Sculpting ion channel functional expression with engineered ubiquitin ligases

The functional repertoire of surface ion channels is sustained by dynamic processes of trafficking, sorting, and degradation. Dysregulation of these processes underlies diverse ion channelopathies including cardiac arrhythmias and cystic fibrosis. Ubiquitination powerfully regulates multiple steps in the channel lifecycle, yet basic mechanistic understanding is confounded by promiscuity among E3 ligase/substrate interactions and ubiquitin code complexity. Here we targeted the catalytic domain of E3 ligase, CHIP, to YFP-tagged KCNQ1 ± KCNE1 subunits with a GFP-nanobody to selectively manipulate this channel complex in heterologous cells and adult rat cardiomyocytes. Engineered CHIP enhanced KCNQ1 ubiquitination, eliminated KCNQ1 surface-density, and abolished reconstituted K+ currents without affecting protein expression. A chemo-genetic variation enabling chemical control of ubiquitination revealed KCNQ1 surface-density declined with a ~ 3.5 hr t1/2 by impaired forward trafficking. The results illustrate utility of engineered E3 ligases to elucidate mechanisms underlying ubiquitin regulation of membrane proteins, and to achieve effective post-translational functional knockdown of ion channels

Educational needs of epileptologists regarding psychiatric comorbidities of the epilepsies: a descriptive quantitative survey.

Psychiatric disorders are relatively frequent comorbidities in epilepsy and they have an impact on morbidity, mortality, and quality of life. This is a report from the Task Force on Education of the ILAE Commission on Neuropsychiatry based on a survey about educational needs of epileptologists regarding management of the psychiatric comorbidities of epilepsy. The Task Force designed a quantitative questionnaire to survey the self-perceived confidence of child and adult epileptologists and psychiatrists in managing major psychiatric comorbidities of epilepsy to identify: (1) critical areas of improvement from a list of skills that are usually considered necessary for effective management of these conditions, and (2) the preferred educational format for improving these skills. A total of 211 respondents from 36 different countries participated in the survey. Confidence and usefulness scores suggest that responders would most value education and training in the management of specific clinical scenarios. Child neurologists identified major Axis I disorders, such as mood and anxiety disorders, while adult neurologists identified attention deficit hyperactivity disorder, intellectual disabilities, and autistic spectrum disorder as key areas. Both adult and child neurologists identified screening skills as the priority. Psychiatrists mainly valued specific training in the management of psychiatric complications of epilepsy surgery or psychiatric adverse events of antiepileptic drugs. Sessions during congresses and face-to-face meetings represent the preferred educational format, while e-learning modules and review papers were chosen by a minority of respondents. Results of this survey identify key areas for improvement in managing the psychiatric comorbidities of epilepsy and suggest specific strategies to develop better training for clinicians involved in epilepsy care

Is it possible to enhance immune response after vaccination? The role of a probiotic with a proven positive effect on all components of the immune system

Preventive vaccination is currently the most affordable and economical way to reduce morbidity and mortality from many infections, improve quality and human life expectancy with an almost ideal balance of benefits and risks among all medical procedures. The article deals with the reasons for variability of the immune response caused by vaccines, between individuals and between populations, which is of fundamental importance for human health. The authors have presented data indicating a key role of the gut microbiota in the control of the immune response to vaccination. Particular attention is paid to the microbial diversity in different loci of the body. The role of microorganisms in the proper functioning of the body and the formation of a number of pathological conditions is described. Most modern vaccines are live-attenuated, killed / inactivated or subunit (recombinant) vaccines, and they are designed for the parenteral route of administration. Most of these vaccines elicit a weak immune response, especially in the mucous membranes, due to the route of administration and are associated with weak cell-mediated immunity. Therefore, mechanisms that can enhance virus-specific vaccine immunity in infants and children are required, such as the use of more potent or selective immunity-enhancing adjuvants. Some probiotic strains may be considered as promising vaccine adjuvants. This article evaluates the recent clinical studies of probiotics used to enhance vaccine-specific immunity in adults and infants. The present-day knowledge on the role of the probiotic strain Lactobacillus rhamnosus GG with the aim of activating immunity after vaccination are presented

Infant colic: from theory to practice

Infant colic is one of the most common, yet least studied, functional disorders of the gastrointestinal tract. Until now, there is no certainty both in the understanding of the nature of this condition and in the approaches to its correction. At the same time, infant crying is of concern to parents, forcing them to seek professional help and incur considerable medical expenses and to resort, sometimes unreasonably, to dietary and medical corrections. This article provides information on the etiology, pathogenesis and management of infantile colic from an evidence-based perspective, based on a review of the current literature. Various preconditions for the occurrence and development of infantile colic are analysed in detail, none of which can affect all occurrences. Evidence for the proven efficacy of including Lactobacillus reuteri in the treatment of intestinal colic in infants is presented. Effects on the gastrointestinal tract microbiome can be of undeniable benefit. Lactobacillus reuteri is one of the most studied and scientifically documented probiotics. 203 completed clinical trials involving 17,200 participants, including 67 trials involving 8,200 participants between 0 and 3 years of age. Numerous placebo-controlled studies have shown that taking Lactobacillus reuteri DSM 17938 can significantly reduce crying time in infants with colic, and in these studies, rates of 50% or more reduction in crying time were 2.3 times higher compared to controls

