore therapeutic strategies aiming to alleviate glial dysfunction.

Myotonic dystrophy type 1 (DM1), the most frequent inherited muscular dystrophy in adults, is caused by the CTG repeat expansion in the 3′UTR of the DMPK gene. Mutant DMPK RNA accumulates in nuclear foci altering diverse cellular functions including alternative splicing regulation. DM1 is a multisystemic condition, with debilitating central nervous system alterations. Although a defective neuroglia communication has been described as a contributor of the brain pathology in DM1, the specific cellular and molecular events potentially affected in glia cells have not been totally recognized. Thus, to study the effects of DM1 mutation on glial physiology, in this work, we have established an inducible DM1 model derived from the MIO-M1 cell line expressing 648 CUG repeats. This new model recreated the molecular hallmarks of DM1 elicited by a toxic RNA gain-of-function mechanism: accumulation of RNA foci colocalized with MBNL proteins and dysregulation of alternative splicing. By applying a microarray whole-transcriptome approach, we identified several gene changes associated with DM1 mutation in MIO-M1 cells, including the immune mediators CXCL10, CCL5, CXCL8, TNFAIP3, and TNFRSF9, as well as the microRNAs miR-222, miR-448, among others, as potential regulators. A gene ontology enrichment analyses revealed that inflammation and immune response emerged as major cellular deregulated processes in the MIO-M1 DM1 cells. Our findings indicate the involvement of an altered immune response in glia cells, opening new windows for the study of glia as potential contributor of the CNS symptoms in DM1.

The toxic gain-of-function of RNA-CUG(exp) in DM1 has been largely studied in skeletal muscle, with little focus on its effects on the central nervous system (CNS). This study aimed to study if oxidative stress is present in DM1, its relationship with the toxic RNA gain-of-function and if natural antioxidants can revert some of the RNA-CUG(exp) toxic effects. Using an inducible glial DM1 model (MIO-M1 cells), we compared OS in expanded vs. unexpanded cells and investigated whether antioxidants can mitigate OS and RNA-CUG(exp) toxicity. OS was measured via superoxide anion and lipid peroxidation assays. RNA foci were identified using FISH, and the mis-splicing of selected exons was analyzed using semi-quantitative RT-PCR. Cells were treated with natural antioxidants, and the effects on OS, foci formation, and mis-splicing were compared between treated and untreated cells. The results showed significantly higher superoxide anion and lipid peroxidation levels in untreated DM1 cells, which decreased after antioxidant treatment (ANOVA, p < 0.001). Foci were present in 51% of the untreated cells but were reduced in a dose-dependent manner following treatment (ANOVA, p < 0.001). Antioxidants also improved the splicing of selected exons (ANOVA, p < 0.001), suggesting OS plays a role in DM1, and antioxidants may offer therapeutic potential.

Background: Severe burns activate systemic inflammation and lead to an increase in cytokine levels. Epigenetic elements are key regulators of inflammation; however, their involvement in severe burns has not been studied. In this work, we aimed to unveil the histone H3 posttranslational modifications (PTM) profile and their enrichment in promoters of inflammatory genes in response to severe burns. Methods: The levels of H3 PTMs were analyzed by ELISA assays in circulating cells from burn patients. ChIP assays were conducted to evaluate the enrichment of H3K9me2 and H3S28p at the promoter of CXCL8, IL-17, TNFA, IL-6, FOS, and IL-1B genes. Results: We found that eight H3 PTMs decreased at 5 days post-burn. Burn patients showed a decreased enrichment of H3K9me2 in CXCL8, IL-17, and TNFA promoters, whereas IL-6, FOS, and IL-1B promoters displayed an H3S28p enrichment diminution during the first 10 days post-burn. Interestingly, burn-injured septic patients exhibited an increased enrichment of H3K9me2 in TNFA, IL-1B, CXCL8, and IL-17 promoters, whereas H3S28p was increased in promoters of TNFA and IL-1B at 1 dpb. Conclusion: Severe burns trigger epigenetic changes and differential H3 PTM enrichment at inflammation gene promoters. Epigenetic misregulation of H3 may be involved in sepsis occurrence after severe burn injury.

