The European Scleroderma Trials and Research group (EUSTAR) task force for the development of revised activity criteria for systemic sclerosis: derivation and validation of a preliminarily revised EUSTAR activity index

Background Validity of European Scleroderma Study Group (EScSG) activity indexes currently used to assess disease activity in systemic sclerosis (SSc) has been criticised. Methods Three investigators assigned an activity score on a 0–10 scale for 97 clinical charts. The median score served as gold standard. Two other investigators labelled the disease as inactive/moderately active or active/very active. Univariate–multivariate linear regression analyses were used to define variables predicting the ‘gold standard’, their weight and derive an activity index. The cut-off point of the index best separating active/very active from inactive/moderately active disease was identified by a receiver-operating curve analysis. The index was validated on a second set of 60 charts assessed by three different investigators on a 0–10 scale and defined as inactive/moderately active or active/very active by other two investigators. One hundred and twenty-three were investigated for changes over time in the index and their relationships with those in the summed Medsger severity score (MSS). Results A weighted 10-point activity index was identified and validated: Δ-skin=1.5 (Δ=patient assessed worsening during the previous month), modified Rodnan skin score (mRss) \u3e18=1.5, digital ulcers=1.5, tendon friction rubs=2.25, C-reactive protein \u3e1 mg/dL=2.25 and diffusing capacity of the lung for CO (DLCO) % predicted \u3c70%=1.0. A cut-off ≥2.5 was found to identify patients with active disease. Changes in the index paralleled those of MSS (p=0.0001). Conclusions A preliminarily revised SSc activity index has been developed and validated, providing a valuable tool for clinical practice and observational studies

Transgenic overexpression of γ-cytoplasmic actin protects against eccentric contraction-induced force loss in mdx mice

<p>Abstract</p> <p>Background</p> <p>γ-cytoplasmic (γ-_cyto) actin levels are elevated in dystrophin-deficient <it>mdx </it>mouse skeletal muscle. The purpose of this study was to determine whether further elevation of γ-_cytoactin levels improve or exacerbate the dystrophic phenotype of <it>mdx </it>mice.</p> <p>Methods</p> <p>We transgenically overexpressed γ-_cytoactin, specifically in skeletal muscle of mdx mice (<it>mdx</it>-TG), and compared skeletal muscle pathology and force-generating capacity between <it>mdx </it>and <it>mdx</it>-TG mice at different ages. We investigated the mechanism by which γ-_cytoactin provides protection from force loss by studying the role of calcium channels and stretch-activated channels in isolated skeletal muscles and muscle fibers. Analysis of variance or independent <it>t</it>-tests were used to detect statistical differences between groups.</p> <p>Results</p> <p>Levels of γ-_cytoactin in <it>mdx</it>-TG skeletal muscle were elevated 200-fold compared to <it>mdx </it>skeletal muscle and incorporated into thin filaments. Overexpression of γ-_cytoactin had little effect on most parameters of <it>mdx </it>muscle pathology. However, γ-_cytoactin provided statistically significant protection against force loss during eccentric contractions. Store-operated calcium entry across the sarcolemma did not differ between <it>mdx </it>fibers compared to wild-type fibers. Additionally, the omission of extracellular calcium or the addition of streptomycin to block stretch-activated channels did not improve the force-generating capacity of isolated extensor digitorum longus muscles from <it>mdx </it>mice during eccentric contractions.</p> <p>Conclusions</p> <p>The data presented in this study indicate that upregulation of γ-_cytoactin in dystrophic skeletal muscle can attenuate force loss during eccentric contractions and that the mechanism is independent of activation of stretch-activated channels and the accumulation of extracellular calcium.</p

On the robustness of bucket brigade quantum RAM

We study the robustness of the bucket brigade quantum random access memory model introduced by Giovannetti, Lloyd, and Maccone [Phys. Rev. Lett. 100, 160501 (2008)]. Due to a result of Regev and Schiff [ICALP '08 pp. 773], we show that for a class of error models the error rate per gate in the bucket brigade quantum memory has to be of order $o(2^{-n/2})$ (where $N=2^n$ is the size of the memory) whenever the memory is used as an oracle for the quantum searching problem. We conjecture that this is the case for any realistic error model that will be encountered in practice, and that for algorithms with super-polynomially many oracle queries the error rate must be super-polynomially small, which further motivates the need for quantum error correction. By contrast, for algorithms such as matrix inversion [Phys. Rev. Lett. 103, 150502 (2009)] or quantum machine learning [Phys. Rev. Lett. 113, 130503 (2014)] that only require a polynomial number of queries, the error rate only needs to be polynomially small and quantum error correction may not be required. We introduce a circuit model for the quantum bucket brigade architecture and argue that quantum error correction for the circuit causes the quantum bucket brigade architecture to lose its primary advantage of a small number of "active" gates, since all components have to be actively error corrected.Comment: Replaced with the published version. 13 pages, 9 figure

