Ito channels are octomeric complexes with four subunits of each Kv4.2 and K+ channel-interacting protein 2.

Mammalian voltage-gated K+ channels are assemblies of pore-forming alpha-subunits and modulating beta-subunits. To operate correctly, Kv4 alpha-subunits in the heart and central nervous system require recently identified beta-subunits of the neuronal calcium sensing protein family called K+ channel-interacting proteins (KChIPs). Here, Kv4.2.KChIP2 channels are purified, integrity of isolated complexes confirmed, molar ratio of the subunits determined, and subunit valence established. A complex has 4 subunits of each type, a stoichiometry expected for other channels employing neuronal calcium sensing beta-subunits

Three-dimensional structure of I(to); Kv4.2-KChIP2 ion channels by electron microscopy at 21 Angstrom resolution.

Regulatory KChIP2 subunits assemble with pore-forming Kv4.2 subunits in 4:4 complexes to produce native voltage-gated potassium (Kv) channels like cardiac I(to) and neuronal I(A) subtypes. Here, negative stain electron microscopy (EM) and single particle averaging reveal KChIP2 to create a novel approximately 35 x 115 x 115 Angstrom, intracellular fenestrated rotunda: four peripheral columns that extend down from the membrane-embedded portion of the channel to enclose the Kv4.2 "hanging gondola" (a platform held beneath the transmembrane conduction pore by four internal columns). To reach the pore from the cytosol, ions traverse one of four external fenestrae to enter the rotundal vestibule and then cross one of four internal windows in the gondola

Three-Dimensional Structure of Ito Kv4.2-KChIP2 Ion Channels by Electron Microscopy at 21 Å Resolution

AbstractRegulatory KChIP2 subunits assemble with pore-forming Kv4.2 subunits in 4:4 complexes to produce native voltage-gated potassium (Kv) channels like cardiac Ito and neuronal IA subtypes. Here, negative stain electron microscopy (EM) and single particle averaging reveal KChIP2 to create a novel ∼35 × 115 × 115 Å, intracellular fenestrated rotunda: four peripheral columns that extend down from the membrane-embedded portion of the channel to enclose the Kv4.2 “hanging gondola” (a platform held beneath the transmembrane conduction pore by four internal columns). To reach the pore from the cytosol, ions traverse one of four external fenestrae to enter the rotundal vestibule and then cross one of four internal windows in the gondola

La géohistoire des inondations au service de l’évaluation critique du zonage du Plan de Prévention des Risques d’Inondation : l’exemple de Thann (Haut-Rhin, France)

Thann, entre Massif Vosgien et plaine d’Alsace, est une des premières villes du Haut-Rhin à avoir fait l’objet d’un Plan de Prévention des Risques d’Inondation (PPRI). La commune est en effet traversée par la Thur, caractérisée par des crues violentes. Pour autant, le zonage du PPRI de la Thur ne mentionne qu’une zone à risque assez réduite. Or la ville a été victime par le passé d’inondations destructrices, telles que le révèle la base de données TRANSRISK. Parmi ces événements, la crue de décembre 1947, très bien documentée, permet, à travers une approche géohistorique (contextualisation, transposition), la confrontation spatiale des zones inondées en 1947 et des zones classées inondables par le PPRI. Les résultats soulèvent de nombreuses questions quant à la qualité du zonage du PPRI qui semble pécher par erreur et par omission. Et en cas de crue centennale, les dégâts seraient catastrophiques. Si la reconstitution de 1947 offre un scénario du pire, cela peut aussi constituer une base de préparation de gestion de crise.Thann, between the Vosges Mountains and the Alsace plain, is one of the first cities of Haut-Rhin to have been concerned by a Flood Risks Prevention Plan (PPRI). The town is indeed crossed by the Thur river, characterized by violent floods. However, the zoning of the PPRI mentions only a relatively small risk area. But the city has suffered in the past from destructive floods, as it is revealed by the TRANSRISK database. Among these events, the flood of December 1947, very well documented, allows, through a geo-historical approach (contextualization, transposition), the spatial confrontation of areas flooded in 1947 and flood areas designated by the PPRI. The results raise many questions about the quality of PPRI zoning that appears to present errors and omissions. And in the case of a 100-year flood, the damage would be catastrophic. If the re-enactment of the 1947 flood features a worst case scenario, this can also be the basis for a preparation for crisis management

The DONE framework: Creation, evaluation, and updating of an interdisciplinary, dynamic framework 2.0 of determinants of nutrition and eating.

