Directional Next-Generation RNA Sequencing and Examination of Premature Termination Codon Mutations in Endoglin/Hereditary Haemorrhagic Telangiectasia

Hereditary haemorrhagic telangiectasia (HHT) is a disease characterised by abnormal vascular structures, and most commonly caused by mutations in ENG, ACVRL1 or SMAD4 encoding endothelial cell-expressed proteins involved in TGF-β superfamily signalling. The majority of mutations reported on the HHT mutation database are predicted to lead to stop codons, either due to frameshifts or direct nonsense substitutions. The proportion is higher for ENG (67%) and SMAD4 (65%) than for ACVRL1 (42%), p < 0.0001. Here, by focussing on ENG, we report why conventional views of these mutations may need to be revised. Of the 111 stop codon-generating ENG mutations, on ExPASy translation, all except one were premature termination codons (PTCs), sited at least 50-55 bp upstream of the final exon-exon boundary of the main endoglin isoform, L-endoglin. This strongly suggests that the mutated RNA species will undergo nonsense-mediated decay. We provide new in vitro expression data to support dominant negative activity of stable truncated endoglin proteins but suggest these will not generate HHT: the single natural stop codon mutation in L-endoglin (sited within 50-55 nucleotides of the final exon-exon boundary) is unlikely to generate functional protein since it replaces the entire transmembrane domain, as would 8 further natural stop codon mutations, if the minor S-endoglin isoform were implicated in HHT pathogenesis. Finally, next-generation RNA sequencing data of 7 different RNA libraries from primary human endothelial cells demonstrate that multiple intronic regions of ENG are transcribed. The potential consequences of heterozygous deletions or duplications of such regions are discussed. These data support the haploinsufficiency model for HHT pathogenesis, explain why final exon mutations have not been detected to date in HHT, emphasise the potential need for functional examination of non-PTC-generating mutations, and lead to proposals for an alternate stratification system of mutational types for HHT genotype-phenotype correlations

Drug repurposing in the treatment of COVID-19: A review

The first outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was in Wuhan, Hubei, China in December 2019 and declared as a pandemic by the World Health Organization. Currently, there is no proven effective vaccine or therapeutic agent to combat the deadly coronavirus disease. Currently, prevention from the infection, control measures and supportive care help to treat against COVID-19. Until an effective vaccine is available for COVID-19 infection, one can repurpose known therapeutic agents that block the entry of the virus into the host cell and control the COVID-19 infection. Drug repurposing is the new use of old drugs. In this review, the most common and possible drug treatment for COVID-19 is highlighted. The therapeutic agents include antiviral drugs like Remdesivir, chloroquine, hydroxychloroquine, lopinavir/ritonavir, umifenovir, favipiravir and oseltamivir and other agents. Clinical trials are ongoing to evaluate the safety and efficacy of these therapeutic agents in COVID-19 patients

Fairness problems at the media access level for high-speed networks

Most lower speed (approx. 10 Mbps) local area networks use adaptive or random access protocols like Ethernet. Others at higher speed use demand assignment like token or slotted rings. These include Cambridge ring and electronic token ring systems. Fairness issues in representatives of such protocols are discussed. In particular, Fiber Distributed Data Interface (FDDI) was selected as a demand access protocol using tokens, Carrier Sensed Multiple Access/Ring Network (CSMA/RN) a random access protocol, and Distributed Queue Dual Bus (DQDB) a demand access protocol using reservations. Fairness at the media access level was the focus, i.e., attaining access or being excessively delayed when a message is queued to be sent as a function of network location. Within that framework, the essential fairness of FDDI was observed along with severe fairness problems in DQDB and some problems for CSMA/RN. Several modifications were investigated and their ameliorative effect is shown. Finally, a unified presentation which allows comparisons of the three protocols' fairness when normalized to their capacity is given

