Challenges in identifying cancer genes by analysis of exome sequencing data.

Massively parallel sequencing has permitted an unprecedented examination of the cancer exome, leading to predictions that all genes important to cancer will soon be identified by genetic analysis of tumours. To examine this potential, here we evaluate the ability of state-of-the-art sequence analysis methods to specifically recover known cancer genes. While some cancer genes are identified by analysis of recurrence, spatial clustering or predicted impact of somatic mutations, many remain undetected due to lack of power to discriminate driver mutations from the background mutational load (13-60% recall of cancer genes impacted by somatic single-nucleotide variants, depending on the method). Cancer genes not detected by mutation recurrence also tend to be missed by all types of exome analysis. Nonetheless, these genes are implicated by other experiments such as functional genetic screens and expression profiling. These challenges are only partially addressed by increasing sample size and will likely hold even as greater numbers of tumours are analysed

Study of a unified hardware and software fault-tolerant architecture

A unified architectural concept, called the Fault Tolerant Processor Attached Processor (FTP-AP), that can tolerate hardware as well as software faults is proposed for applications requiring ultrareliable computation capability. An emulation of the FTP-AP architecture, consisting of a breadboard Motorola 68010-based quadruply redundant Fault Tolerant Processor, four VAX 750s as attached processors, and four versions of a transport aircraft yaw damper control law, is used as a testbed in the AIRLAB to examine a number of critical issues. Solutions of several basic problems associated with N-Version software are proposed and implemented on the testbed. This includes a confidence voter to resolve coincident errors in N-Version software. A reliability model of N-Version software that is based upon the recent understanding of software failure mechanisms is also developed. The basic FTP-AP architectural concept appears suitable for hosting N-Version application software while at the same time tolerating hardware failures. Architectural enhancements for greater efficiency, software reliability modeling, and N-Version issues that merit further research are identified

Developing Predictive Molecular Maps of Human Disease through Community-based Modeling

The failure of biology to identify the molecular causes of disease has led to disappointment in the rate of development of new medicines. By combining the power of community-based modeling with broad access to large datasets on a platform that promotes reproducible analyses we can work towards more predictive molecular maps that can deliver better therapeutics

New age data on the geological evolution of Southern India

The Peninsular Gneisses of Southern India developed over a period of several hundred Ma in the middle-to-late Archaean. Gneisses in the Gorur-Hassan area of southern Karnataka are the oldest recognized constituents: Beckinsale et al. reported a preliminary Rb-Sr whole-rock isochron age of 33558 + or - 66 Ma, but further Rb-Sr and Pb/Pb whole-rock isochron determinations indicate a slightly younger, though more precise age of ca 3305 Ma (R. D. Beckinsale, Pers. Comm.). It is well established that the Peninsular Gneisses constitute basement on which the Dharwar schist belts were deposited. Well-documented exposures of unconformities, with basal quartz pebble conglomerates of the Dharwar Supergroup overlying Peninsular Gneisses, have been reported from the Chikmagalur and Chitradurga areas, and basement gneisses in these two areas have been dated by Rb-Sr and Pb/Pb whole-rock isochron methods at ca 3150 Ma and ca 3000 Ma respectively. Dharwar supracrustal rocks of the Chitradurga schist belt are intruded by the Chitradurga Granite, dated by a Pb/Pb whole-rock isochron at 2605 + or - 18 Ma. These results indicate that the Dharwar Supergroup in the Chitradurga belt was deposited between 3000 Ma and 2600 Ma

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

A nano-patterned photonic crystal laser with a dye-doped liquid crystal

Covering a nano-patterned titanium dioxide photonic crystal (PC) within a well-oriented film of dye-doped liquid crystal (LC), a distributed feedback laser is constructed whereby the emission characteristics can be manipulated in-situ using an electric field. This hybrid organic-inorganic structure permits simultaneous selectivity of both the beam pattern and laser wavelength by electrical addressing of the LC director. In addition, laser emission is obtained both in the plane and normal to the PC. Along with experimental data, a theoretical model is presented that is based upon an approximate calculation of the band structure of this birefringent, tuneable laser device

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