Phase Diagram for Charge Density Waves in a Magnetic Field

The influence of an external magnetic field on a quasi one-dimensional system with a charge density wave (CDW) instability is treated within the random phase approximation which includes both CDW and spin density wave correlations. We show that the CDW is sensitive to both orbital and Pauli effects of the field. In the case of perfect nesting, the critical temperature decreases monotonously with the field, and the wave vector of the instability starts to shift above some critical value of magnetic field. Depending on the ratio between the spin and charge coupling constants and on the direction of the applied magnetic field, the wave vector shift is either parallel ($CDW_x$ order) or perpendicular ($CDW_y$ order) to the most conducting direction. The $CDW_x$ order is a field dependent linear combination of the charge and spin density waves and is sensible only to the Pauli effect. The wave vector shift in $CDW_y$ depends on the interchain coupling, but the critical temperature does not. This order is affected by the confinement of the electronic orbits. By increasing the relative strength of the orbital effect with respect to the Pauli effect, one can destroy the $CDW_y$, establishing either a $CDW_x$, or a $CDW_0$ (corresponding to perfect nesting wave vector). We also show that by increasing the imperfect nesting parameter, one passes from the regime where the critical temperature decreases with the field to the regime where it is initially enhanced by the orbital effect and eventually suppressed by the Pauli effect. For a bad nesting, the quantized phases of the field-induced CDW appear.Comment: 30 pages (LaTeX) + 15 figure

Electromagnetic follow-up of gravitational wave transient signal candidates

Pioneering efforts aiming at the development of multi-messenger gravitational wave and electromagnetic astronomy have been made. An electromagnetic observation follow-up program of candidate gravitational wave events has been performed (Dec 17 2009 to Jan 8 2010 and Sep 4 to Oct 20 2010) during the recent runs of the LIGO and Virgo gravitational wave detectors. It involved ground-based and space electromagnetic facilities observing the sky at optical, X-ray and radio wavelengths. The joint gravitational wave and electromagnetic observation study requires the development of specific image analysis procedures able to discriminate the possible electromagnetic counterpart of gravitational wave triggers from contaminant/background events. The paper presents an overview of the electromagnetic follow-up program and the image analysis procedures.Comment: Proceedings of the 12th International Conference on "Topics in Astroparticle and Underground Physics" (TAUP 2011), Munich, September 2011 (to appear in IoP Journal of Physics: Conference Series

Toward an optimal search strategy of optical and gravitational wave emissions from binary neutron star coalescence

Observations of an optical source coincident with gravitational wave emission detected from a binary neutron star coalescence will improve the confidence of detection, provide host galaxy localisation, and test models for the progenitors of short gamma ray bursts. We employ optical observations of three short gamma ray bursts, 050724, 050709, 051221, to estimate the detection rate of a coordinated optical and gravitational wave search of neutron star mergers. Model R-band optical afterglow light curves of these bursts that include a jet-break are extrapolated for these sources at the sensitivity horizon of an Advanced LIGO/Virgo network. Using optical sensitivity limits of three telescopes, namely TAROT (m=18), Zadko (m=21) and an (8-10) meter class telescope (m=26), we approximate detection rates and cadence times for imaging. We find a median coincident detection rate of 4 yr^{-1} for the three bursts. GRB 050724 like bursts, with wide opening jet angles, offer the most optimistic rate of 13 coincident detections yr^{-1}, and would be detectable by Zadko up to five days after the trigger. Late time imaging to m=26 could detect off-axis afterglows for GRB 051221 like bursts several months after the trigger. For a broad distribution of beaming angles, the optimal strategy for identifying the optical emissions triggered by gravitational wave detectors is rapid response searches with robotic telescopes followed by deeper imaging at later times if an afterglow is not detected within several days of the trigger.Comment: 6 pages, 1 figure, Accepted for publication in MNRAS Letters (2011 April 22

A List of Galaxies for Gravitational Wave Searches

We present a list of galaxies within 100 Mpc, which we call the Gravitational Wave Galaxy Catalogue (GWGC), that is currently being used in follow-up searches of electromagnetic counterparts from gravitational wave searches. Due to the time constraints of rapid follow-up, a locally available catalogue of reduced, homogenized data is required. To achieve this we used four existing catalogues: an updated version of the Tully Nearby Galaxy Catalog, the Catalog of Neighboring Galaxies, the V8k catalogue and HyperLEDA. The GWGC contains information on sky position, distance, blue magnitude, major and minor diameters, position angle, and galaxy type for 53,255 galaxies. Errors on these quantities are either taken directly from the literature or estimated based on our understanding of the uncertainties associated with the measurement method. By using the PGC numbering system developed for HyperLEDA, the catalogue has a reduced level of degeneracies compared to catalogues with a similar purpose and is easily updated. We also include 150 Milky Way globular clusters. Finally, we compare the GWGC to previously used catalogues, and find the GWGC to be more complete within 100 Mpc due to our use of more up-to-date input catalogues and the fact that we have not made a blue luminosity cut.Comment: Accepted for publication in Classical and Quantum Gravity, 13 pages, 7 figure

Pressure Tuning of the Charge Density Wave in the Halogen-Bridged Transition-Metal (MX) Solid Pt2Br6(NH3)4Pt_2Br_6(NH_3)_4

We report the pressure dependence up to 95 kbar of Raman active stretching modes in the quasi-one-dimensional MX chain solid $Pt_2Br_6(NH_3)_4$. The data indicate that a predicted pressure-induced insulator-to-metal transition does not occur, but are consistent with the solid undergoing either a three-dimensional structural distortion, or a transition from a charge-density wave to another broken-symmetry ground state. We show that such a transition cacan be well-modeled within a Peierls-Hubbard Hamiltonian. 1993 PACS: 71.30.+h, 71.45.Lr, 75.30.Fv, 78.30.-j, 81.40.VwComment: 4 pages, ReVTeX 3.0, figures available from the authors on request (Gary Kanner, [email protected]), to be published in Phys Rev B Rapid Commun, REVISION: minor typos corrected, LA-UR-94-246