Nebraska Rainbow Trout

Chapter 1 Lethal and Preferred Temperatures of Lake McConaughy Rainbow Trout Versus Domestic Strain Rainbow Trout By R. Vancil, G. Zuerlein and L. Hesse Chapter 2 A Nitrifying Filter-Cooling Condenser System for Total Water Re-use in Cold-Water Fish Holding or Rearing Applications By L. Hesse, G. Zuerlein and R. Vancil Chapter 3 Biochemical Genetic Analysis of Two Strains of Nebraska Rainbow Trout By J. Seeb and L. Wishard The self-sustaining rainbow trout population living in Lake Mcconaughy and the North Platte River tributaries is unique to the Great Plains region. The population spends most of its adult life in the reservoir, but moves into tributary streams to spawn. Two spawning runs occur. The largest is from September through November followed by a reduced migration. in March and April of the following spring. Rainbow trout fingerlings spend about a year in the stream before smolting and migrating to the reservoir. Fishing for Mcconaughy rainbows in the tributaries and reservoir began in the late 1940\u27s. Concern for the maintenance of this fishery prompted several investigations which were directed at development of a management plan. From these studies it was evident that the McConaughy rainbow possessed a selective advantage over hatchery origin fish stocked in the streams and reservoir. Temperatures, normally too high for successful rainbow survival, were often encountered in the streams and the eutrophying Lake McConaughy. This study was designed to compare the temperature tolerance and preference of Mcconaughy rainbow trout with hatchery origin fish. Chapter 1 describes the results of this study. Chapter 2 describes the laboratory facility developed to hold fish for relatively long periods while conducting the experiments. Chapter 3 contains the results of studies designed to characterize the genetic differences between hatchery fish from Massachusetts and the self-sustaining Mcconaughy rainbow trout. The Pacific Fisheries Research Laboratory in Olympia, Washington, was contracted to perform an electrophoresis characterization of the frequency of biochemical genetic variants among the McConaughy and hatchery rainbow groups

Epidemiology of Distal Renal Tubular Acidosis: A Study Using Linked UK Primary Care and Hospital Data

Introduction: Distal renal tubular acidosis (dRTA), or RTA type 1, a rare inherited or acquired disease, is a disorder of the distal tubule caused by impaired urinary acid secretion. Due to associated conditions and nonspecific symptoms, dRTA may go undetected. This analysis aims to estimate the prevalence of dRTA in the UK Clinical Practice Research Datalink (CPRD) databases and extrapolate it to European Union Five (EU5) populations. Methods: A retrospective analysis was conducted using the CPRD GOLD database and linked Hospital Episode Statistics (HES) data to identify diagnosed and potentially undiagnosed or miscoded patients (suspected patients). Patients’ records with at least one diagnosis code for dRTA, RTA, specific autoimmune diseases, or renal disorders recorded between January 1987 and November 2017 were obtained and analyzed. An algorithm was developed to detect potentially undiagnosed/miscoded dRTA, based on associated conditions and prescriptions. Results: A total of 216 patients with diagnosis of RTA or dRTA were identified (with 98 linked to hospital data), and 447 patients were identified as having suspected dRTA. dRTA prevalence for 2017 was estimated between 0.46 (recorded cases, of which 22.1% were considered primary) and 1.60 when including suspected cases (7.6% primary) per 10,000 people. Prescription and clinical records of diagnosed patients revealed a wide range of comorbidities and a need for pharmacological treatment to manage associated symptoms. Conclusion: The study provides new estimates of dRTA prevalence in Europe and suggests that patients may often be unreported or miscoded, potentially confounding appropriate disease management

Temporal regulation of expression of immediate early and second phase transcripts by endothelin-1 in cardiomyocytes

Background: Endothelin-1 stimulates Gq protein-coupled receptors to promote proliferation in dividing cells or hypertrophy in terminally differentiated cardiomyocytes. In cardiomyocytes, endothelin-1 rapidly (within minutes) stimulates protein kinase signaling, including extracellular-signal regulated kinases 1/2 (ERK1/2; though not ERK5), with phenotypic/physiological changes developing from approximately 12 h. Hypertrophy is associated with changes in mRNA/protein expression, presumably consequent to protein kinase signaling, but the connections between early, transient signaling events and developed hypertrophy are unknown. Results: Using microarrays, we defined the early transcriptional responses of neonatal rat cardiomyocytes to endothelin-1 over 4 h, differentiating between immediate early gene (IEG) and second phase RNAs with cycloheximide. IEGs exhibited differential temporal and transient regulation, with expression of second phase RNAs within 1 h. Of transcripts upregulated at 30 minutes encoding established proteins, 28 were inhibited >50% by U0126 (which inhibits ERK1/2/5 signaling), with 9 inhibited 25-50%. Expression of only four transcripts was not inhibited. At 1 h, most RNAs (approximately 67%) were equally changed in total and polysomal RNA with approximately 17% of transcripts increased to a greater extent in polysomes. Thus, changes in expression of most protein-coding RNAs should be reflected in protein synthesis. However, approximately 16% of transcripts were essentially excluded from the polysomes, including some protein-coding mRNAs, presumably inefficiently translated. Conclusion: The phasic, temporal regulation of early transcriptional responses induced by endothelin-1 in cardiomyocytes indicates that, even in terminally differentiated cells, signals are propagated beyond the primary signaling pathways through transcriptional networks leading to phenotypic changes (that is, hypertrophy). Furthermore, ERK1/2 signaling plays a major role in this response

