Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Identification de facteurs régulant en trans la maturation différentielle de la région 3' terminale de l'ARN pré-messager tropomyosine a chez Xenopus laevis

Nous utilisons le gène de la tropomyosine de xénope comme modèle moléculaire pour étudier les déterminants de la régulation tissulaire de l'épissage et de la polyadénylation. Ce gène contient dans sa région 3' terminale un exon alternatif, l'exon 9A9', dont l'utilisation, dans l'embryon de xénope, est dépendante de l'environnement tissulaire. Deux séquences, l'une inhibitrice l'autre activatrice, qui régulent l'épissage de cet exon, avait précédemment été identifiées. Afin de caractériser les mécanismes d'action de ces deux séquences, nous avons recherché les facteurs qui contrôlent l'utilisation de l'exon 9A9' via ces dernières. Nous avons identifié la protéine xPTB comme un facteur majeur de la répression de l'exon 9A9' et certains membres de la famille des protéines SR comme des facteurs capables d'activer cet exon. Nous avons par la suite démontré qu'il existe un antagonisme fonctionnel entre la protéine xPTB et la famille des protéines SR dans la régulation de l'exon 9A9'.RENNES1-BU Sciences Philo (352382102) / SudocSudocFranceF

PTB Regulates the Processing of a 3′-Terminal Exon by Repressing both Splicing and Polyadenylation

The polypyrimidine tract binding protein (PTB) has been described as a global repressor of regulated exons. To investigate PTB functions in a physiological context, we used a combination of morpholino-mediated knockdown and transgenic overexpression strategies in Xenopus laevis embryos. We show that embryonic endoderm and skin deficient in PTB displayed a switch of the α-tropomyosin pre-mRNA 3′ end processing to the somite-specific pattern that results from the utilization of an upstream 3′-terminal exon designed exon 9A9′. Conversely, somitic targeted overexpression of PTB resulted in the repression of the somite-specific exon 9A9′ and a switch towards the nonmuscle pattern. These results validate PTB as a key physiological regulator of the 3′ end processing of the α-tropomyosin pre-mRNA. Moreover, using a minigene strategy in the Xenopus oocyte, we show that in addition to repressing the splicing of exon 9A9′, PTB regulates the cleavage/polyadenylation of this 3′-terminal exon

Polypyrimidine Tract-binding Protein Is Involved in Vivo in Repression of a Composite Internal/3′ -Terminal Exon of the Xenopus α-Tropomyosin Pre-mRNA

International audienceThe Xenopus alpha(fast)-tropomyosin gene contains, at its 3' -end, a composite internal/3' -terminal exon (exon 9A9'), which is subjected to three different patterns of splicing according to the cell type. Exon 9A9' is included as a terminal exon in the myotome and as an internal exon in adult striated muscles, whereas it is skipped in nonmuscle cells. We have developed an in vivo model based on transient expression of minigenes encompassing the regulated exon 9A9' in Xenopus oocytes and embryos. We first show that the different alpha-tropomyosin minigenes recapitulate the splicing pattern of the endogenous gene and constitute valuable tools to seek regulatory sequences involved in exon 9A9' usage. A mutational analysis led to the identification of an intronic element that is involved in the repression of exon 9A9' in nonmuscle cells. This element harbors four polypyrimidine track-binding protein (PTB) binding sites that are essential for the repression of exon 9A9'. We show using UV cross-linking and immunoprecipitation experiments that Xenopus PTB (XPTB) interacts with these PTB binding sites. Finally, we show that depletion of endogenous XPTB in Xenopus embryos using a morpholinobased translational inhibition strategy resulted in exon 9A9' inclusion in embryonic epidermal cells. These results demonstrate that XPTB is required in vivo to repress the terminal exon 9A9' and suggest that PTB could be a major actor in the repression of regulated 3' -terminal exon

Transcription elongation regulator 1 (TCERG1) regulates competent RNA polymerase II-mediated elongation of HIV-1 transcription and facilitates efficient viral replication

