An Inducer of VGF Protects Cells against ER Stress-Induced Cell Death and Prolongs Survival in the Mutant SOD1 Animal Models of Familial ALS

Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease, and recent evidence has suggested that endoplasmic reticulum (ER) stress signaling is involved in the pathogenesis of ALS. Here we identified a small molecule, SUN N8075, which has a marked protective effect on ER stress-induced cell death, in an in vitro cell-based screening, and its protective mechanism was mediated by an induction of VGF nerve growth factor inducible (VGF): VGF knockdown with siRNA completely abolished the protective effect of SUN N8075 against ER-induced cell death, and overexpression of VGF inhibited ER-stress-induced cell death. VGF level was lower in the spinal cords of sporadic ALS patients than in the control patients. Furthermore, SUN N8075 slowed disease progression and prolonged survival in mutant SOD1 transgenic mouse and rat models of ALS, preventing the decrease of VGF expression in the spinal cords of ALS mice. These data suggest that VGF plays a critical role in motor neuron survival and may be a potential new therapeutic target for ALS, and SUN N8075 may become a potential therapeutic candidate for treatment of ALS

Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion

Endocrine therapies target the activation of the oestrogen receptor alpha (ERα) via distinct mechanisms, but it is not clear whether breast cancer cells can adapt to treatment using drug-specific mechanisms. Here we demonstrate that resistance emerges via drug-specific epigenetic reprogramming. Resistant cells display a spectrum of phenotypical changes with invasive phenotypes evolving in lines resistant to the aromatase inhibitor (AI). Orthogonal genomics analysis of reprogrammed regulatory regions identifies individual drug-induced epigenetic states involving large topologically associating domains (TADs) and the activation of super-enhancers. AI-resistant cells activate endogenous cholesterol biosynthesis (CB) through stable epigenetic activation in vitro and in vivo. Mechanistically, CB sparks the constitutive activation of oestrogen receptors alpha (ERα) in AI-resistant cells, partly via the biosynthesis of 27-hydroxycholesterol. By targeting CB using statins, ERα binding is reduced and cell invasion is prevented. Epigenomic-led stratification can predict resistance to AI in a subset of ERα-positive patients

Impact of Treadmill Running and Sex on Hippocampal Neurogenesis in the Mouse Model of Amyotrophic Lateral Sclerosis

Hippocampal neurogenesis in the subgranular zone (SGZ) of dentate gyrus (DG) occurs throughout life and is regulated by pathological and physiological processes. The role of oxidative stress in hippocampal neurogenesis and its response to exercise or neurodegenerative diseases remains controversial. The present study was designed to investigate the impact of oxidative stress, treadmill exercise and sex on hippocampal neurogenesis in a murine model of heightened oxidative stress (G93A mice). G93A and wild type (WT) mice were randomized to a treadmill running (EX) or a sedentary (SED) group for 1 or 4 wk. Immunohistochemistry was used to detect bromodeoxyuridine (BrdU) labeled proliferating cells, surviving cells, and their phenotype, as well as for determination of oxidative stress (3-NT; 8-OHdG). BDNF and IGF1 mRNA expression was assessed by in situ hybridization. Results showed that: (1) G93A-SED mice had greater hippocampal neurogenesis, BDNF mRNA, and 3-NT, as compared to WT-SED mice. (2) Treadmill running promoted hippocampal neurogenesis and BDNF mRNA content and lowered DNA oxidative damage (8-OHdG) in WT mice. (3) Male G93A mice showed significantly higher cell proliferation but a lower level of survival vs. female G93A mice. We conclude that G93A mice show higher hippocampal neurogenesis, in association with higher BDNF expression, yet running did not further enhance these phenomena in G93A mice, probably due to a ‘ceiling effect’ of an already heightened basal levels of hippocampal neurogenesis and BDNF expression

Effect of road geometry, weather and traffic flow on road safety

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Genetic diversity and demographic parameters for the 18 populations of <i>T</i>. <i>roseoalba</i>, for combined cpDNA data and ITS nrDNA.

<p>Demographic parameters were estimated based on concatenated data.</p

Coalescent Simulation and Paleodistribution Modeling for <i>Tabebuia rosealba</i> Do Not Support South American Dry Forest Refugia Hypothesis

<div><p>Studies based on contemporary plant occurrences and pollen fossil records have proposed that the current disjunct distribution of seasonally dry tropical forests (SDTFs) across South America is the result of fragmentation of a formerly widespread and continuously distributed dry forest during the arid climatic conditions associated with the Last Glacial Maximum (LGM), which is known as the modern-day dry forest refugia hypothesis. We studied the demographic history of <i>Tabebuia rosealba</i> (Bignoniaceae) to understand the disjunct geographic distribution of South American SDTFs based on statistical phylogeography and ecological niche modeling (ENM). We specifically tested the dry forest refugia hypothesis; i.e., if the multiple and isolated patches of SDTFs are current climatic relicts of a widespread and continuously distributed dry forest during the LGM. We sampled 235 individuals across 18 populations in Central Brazil and analyzed the polymorphisms at chloroplast (<i>trnS-trnG</i>, <i>psbA-trnH</i> and <i>ycf6-trnC</i> intergenic spacers) and nuclear (ITS nrDNA) genomes. We performed coalescence simulations of alternative hypotheses under demographic expectations from two <i>a priori</i> biogeographic hypotheses (1. the Pleistocene Arc hypothesis and, 2. a range shift to Amazon Basin) and other two demographic expectances predicted by ENMs (3. expansion throughout the Neotropical South America, including Amazon Basin, and 4. retraction during the LGM). Phylogenetic analyses based on median-joining network showed haplotype sharing among populations with evidence of incomplete lineage sorting. Coalescent analyses showed smaller effective population sizes for <i>T</i>. <i>roseoalba</i> during the LGM compared to the present-day. Simulations and ENM also showed that its current spatial pattern of genetic diversity is most likely due to a scenario of range retraction during the LGM instead of the fragmentation from a once extensive and largely contiguous SDTF across South America, not supporting the South American dry forest refugia hypothesis.</p></div

The demographic history scenarios simulated for <i>T</i>. <i>roseoalba</i> and their geographical representation.

<p>The size and location of circle during the LGM indicate demographic population expansion or shrink, and geographic range shift at that time. LIG: last interglacial; LGM: last glacial maximum; Pres: present-day; N0: effective population size at time t0 (present); N1: effective population size at time t1750 (1,750 generations ago). The demographic scenarios correspond to: PLAH, Pleistocene Arc hypothesis; PPPH, the ‘Amazonian SDF’ hypothesis; Both (PLAH+PPPH), i.e., an expansion throughout the Central and Southwest Brazil and also westward toward the Amazonian Basin; Retraction, a retraction in geographic range in Central Brazil.</p