Fragile X Mental Retardation Protein Regulates Proliferation and Differentiation of Adult Neural Stem/Progenitor Cells

Fragile X syndrome (FXS), the most common form of inherited mental retardation, is caused by the loss of functional fragile X mental retardation protein (FMRP). FMRP is an RNA–binding protein that can regulate the translation of specific mRNAs. Adult neurogenesis, a process considered important for neuroplasticity and memory, is regulated at multiple molecular levels. In this study, we investigated whether Fmrp deficiency affects adult neurogenesis. We show that in a mouse model of fragile X syndrome, adult neurogenesis is indeed altered. The loss of Fmrp increases the proliferation and alters the fate specification of adult neural progenitor/stem cells (aNPCs). We demonstrate that Fmrp regulates the protein expression of several components critical for aNPC function, including CDK4 and GSK3β. Dysregulation of GSK3β led to reduced Wnt signaling pathway activity, which altered the expression of neurogenin1 and the fate specification of aNPCs. These data unveil a novel regulatory role for Fmrp and translational regulation in adult neurogenesis

The Atlas3D project -- XIII. Mass and morphology of HI in early-type galaxies as a function of environment

We present the Atlas3D HI survey of 166 nearby early-type galaxies (ETGs) down to M(HI)~10^7 M_sun. We detect HI in ~40% of all ETGs outside the Virgo cluster and in ~10% of all ETGs inside it. This demonstrates that it is common for non-cluster ETGs to host HI. The HI morphology varies from regular discs/rings (the majority of the detections) to unsettled gas distributions. The former are either small discs (M(HI)<10^8 M_sun) confined within the stellar body and sharing the same kinematics of the stars, or large discs/rings (M(HI) up to 5x10^9 M_sun) extending to tens of kpc from the host galaxy and frequently kinematically decoupled from the stars. Neutral hydrogen provides material for star formation in ETGs. Galaxies with central HI exhibit signatures of star formation in ~70% of the cases, ~5 times more frequently than galaxies without central HI. The central ISM is dominated by molecular gas. In ETGs with a small gas disc the conversion of HI into H_2 is as efficient as in spirals. The ETG HI mass function has M*~2x10^9 M_sun and slope=-0.7. ETGs host much less HI than spirals as a family. However, a significant fraction of them is as HI-rich as spirals. The main difference between ETGs and spirals is that the former lack the high-column-density HI typical of the bright stellar disc of the latter. We find an envelope of decreasing M(HI) with increasing environment density. The gas-richest ETGs live in the poorest environments (where star-formation is more common), galaxies in the centre of Virgo have the lowest HI content, and the cluster outskirts are a transition region. We find an HI morphology-density relation. At low environment density HI is mostly distributed on large discs/rings. More disturbed HI morphologies dominate environment densities typical of rich groups, confirming the importance of processes occurring on a galaxy-group scale for the evolution of ETGs.Comment: Accepted for publication on MNRA

CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). Methods: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. Results: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. Conclusion: We significantly broaden the mutational and clinical spectrum of CTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.Peer reviewe

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

Relatório de estágio em farmácia comunitária

Relatório de estágio realizado no âmbito do Mestrado Integrado em Ciências Farmacêuticas, apresentado à Faculdade de Farmácia da Universidade de Coimbr

Glove material selection for cleanroom gloveboxes

The purpose of this project was to recommend the best overall glove materials for use in two different types of sample containment units at NASA's Johnson Space Center: one for lunar samples, and one for future Martian samples. In both cases, material selection was dependent on properties that related to cross-contamination such as gas permeability and offgassing. The recommended glove material prevents contamination of the Earth by the sample, while at the same time keeping the sample pristine

Use of proposed technologies at the Worcester EcoTarium

The objective of this project was to develop effective ways for the EcoTarium in Worcester to use its new Telecommunications Theater. This report discusses ideas we formulated or expanded upon to make use of the facility and its technologically advanced capabilities. Our most important ideas revolved around the usage of digital cameras by patrons and staff, with the Telecommunications Theater as a means to combine the new technology with existing presentation practices

Nicotine Enhances Footshock- and Lithium Chloride-Conditioned Place Avoidance in Male Rats

Introduction: Numerous studies have shown that nicotine (NIC) can enhance the reinforcing effects of non-NIC stimuli through a nonassociative mechanism. To date, it is unclear whether NIC reinforcement enhancement serves to increase behaviors motivated by rewarding stimuli only, or whether NIC potentiates behavior motivated by all stimuli, regardless of valence. Methods: The current study used a place conditioning procedure to examine whether acute NIC injection modulates avoidance of an environment previously associated with an aversive stimulus. Separate groups of rats underwent place conditioning using either lithium chloride (125 mg/kg/ml, i.p.) or footshock (0.75 mA) as the aversive stimulus. Other rats served as nonconditioned controls. The magnitude of place avoidance was assessed after acute NIC (0.1 or 0.4 mg/kg/ml, s.c.) or saline. Results: Rats avoided chambers previously paired with either lithium chloride or footshock, and conditioned place avoidance was significantly enhanced by NIC pre-treatment. Conclusions: These results demonstrate that the ability of NIC to enhance motivated behavior extends to behaviors elicited by aversive stimuli, evidence that NIC affects behavior motivated by a broader range of stimuli than previously appreciated. Implications: The current study examined whether the reinforcement enhancement properties of NIC apply to aversive stimuli by testing NIC enhancement of conditioned place avoidance in rats. The results demonstrate that NIC enhances the motivational impact of these distinct aversive stimuli, providing novel evidence that NIC affects behavior motivated by a broader range of stimuli than has previously been demonstrated