Abstract Background Control of RNA polymerase II (RNAPII) release from pausing has been proposed as a checkpoint mechanism to ensure optimal RNAPII activity, especially in large, highly regulated genes. HIV-1 gene expression is highly regulated at the level of elongation, which includes transcriptional pausing that is mediated by both viral and cellular factors. Here, we present evidence for a specific role of the elongation-related factor TCERG1 in regulating the extent of HIV-1 elongation and viral replication in vivo. Results We show that TCERG1 depletion diminishes the basal and viral Tat-activated transcription from the HIV-1 LTR. In support of a role for an elongation mechanism in the transcriptional control of HIV-1, we found that TCERG1 modifies the levels of pre-mRNAs generated at distal regions of HIV-1. Most importantly, TCERG1 directly affects the elongation rate of RNAPII transcription in vivo. Furthermore, our data demonstrate that TCERG1 regulates HIV-1 transcription by increasing the rate of RNAPII elongation through the phosphorylation of serine 2 within the carboxyl-terminal domain (CTD) of RNAPII and suggest a mechanism for the involvement of TCERG1 in relieving pausing. Finally, we show that TCERG1 is required for HIV-1 replication. Conclusions Our study reveals that TCERG1 regulates HIV-1 transcriptional elongation by increasing the elongation rate of RNAPII and phosphorylation of Ser 2 within the CTD. Based on our data, we propose a general mechanism for TCERG1 acting on genes that are regulated at the level of elongation by increasing the rate of RNAPII transcription through the phosphorylation of Ser2. In the case of HIV-1, our evidence provides the basis for further investigation of TCERG1 as a potential therapeutic target for the inhibition of HIV-1 replicationThis work was supported by grants from the Spanish Ministry of Science and Innovation (BFU2011-24577), the Foundation for Research and Prevention of AIDS in Spain (FIPSE-36768/08), and the Andalusian Government (Excellence Project CVI-4626/2009) to C.S.; by the Spanish Ministry of Science and Innovation (BFU2009-08796), and the Andalusian Government (Excellence Project CTS-6587) to C.H.M; and by FIPSE (360924/10), the Spanish Ministry of Economy and Competitiveness (SAF2010-18388; FIS PI0120506), the Spanish Ministry of Health (EC11-285, -278), Instituto de Salud Carlos III, AIDS Network ISCIII-RETIC (RD12/0017/0015), and the Health Programme 2009 on Combined Highly Active Anti-Retroviral Microbicides (CHAARM) to M.C. and J.A. Support from the European Region Development Fund, ERDF (FEDER) is also acknowledged. M.M. was supported by a fellowship from the Spanish Ministry of Education (FPU program). M.R.L.H was supported by a fellowship from the European Union (CHAARM). C.L.S. was funded by a fellowship from the Foundation for Medical Research (F.R.M., France) and by funds from NIH RO1 GM071037 (USA) to M.A.G-B.Peer Reviewe

GRK2 plays a role in viral RNA synthesis.

<p>(A) Schematic of the DENV replicon construct which expresses Renilla luciferase (Rluc), adapted from Clyde <i>et al. </i><a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001820#pntd.0001820-Clyde1" target="_blank">[14]</a>. (B) HuH-7 cells treated with siNSC or siGRK2_2 were electroporated with DRrep and DRrep-RdRPmut RNA and assayed for Rluc activity at 1, 3, 6, 12, 26, 48, and 72 hours post-electroporation. Data represent the mean of relative light units (RLU) detected in triplicate samples. Error bars indicate the standard deviation and are sometimes hidden by the symbol.</p

Genome-scale siRNA screens identify YFV human host factors.

<p>(A) Schematic of the protocol used in the siRNA screens and of the method used to identify hits. (B) Percentage of infection for the population in GS1AB (Genomic Screen 1, AB siRNA set) plotted against the percentage of infection for the corresponding wells within GS1CD (GS1, CD siRNA set). The black diamonds represent the identified hits and the grey diamonds represent the rest of the wells. (C) Similar to B, except that percentage of infection for the population in GS2AB (Genomic Screen 2, AB siRNA set) is plotted against percentage of infection for the corresponding wells within GS2CD (GS2, CD siRNA set).</p