The question of which factors drive human eating and nutrition is a key issue in many branches of science. We describe the creation, evaluation, and updating of an interdisciplinary, interactive, and evolving "framework 2.0" of Determinants Of Nutrition and Eating (DONE). The DONE framework was created by an interdisciplinary workgroup in a multiphase, multimethod process. Modifiability, relationship strength, and population-level effect of the determinants were rated to identify areas of priority for research and interventions. External experts positively evaluated the usefulness, comprehensiveness, and quality of the DONE framework. An approach to continue updating the framework with the help of experts was piloted. The DONE framework can be freely accessed (http://uni-konstanz.de/DONE) and used in a highly flexible manner: determinants can be sorted, filtered and visualized for both very specific research questions as well as more general queries. The dynamic nature of the framework allows it to evolve as experts can continually add new determinants and ratings. We anticipate this framework will be useful for research prioritization and intervention development

The role of leadership in salespeople’s price negotiation behavior

Salespeople assume a key role in defending firms’ price levels in price negotiations with customers. The degree to which salespeople defend prices should critically depend upon their leaders’ influence. However, the influence of leadership on salespeople’s price defense behavior is barely understood, conceptually or empirically. Therefore, building on social learning theory, the authors propose that salespeople might adopt their leaders’ price defense behavior given a transformational leadership style. Furthermore, drawing on the contingency leadership perspective, the authors argue that this adoption fundamentally depends on three variables deduced from the motivation–ability–opportunity (MAO) framework, that is, salespeople’s learning motivation, negotiation efficacy, and perceived customer lenience. Results of a multi-level model using data from 92 salespeople and 264 salesperson–customer interactions confirm these predictions. The first to explore contingencies of salespeople’s adoption of their transformational leaders’ price negotiation behaviors, this study extends marketing theory and provides actionable guidance to practitioners

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update

Recent insights in rheumatoid arthritis (RA) necessitated updating the European League Against Rheumatism (EULAR) RA management recommendations. A large international Task Force based decisions on evidence from 3 systematic literature reviews, developing 4 overarching principles and 12 recommendations (vs 3 and 14, respectively, in 2013). The recommendations address conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GC); biological (b) DMARDs (tumour necrosis factor (TNF)-inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, clazakizumab, sarilumab and sirukumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (Janus kinase (Jak) inhibitors tofacitinib, baricitinib). Monotherapy, combination therapy, treatment strategies (treat-to-target) and the targets of sustained clinical remission (as defined by the American College of Rheumatology-(ACR)-EULAR Boolean or index criteria) or low disease activity are discussed. Cost aspects were taken into consideration. As first strategy, the Task Force recommends MTX (rapid escalation to 25 mg/week) plus short-term GC, aiming at >50% improvement within 3 and target attainment within 6 months. If this fails stratification is recommended. Without unfavourable prognostic markers, switching to—or adding—another csDMARDs (plus short-term GC) is suggested. In the presence of unfavourable prognostic markers (autoantibodies, high disease activity, early erosions, failure of 2 csDMARDs), any bDMARD (current practice) or Jak-inhibitor should be added to the csDMARD. If this fails, any other bDMARD or tsDMARD is recommended. If a patient is in sustained remission, bDMARDs can be tapered. For each recommendation, levels of evidence and Task Force agreement are provided, both mostly very high. These recommendations intend informing rheumatologists, patients, national rheumatology societies, hospital officials, social security agencies and regulators about EULAR's most recent consensus on the management of RA, aimed at attaining best outcomes with current therapies

Racial differences in systemic sclerosis disease presentation: a European Scleroderma Trials and Research group study

Objectives. Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations.Methods. SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses.Results. The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P < 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P < 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P < 0.001) diffuse skin involvement than had WP.AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P < 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P < 0.001; OR(BP) = 2.4, P < 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P < 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P < 0.001].Conclusion. Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality

Hybrid cosmic ray measurements using the IceAct telescopes in coincidence with the IceCube and IceTop detectors

IceAct is a proposed surface array of compact (50 cm diameter) and cost-effective Imaging Air Cherenkov Telescopes installed at the site of the IceCube Neutrino Observatory at the geographic South Pole. Since January 2019, two IceAct telescope demonstrators, featuring 61 silicon photomultiplier (SiPM) pixels have been taking data in the center of the IceTop surface array during the austral winter. We present the first analysis of hybrid cosmic ray events detected by the IceAct imaging air-Cherenkov telescopes in coincidence with the IceCube Neutrino Observatory, including the IceTop surface array and the IceCube in-ice array. By featuring an energy threshold of about 10 TeV and a wide field-of-view, the IceAct telescopes show promising capabilities of improving current cosmic ray composition studies: measuring the Cherenkov light emissions in the atmosphere adds new information about the shower development not accessible with the current detectors, enabling significantly better primary particle type discrimination on a statistical basis. The hybrid measurement also allows for detailed feasibility studies of detector cross-calibration and of cosmic ray veto capabilities for neutrino analyses. We present the performance of the telescopes, the results from the analysis of two years of data, and an outlook of a hybrid simulation for a future telescope array