Enhancer turnover and conserved regulatory function in vertebrate evolution

Mutations in regulatory regions including enhancers are an important source of variation and innovation during evolution. Enhancers can evolve by changes in the sequence, arrangement and repertoire of transcription factor binding sites, but whole enhancers can also be lost or gained in certain lineages in a process of turnover. The proopiomelanocortin gene (Pomc), which encodes a prohormone, is expressed in the pituitary and hypothalamus of all jawed vertebrates. We have previously described that hypothalamic Pomc expression in mammals is controlled by two enhancers?nPE1 and nPE2?that are derived from transposable elements and that presumably replaced the ancestral neuronal Pomc regulatory regions. Here, we show that nPE1 and nPE2, even though they are mammalian novelties with no homologous counterpart in other vertebrates, nevertheless can drive gene expression specifically to POMC neurons in the hypothalamus of larval and adult transgenic zebrafish. This indicates that when neuronal Pomc enhancers originated de novo during early mammalian evolution, the newly created cis- and trans-codes were similar to the ancestral ones. We also identify the neuronal regulatory region of zebrafish pomca and confirm that it is not homologous to the mammalian enhancers. Our work sheds light on the process of gene regulatory evolution by showing how a locus can undergo enhancer turnover and nevertheless maintain the ancestral transcriptional output.Fil: Domene, Sabina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; ArgentinaFil: Bumaschny, Viviana Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Silva Junqueira de Souza, Flavio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Franchini, Lucia Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; ArgentinaFil: Nasif, Sofia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; ArgentinaFil: Low, Malcolm J.. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados UnidosFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentin

Analysis of ECN/RED and SAP-LAW with simultaneous TCP and UDP traffic

Internetworking often requires a large amount of users to share a common gateway to obtain connectivity to the Internet. Congestion avoidance mechanisms are used to prevent the saturation of the gateway which represents a bottleneck of the system. The most popular congestion avoidance mechanisms are the Explicit Congestion Notification (ECN) and the Random Early Detection (RED). Recently, a new method for the congestion avoidance has been proposed: the Smart Access Point with Limited Advertised Window (SAP-LAW). The main idea is to hijack the acknowledge packets in the TCP connections in order to artificially reduce the advertised destination window according to some bandwidth allocation policy. Therefore, the flux control mechanism is artificially exploited to control the congestion at the bottleneck. The advantage of this approach is that it does not require any modification in the TCP implementations at the clients. In this paper, we propose stochastic models for the ECN/RED and SAP-LAW mechanisms in order to compare their performances under different scenarios. The models are studied in mean field regime, i.e., under a great number of TCP connections and UDP based transmissions. Augmenting previous work on ECN/RED, we consider the presence of UDP traffic with bursts, and short lived TCP connections. The models for SAP-LAW are totally new. The comparison is performed in terms of different performance indices including average queue length, system throughput and expected queuing time.Internetworking often requires a large amount of users to share a common gateway to obtain connectivity to the Internet. Congestion avoidance mechanisms are used to prevent the saturation of the gateway which represents a bottleneck of the system. The most popular congestion avoidance mechanisms are the Explicit Congestion Notification (ECN) and the Random Early Detection (RED). Recently, a new method for the congestion avoidance has been proposed: the Smart Access Point with Limited Advertised Window (SAP-LAW). The main idea is to hijack the acknowledge packets in the TCP connections in order to artificially reduce the advertised destination window according to some bandwidth allocation policy. Therefore, the flux control mechanism is artificially exploited to control the congestion at the bottleneck. The advantage of this approach is that it does not require any modification in the TCP implementations at the clients. In this paper, we propose stochastic models for the ECN/RED and SAP-LAW mechanisms in order to compare their performances under different scenarios. The models are studied in mean field regime, i.e., under a great number of TCP connections and UDP based transmissions. Augmenting previous work on ECN/RED, we consider the presence of UDP traffic with bursts, and short lived TCP connections. The models for SAP-LAW are totally new. The comparison is performed in terms of different performance indices including average queue length, system throughput and expected queuing time. (C) 2016 Elsevier B.V. All rights reserved

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

Outcomes From a School-Randomized Controlled Trial of Steps to Respect: A Bullying Prevention Program

This study reports the outcomes of a randomized controlled trial of Steps to Respect: A Bullying Prevention Program conducted in 33 California elementary schools. Schools were matched on school demographic characteristics and assigned randomly to intervention or waitlisted control conditions. Outcome measures were obtained from (a) all school staff; (b) a randomly selected subset of third-, fourth-, and fifth-grade teachers in each school; and (c) all students in classrooms of selected teachers. Multilevel analyses indicated significant (p < .05) positive effects of the program on a range of outcomes (e.g., improved student climate, lower levels of physical bullying perpetration, less school bullying-related problems). Results of this study support the program as an efficacious intervention for the prevention of bullying in schools

Engagement Matters: Lessons from Assessing Classroom Implementation of Steps to Respect: A Bullying Prevention Program Over a One-year Period

Steps to Respect: A Bullying Prevention Program (STR) relies on a social–ecological model of prevention to increase school staff awareness and responsiveness, foster socially responsible beliefs among students, and teach social–emotional skills to students to reduce bullying behavior. As part of a school-randomized controlled trial of STR, we examined predictors and outcomes associated with classroom curriculum implementation in intervention schools. Data on classroom implementation (adherence and engagement) were collected from a sample of teachers using a weekly on-line Teacher Implementation Checklist system. Pre-post data related to school bullying-related outcomes were collected from 1,424 students and archival school demographic data were obtained from the National Center for Education Statistics. Results of multilevel analyses indicated that higher levels of program engagement were influenced by school-level percentage of students receiving free/reduced lunch, as well as classroom-level climate indicators. Results also suggest that higher levels of program engagement were related to lower levels of school bullying problems, enhanced school climate and attitudes less supportive of bullying. Predictors and outcomes related to program fidelity (i.e., adherence) were largely nonsignificant. Results suggest that student engagement is a key element of program impact, though implementation is influenced by both school-level demographics and classroom contexts