Destabilization of the Dystrophin-Glycoprotein Complex without Functional Deficits in α-Dystrobrevin Null Muscle

α-Dystrobrevin is a component of the dystrophin-glycoprotein complex (DGC) and is thought to have both structural and signaling roles in skeletal muscle. Mice deficient for α-dystrobrevin (adbn−/−) exhibit extensive myofiber degeneration and neuromuscular junction abnormalities. However, the biochemical stability of the DGC and the functional performance of adbn−/− muscle have not been characterized. Here we show that the biochemical association between dystrophin and β-dystroglycan is compromised in adbn−/− skeletal muscle, suggesting that α-dystrobrevin plays a structural role in stabilizing the DGC. However, despite muscle cell death and DGC destabilization, costamere organization and physiological performance is normal in adbn−/− skeletal muscle. Our results demonstrate that myofiber degeneration alone does not cause functional deficits and suggests that more complex pathological factors contribute to the development of muscle weakness in muscular dystrophy

Isolation of a Human Anti-HIV gp41 Membrane Proximal Region Neutralizing Antibody by Antigen-Specific Single B Cell Sorting

Broadly neutralizing antibodies are not commonly produced in HIV-1 infected individuals nor by experimental HIV-1 vaccines. When these antibodies do occur, it is important to be able to isolate and characterize them to provide clues for vaccine design. CAP206 is a South African subtype C HIV-1-infected individual previously shown to have broadly neutralizing plasma antibodies targeting the envelope gp41 distal membrane proximal external region (MPER). We have now used a fluoresceinated peptide tetramer antigen with specific cell sorting to isolate a human neutralizing monoclonal antibody (mAb) against the HIV-1 envelope gp41 MPER. The isolated recombinant mAb, CAP206-CH12, utilized a portion of the distal MPER (HXB2 amino acid residues, 673–680) and neutralized a subset of HIV-1 pseudoviruses sensitive to CAP206 plasma antibodies. Interestingly, this mAb was polyreactive and used the same germ-line variable heavy (VH1-69) and variable kappa light chain (VK3-20) gene families as the prototype broadly neutralizing anti-MPER mAb, 4E10 (residues 672–680). These data indicate that there are multiple immunogenic targets in the C-terminus of the MPER of HIV-1 gp41 envelope and suggests that gp41 neutralizing epitopes may interact with a restricted set of naive B cells during HIV-1 infection

The psychological science accelerator’s COVID-19 rapid-response dataset

In response to the COVID-19 pandemic, the Psychological Science Accelerator coordinated three large-scale psychological studies to examine the effects of loss-gain framing, cognitive reappraisals, and autonomy framing manipulations on behavioral intentions and affective measures. The data collected (April to October 2020) included specific measures for each experimental study, a general questionnaire examining health prevention behaviors and COVID-19 experience, geographical and cultural context characterization, and demographic information for each participant. Each participant started the study with the same general questions and then was randomized to complete either one longer experiment or two shorter experiments. Data were provided by 73,223 participants with varying completion rates. Participants completed the survey from 111 geopolitical regions in 44 unique languages/dialects. The anonymized dataset described here is provided in both raw and processed formats to facilitate re-use and further analyses. The dataset offers secondary analytic opportunities to explore coping, framing, and self-determination across a diverse, global sample obtained at the onset of the COVID-19 pandemic, which can be merged with other time-sampled or geographic data

A global experiment on motivating social distancing during the COVID-19 pandemic

Finding communication strategies that effectively motivate social distancing continues to be a global public health priority during the COVID-19 pandemic. This cross-country, preregistered experiment (n = 25,718 from 89 countries) tested hypotheses concerning generalizable positive and negative outcomes of social distancing messages that promoted personal agency and reflective choices (i.e., an autonomy-supportive message) or were restrictive and shaming (i.e., a controlling message) compared with no message at all. Results partially supported experimental hypotheses in that the controlling message increased controlled motivation (a poorly internalized form of motivation relying on shame, guilt, and fear of social consequences) relative to no message. On the other hand, the autonomy-supportive message lowered feelings of defiance compared with the controlling message, but the controlling message did not differ from receiving no message at all. Unexpectedly, messages did not influence autonomous motivation (a highly internalized form of motivation relying on one’s core values) or behavioral intentions. Results supported hypothesized associations between people’s existing autonomous and controlled motivations and self-reported behavioral intentions to engage in social distancing. Controlled motivation was associated with more defiance and less long-term behavioral intention to engage in social distancing, whereas autonomous motivation was associated with less defiance and more short- and long-term intentions to social distance. Overall, this work highlights the potential harm of using shaming and pressuring language in public health communication, with implications for the current and future global health challenges