“manual para el procesamiento de agua de inyección en un campo petrolero”

El presente trabajo trata acerca de resumir las operaciones más comunes realizadas en un campo petrolero para el análisis de aguas de rio en un proyecto de inyección de aguas. Entre los puntos que destacamos están los problemas mas comunes en el agua de rio como son la corrosión, la escala, la presencia de gases disueltos, presencia bacterial y los solidos disueltos. Además se hizo un pequeño estudio de las pruebas mas comunes antes de una inyección, con datos reales de un pozo del campo ecuatoriano, entre los puntos analizados tenemos las pruebas de compatibilidad y la prueba de Fall off test. Las cuales nos dan la máxima tasa de inyección a la cual se podrá someter el pozo inyector, con esta prueba podremos hallar de igual manera la presión de fractura. La importancia de realizar estos tipos de análisis son para evitar problemas futuros en las líneas de superficie, en el fondo del pozo o para la realización de futuras recuperaciones mejoradas con base a la presión de fondo de pozo y su presión de fractura. Para la realización del tratamiento del agua se recomienda un orden, el cual mejorara su calidad, los cuales son: Desbaste Desarenado Clarificación Filtración Des aeración Tratamiento Bacteriológico Tratamiento anticorrosivo Así mismo para realización de un adecuado tratamiento los parámetros a medir son: Cationes y aniones Ph Bacterias Solidos Suspendidos Turbidez Calidad de Agua Gases Disueltos Temperatura Conductividad

Turner et al. Reply to "Emergence of the Same Successful Clade among Distinct Populations of emm89 Streptococcus pyogenes in Multiple Geographic Regions"

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Exploring user motor behaviour in bimanual interactive video games

Video games have proved very valuable in rehabilitation technologies. They guide therapy and keep patients engaged and motivated. However, in order to realize their full potential, a good understanding is required of the players' motor control. In particular, little is known regarding player behaviour in tasks demanding bimanual interaction. In this work, an experiment was designed to improve the understanding of such tasks. A driving game was developed in which players were asked to guide a differential wheeled robot (depicted as a rocket) along a trajectory. The rocket could be manipulated by using an Xbox controller's triggers, each supplying torque to the corresponding side of the robot. Such a task is redundant, i.e. there exists an infinite number of input combinations to yield a given outcome. This allows the player to strategize according to their own preference. 10 participants were recruited to play this game and their input data was logged for subsequent analysis. Two different motor strategies were identified: an "intermittent" input pattern versus a "continuous" one. It is hypothesized that the choice of behaviour depends on motor skill and minimization of effort and error. Further testing is necessary to determine the exact relationship between these aspects

Analyse des délais de prise en charge des cancers thoraciques : étude prospective

RésuméIntroductionLe cancer broncho-pulmonaire est la première cause de décès par cancer en France. Son diagnostic est le plus souvent tardif, alors que le délai entre le début des symptômes et la prise en charge est considéré comme un facteur aggravant.Matériel et méthodesNotre étude prospective a recueilli les différentes dates de prise en charge de 139 patients consécutifs bénéficiant d’un traitement primaire pour un cancer thoracique dans notre hôpital entre novembre 2008 et mai 2009. L’objectif de cette étude était d’évaluer différents délais de prise en charge des patients porteurs d’un cancer thoracique quelle que soit sa prise en charge thérapeutique (médicale ou chirurgicale) et de déterminer la cause de ces délais.RésultatsLe délai médian entre la première imagerie pathologique et le traitement est de 9,6 semaines. Les délais étaient significativement plus courts dans les stades tardifs et les carcinomes à petites cellules (p=0,001). Il existait une tendance à des délais plus courts pour les femmes et des délais plus longs pour les classes d’âge les plus élevées.ConclusionL’évaluation des délais de prise en charge, en particulier pour les stades précoces, s’intègre dans le contrôle de la qualité de prise en charge de ces pathologies.SummaryIntroductionLung cancer is the main cause of cancer death in France. The diagnosis is often late and the delay between the onset of symptoms and management is considered an aggravating factor.Material and methodsOur prospective study collected the dates of the start of management of 139 consecutive patients receiving first line treatment for thoracic cancer in our hospital between November 2008 and May 2009. The aim of this study was to evaluate the delays in medical or surgical treatments in patients with thoracic cancer and to determine the cause of these delays.ResultsThe median delay between the first abnormal chest X-ray and treatment was 9.6 weeks. The delays were significantly shorter in the late stages and in small cell cancer (P=0.001). There was a tendency for shorter delays in women and for longer delays in older patients.ConclusionEvaluation of the delays in treatment, particularly in the early stages, is part of the quality control of management of these diseases