The function of NaV1.8 clusters in lipid rafts

NaV1.8 is a voltage gated sodium channel mainly expressed on the membrane of thin diameter c-fibre neurons involved in the transmission of pain signals. In these neurons NaV1.8 is essential for the propagation of action potentials. NaV1.8 is located in lipid rafts along the axons of sensory neurons and disruption of these lipid rafts leads to NaV1.8 dependant conduction failure. Using computational modelling, I show that the clustering of NaV1.8 channels in lipid rafts along the axon of thin diameter neurons is energetically advantageous and requires fewer channels to conduct action potentials. During an action potential NaV1.8 currents across the membrane in these thin axons are large enough to dramatically change the sodium ion concentration gradient and thereby void the assumptions upon which the cable equation is based. Using scanning electron microscopy NaV1.8 is seen to be clustered, as are lipid raft marker proteins, on neurites at scales below 200nm. FRET signals show that the lipid raft marker protein Flotillin is densely packed on the membrane however disruption of rafts does not reduce the FRET signal from dense protein packing. Using mass spectrometry I investigated the population of proteins found in the lipid rafts of sensory neurons. I found that the membrane pump NaK-ATPase, which restores the ion concentrations across the membrane, is also contained in lipid rafts. NaK-ATPase may help to offset concentration changes due to NaV1.8 currents enabling the repeated firing of c-fibres, which is associated with spontaneous pain in chronic pain disorders.Open Acces

Widening the lens: An interdisciplinary approach to examining the effect of exposure therapy on public speaking state anxiety.

This study used an interdisciplinary approach to examine an intervention for reducing public speaking state anxiety. A quasi-experiment was conducted to determine if a multiple-exposure treatment technique (TRIPLESPEAK) would help to attenuate public speaking anxiety. The treatment group reported experiencing significantly less state anxiety during their post-test presentation than did the control group. This lead to the conclusion that exposure therapy can be used to help students enrolled in basic communication classes begin to overcome their fear of speaking in front of an audience. Follow-up analysis of the treatment group's reported anxiety levels during all five presentations (pre-test, Treatment Presentation 1, Treatment Presentation 2, Treatment Presentation 3, and post-test) revealed an increase in anxiety from the last treatment presentation to the post-test presentation. In order to explore this issue, Shannon's entropy was utilized to calculate the amount of information in each speaking environment. Anderson's functional ontology construction approach served as a model to explain the role of the environment in shaping speakers' current and future behaviors and reports of anxiety. The exploratory analysis revealed a functional relationship between information and anxiety. In addition, a qualitative study was conducted to determine which environmental stimuli speakers perceived contributed to their anxiety levels. Students reported experiencing anxiety based on four categories, which included speaker concerns, audience characteristics, contextual factors and assignment criteria. Students' reports of anxiety were dependent upon their previous speaking experiences, and students suggested differences existed between the traditional presentations and the treatment presentations. Pedagogical and theoretical implications are discussed

GravEn: Software for the simulation of gravitational wave detector network response

Physically motivated gravitational wave signals are needed in order to study the behaviour and efficacy of different data analysis methods seeking their detection. GravEn, short for Gravitational-wave Engine, is a MATLAB software package that simulates the sampled response of a gravitational wave detector to incident gravitational waves. Incident waves can be specified in a data file or chosen from among a group of pre-programmed types commonly used for establishing the detection efficiency of analysis methods used for LIGO data analysis. Every aspect of a desired signal can be specified, such as start time of the simulation (including inter-sample start times), wave amplitude, source orientation to line of sight, location of the source in the sky, etc. Supported interferometric detectors include LIGO, GEO, Virgo and TAMA.Comment: 10 Pages, 3 Figures, Presented at the 10th Gravitational Wave Data Analysis Workshop (GWDAW-10), 14-17 December 2005 at the University of Texas, Brownsvill