Dystrophin Dp71 is the most abundant product of the Duchenne muscular dystrophy gene in the nervous system, and mutations impairing its function have been associated with the neurodevelopmental symptoms present in a third of DMD patients. Dp71 is required for the clustering of neurotransmitter receptors and the neuronal differentiation of cultured cells; nonetheless, its precise role in neuronal cells remains to be poorly understood. In this study, we analyzed the effect of two pathogenic DMD gene point mutations on the Dp71 function in neurons. We engineered C272Y and E299del mutations to express GFP-tagged Dp71 protein variants in N1E-115 and SH-SY5Y neuronal cells. Unexpectedly, the ectopic expression of Dp71 mutants resulted in protein aggregation, which may be mechanistically caused by the effect of the mutations on Dp71 structure, as predicted by protein modeling and molecular dynamics simulations. Interestingly, Dp71 mutant variants acquired a dominant negative function that, in turn, dramatically impaired the distribution of different Dp71 protein partners, including β-dystroglycan, nuclear lamins A/C and B1, the high-mobility group (HMG)-containing protein (BRAF35) and the BRAF35-family-member inhibitor of BRAF35 (iBRAF). Further analysis of Dp71 mutants provided evidence showing a role for Dp71 in modulating both heterochromatin marker H3K9me2 organization and the neuronal genes’ expression, via its interaction with iBRAF and BRAF5.

The arginine vasopressin (AVP)-magnocellular neurosecretory system (AVPMNS) in the hypothalamus plays a critical role in homeostatic regulation as well as in allostatic motivational behaviors. However, it remains unclear whether adult neurogenesis exists in the AVPMNS. By using immunoreaction against AVP, neurophysin II, glial fibrillar acidic protein (GFAP), cell division marker (Ki67), migrating neuroblast markers (doublecortin, DCX), microglial marker (Ionized calcium binding adaptor molecule 1, Iba1), and 5′-bromo-2′-deoxyuridine (BrdU), we report morphological evidence that low-rate neurogenesis and migration occur in adult AVPMNS in the rat hypothalamus. Tangential AVP/GFAP migration routes and AVP/DCX neuronal chains as well as ascending AVP axonal scaffolds were observed. Chronic water deprivation significantly increased the BrdU+ nuclei within both the supraaoptic (SON) and paraventricular (PVN) nuclei. These findings raise new questions about AVPMNS’s potential hormonal role for brain physiological adaptation across the lifespan, with possible involvement in coping with homeostatic adversities.

Today, neurorehabilitation has become in a widely used therapeutic approach in spinocerebellar ataxias; however, there are scarce powerful clinical studies supporting this notion, and these studies require extension to other specific SCA subtypes in order to be able to form conclusions concerning its beneficial effects. Therefore, in this study, we perform for the first time a case-control pilot randomized, single-blinded, cross-sectional, and observational study to evaluate the effects of physical neurorehabilitation on the clinical and biochemical features of patients with spinocerebellar ataxia type 7 (SCA7) in 18 patients diagnosed with SCA7. In agreement with the exercise regimen, the participants were assigned to groups as follows: (a) the intensive training group, (b) the moderate training group, and (c) the non-training group (control group).We found that both moderate and intensive training groups showed a reduction in SARA scores but not INAS scores, compared with the control group (p < 0.05). Furthermore, trained patients exhibited improvement in the SARA sub-scores in stance, gait, dysarthria, dysmetria, and tremor, as compared with the control group (p < 0.05). No significant improvements were found in daily living activities, as revealed by Barthel and Lawton scales (p > 0.05). Patients under physical training exhibited significantly decreased levels in lipid-damage biomarkers and malondialdehyde, as well as a significant increase in the activity of the antioxidant enzyme PON-1, compared with the control group (p < 0.05). Physical exercise improved some cerebellar characteristics and the oxidative state of patients with SCA7, which suggest a beneficial effect on the general health condition of patients.

DNA methylation is a key epigenetic modification to regulate gene expression in mammalian cells. Abnormal DNA methylation in gene promoters is common across human cancer types. DNMT3B is the main de novo methyltransferase enhanced in several primary tumors. How de novo methylation is established in genes related to cancer is poorly understood. CpG islands (CGIs), common sequences, and transcription factors (TFs) that interact with DNMT3B have been associated with abnormal de novo methylation. We initially identified cis elements associated with DNA methylation to investigate the contribution of DNMT3B overexpression to the deregulation of its possible target genes in an epithelial cell model. In a set of downregulated genes (n = 146) from HaCaT cells with DNMT3B overexpression, we found CGI, common sequences, and TFs Binding Sites that interact with DNMT3B (we called them P-down-3B). PPL1, VAV3, IRF1, and BRAF are P-down-3B genes that are downregulated and increased their methylation in DNMT3B presence. Together these findings suggest that methylated promoters aberrantly have some cis elements that could conduce de novo methylation by DNMT3B.