The mPower Study, Parkinson Disease Mobile Data Collected Using Researchkit

Current measures of health and disease are often insensitive, episodic, and subjective. Further, these measures generally are not designed to provide meaningful feedback to individuals. The impact of high-resolution activity data collected from mobile phones is only beginning to be explored. Here we present data from mPower, a clinical observational study about Parkinson disease conducted purely through an iPhone app interface. The study interrogated aspects of this movement disorder through surveys and frequent sensor-based recordings from participants with and without Parkinson disease. Benefitting from large enrollment and repeated measurements on many individuals, these data may help establish baseline variability of real-world activity measurement collected via mobile phones, and ultimately may lead to quantification of the ebbs-and-flows of Parkinson symptoms. App source code for these data collection modules are available through an open source license for use in studies of other conditions. We hope that releasing data contributed by engaged research participants will seed a new community of analysts working collaboratively on understanding mobile health data to advance human health

Expression profiling predicts outcome in breast cancer

Gruvberger et al. postulate, in their commentary [1] published in this issue of Breast Cancer Research, that our “prognostic gene set may not be broadly applicable to other breast tumor cohorts”, and they suggest that “it may be important to define prognostic expression profiles separately in estrogen receptor (ER) positive and negative tumors”. This is based on two observations derived from our gene expression profiling data in breast cancer [2]: the overlap between reporter genes for prognosis and ER status, and Gruvberger et al.’s inability to confirm the prognosis prediction using a nonoptimal selection of 58 of our 231 prognosis reporter genes. The overlap between our prognosis reporter genes and the ER status genes is certainly very large, mainly because ~10 % of all genes on our microarray contain informatio

Autoreactivity and Exceptional CDR Plasticity (but Not Unusual Polyspecificity) Hinder Elicitation of the Anti-HIV Antibody 4E10

The broadly-neutralizing anti-HIV antibody 4E10 recognizes an epitope in the membrane-proximal external region of the HIV envelope protein gp41. Previous attempts to elicit 4E10 by vaccination with envelope-derived or reverse-engineered immunogens have failed. It was presumed that the ontogeny of 4E10-equivalent responses was blocked by inherent autoreactivity and exceptional polyreactivity. We generated 4E10 heavy-chain knock-in mice, which displayed significant B cell dysregulation, consistent with recognition of autoantigen/s by 4E10 and the presumption that tolerance mechanisms may hinder the elicitation of 4E10 or 4E10-equivalent responses. Previously proposed candidate 4E10 autoantigens include the mitochondrial lipid cardiolipin and a nuclear splicing factor, 3B3. However, using carefully-controlled assays, 4E10 bound only weakly to cardiolipin-containing liposomes, but also bound negatively-charged, non-cardiolipin-containing liposomes comparably poorly. 4E10/liposome binding was predominantly mediated by electrostatic interactions rather than presumed hydrophobic interactions. The crystal structure of 4E10 free of bound ligands showed a dramatic restructuring of the combining site, occluding the HIV epitope binding site and revealing profound flexibility, but creating an electropositive pocket consistent with non-specific binding of phospholipid headgroups. These results strongly suggested that antigens other than cardiolipin mediate 4E10 autoreactivity. Using a synthetic peptide library spanning the human proteome, we determined that 4E10 displays limited and focused, but unexceptional, polyspecificity. We also identified a novel autoepitope shared by three ER-resident inositol trisphosphate receptors, validated through binding studies and immunohistochemistry. Tissue staining with 4E10 demonstrated reactivity consistent with the type 1 inositol trisphosphate receptor as the most likely candidate autoantigen, but is inconsistent with splicing factor 3B3. These results demonstrate that 4E10 recognition of liposomes competes with MPER recognition and that HIV antigen and autoepitope recognition may be distinct enough to permit eliciting 4E10-like antibodies, evading autoimmunity through directed engineering. However, 4E10 combining site flexibility, exceptional for a highly-matured antibody, may preclude eliciting 4E10 by conventional immunization strategies

Comparison of the performance of photonic band-edge liquid crystal lasers using different dyes as the gain medium

The primary concern of this work is to study the emission characteristics of a series of chiral nematic liquid crystal lasers doped with different laser dyes (DCM, pyrromethene 580, and pyrromethene 597) at varying concentrations by weight (0.5-2 wt %) when optically pumped at 532 nm. Long-wavelength photonic band-edge laser emission is characterized in terms of threshold energy and slope efficiency. At every dye concentration investigated, the pyrromethene 597-doped lasers exhibit the highest slope efficiency (ranging from 15% to 32%) and the DCM-doped lasers the lowest (ranging from 5% to 13%). Similarly, the threshold was found to be, in general, higher for the DCM-doped laser samples in comparison to the pyrromethene-doped laser samples. These results are then compared with the spectral properties, quantum efficiencies and, where possible, fluorescence lifetimes of the dyes dispersed in a common nematic host. In accordance with the low thresholds and high slope efficiencies, the results show that the molar extinction coefficients and quantum efficiencies are considerably larger for the pyrromethene dyes in comparison to DCM, when dispersed in the liquid crystal host.open191

Ontogeny of Recognition Specificity and Functionality for the Broadly Neutralizing Anti-HIV Antibody 4E10

The process of antibody ontogeny typically improves affinity, on-rate, and thermostability, narrows polyspecificity, and rigidifies the combining site to the conformer optimal for binding from the broader ensemble accessible to the precursor. However, many broadly-neutralizing anti-HIV antibodies incorporate unusual structural elements and recognition specificities or properties that often lead to autoreactivity. The ontogeny of 4E10, an autoreactive antibody with unexpected combining site flexibility, was delineated through structural and biophysical comparisons of the mature antibody with multiple potential precursors. 4E10 gained affinity primarily by off-rate enhancement through a small number of mutations to a highly conserved recognition surface. Controverting the conventional paradigm, the combining site gained flexibility and autoreactivity during ontogeny, while losing thermostability, though polyspecificity was unaffected. Details of the recognition mechanism, including inferred global effects due to 4E10 binding, suggest that neutralization by 4E10 may involve mechanisms beyond simply binding, also requiring the ability of the antibody to induce conformational changes distant from its binding site. 4E10 is, therefore, unlikely to be re-elicited by conventional vaccination strategies