A First Comparison of SLOPE and Other LIGO Burst Event Trigger Generators

A number of different methods have been proposed to identify unanticipated burst sources of gravitational waves in data arising from LIGO and other gravitational wave detectors. When confronted with such a wide variety of methods one is moved to ask if they are all necessary, i.e. given detector data that is assumed to have no gravitational wave signals present, do they generally identify the same events with the same efficiency, or do they each 'see' different things in the detector? Here we consider three different methods, which have been used within the LIGO Scientific Collaboration as part of its search for unanticipated gravitational wave bursts. We find that each of these three different methods developed for identifying candidate gravitational wave burst sources are, in fact, attuned to significantly different features in detector data, suggesting that they may provide largely independent lists of candidate gravitational wave burst events.Comment: 10 Pages, 5 Figures, Presented at the 10th Gravitational Wave Data Analysis Workshop (GWDAW-10), 14-17 December 2005 at the University of Texas, Brownsvill

Prospectus, March 12, 2003

https://spark.parkland.edu/prospectus_2003/1007/thumbnail.jp

Assessing Communication Practice during Clinical Trial Recruitment and Consent: The Clinical Trial Communication Inventory (CTCI)

The development and evaluation of training programs with the potential to improve informed consent and accrual to clinical trials depend heavily on the ability to measure outcomes of these trainings. In this chapter, we present the development of an instrument, the clinical trial communication inventory (CTCI). Data were collected from 87 clinical research professionals at three academic medical centers, which were analyzed using factor analytic methods and reliability testing procedures. This testing resulted in eight subscales representing verbal, nonverbal, and privacy protection behaviors. While the final CTCI instrument would benefit from further validity testing, it represents a resource that can be used to evaluate future trainings of research professionals

Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.

Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.Funding for the project was provided by the Wellcome Trust for UK10K (WT091310) and DDD Study. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF-1009-003] - see www.ddduk.org/access.html for full acknowledgement. This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute and the Common Fund, NIH Office of the Director. This work was supported in part by the German Ministry of Research and Education (grant nos. 01GS08160 and 01GS08167; German Mental Retardation Network) as part of the National Genome Research Network to A.R. and D.W. and by the Deutsche Forschungsgemeinschaft (AB393/2-2) to A.R. Brain expression data was provided by the UK Human Brain Expression Consortium (UKBEC), which comprises John A. Hardy, Mina Ryten, Michael Weale, Daniah Trabzuni, Adaikalavan Ramasamy, Colin Smith and Robert Walker, affiliated with UCL Institute of Neurology (J.H., M.R., D.T.), King’s College London (M.R., M.W., A.R.) and the University of Edinburgh (C.S., R.W.)

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Researching COVID to enhance recovery (RECOVER) tissue pathology study protocol: Rationale, objectives, and design.

ImportanceSARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or organ dysfunction after the acute phase of infection, termed Post-Acute Sequelae of SARS-CoV-2 (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are poorly understood. The objectives of the Researching COVID to Enhance Recovery (RECOVER) tissue pathology study (RECOVER-Pathology) are to: (1) characterize prevalence and types of organ injury/disease and pathology occurring with PASC; (2) characterize the association of pathologic findings with clinical and other characteristics; (3) define the pathophysiology and mechanisms of PASC, and possible mediation via viral persistence; and (4) establish a post-mortem tissue biobank and post-mortem brain imaging biorepository.MethodsRECOVER-Pathology is a cross-sectional study of decedents dying at least 15 days following initial SARS-CoV-2 infection. Eligible decedents must meet WHO criteria for suspected, probable, or confirmed infection and must be aged 18 years or more at the time of death. Enrollment occurs at 7 sites in four U.S. states and Washington, DC. Comprehensive autopsies are conducted according to a standardized protocol within 24 hours of death; tissue samples are sent to the PASC Biorepository for later analyses. Data on clinical history are collected from the medical records and/or next of kin. The primary study outcomes include an array of pathologic features organized by organ system. Causal inference methods will be employed to investigate associations between risk factors and pathologic outcomes.DiscussionRECOVER-Pathology is the largest autopsy study addressing PASC among US adults. Results of this study are intended to elucidate mechanisms of organ injury and disease and enhance our understanding of the pathophysiology of PASC