Open chromatin profiling of human postmortem brain infers functional roles for non-coding schizophrenia loci.

Open chromatin provides access to DNA-binding proteins for the correct spatiotemporal regulation of gene expression. Mapping chromatin accessibility has been widely used to identify the location of cis regulatory elements (CREs) including promoters and enhancers. CREs show tissue- and cell-type specificity and disease-associated variants are often enriched for CREs in the tissues and cells that pertain to a given disease. To better understand the role of CREs in neuropsychiatric disorders we applied the Assay for Transposase Accessible Chromatin followed by sequencing (ATAC-seq) to neuronal and non-neuronal nuclei isolated from frozen postmortem human brain by fluorescence-activated nuclear sorting (FANS). Most of the identified open chromatin regions (OCRs) are differentially accessible between neurons and non-neurons, and show enrichment with known cell type markers, promoters and enhancers. Relative to those of non-neurons, neuronal OCRs are more evolutionarily conserved and are enriched in distal regulatory elements. Transcription factor (TF) footprinting analysis identifies differences in the regulome between neuronal and non-neuronal cells and ascribes putative functional roles to a number of non-coding schizophrenia (SCZ) risk variants. Among the identified variants is a Single Nucleotide Polymorphism (SNP) proximal to the gene encoding SNX19. In vitro experiments reveal that this SNP leads to an increase in transcriptional activity. As elevated expression of SNX19 has been associated with SCZ, our data provide evidence that the identified SNP contributes to disease. These results represent the first analysis of OCRs and TF-binding sites in distinct populations of postmortem human brain cells and further our understanding of the regulome and the impact of neuropsychiatric disease-associated genetic risk variants.

Crowdsourced estimation of cognitive decline and resilience in Alzheimer's disease.

Identifying accurate biomarkers of cognitive decline is essential for advancing early diagnosis and prevention therapies in Alzheimer's disease. The Alzheimer's disease DREAM Challenge was designed as a computational crowdsourced project to benchmark the current state-of-the-art in predicting cognitive outcomes in Alzheimer's disease based on high dimensional, publicly available genetic and structural imaging data. This meta-analysis failed to identify a meaningful predictor developed from either data modality, suggesting that alternate approaches should be considered for prediction of cognitive performance.

Hydrologic variation influences stream fish assemblage dynamics through flow regime and drought.

Hydrologic variation can play a major role in structuring stream fish assemblages and relationships between hydrology and biology are likely to be influenced by flow regime. We hypothesized that more variable flow regimes would have lower and more variable species richness, higher species turnover and lower assemblage stability, and greater abiotic environment-fish relationships than more stable flow regimes. We sampled habitats (pool, run, and riffle) in three Runoff/Intermittent Flashy streams (highly variable flow regime) and three Groundwater Flashy streams (less variable flow regime) seasonally (spring, early summer, summer and autumn) in 2002 (drought year) and 2003 (wet year). We used backpack electrofishing and three-pass removal techniques to estimate fish species richness, abundance and density. Fish species richness and abundance remained relatively stable within streams and across seasons, but densities changed substantially as a result of decreased habitat volume. Mixed model analysis showed weak response variable-habitat relationships with strong season effects in 2002, and stronger habitat relationships and no season effect in 2003, and flow regime was not important in structuring these relationships. Seasonal fish species turnover was significantly greater in 2002 than 2003, but did not differ between flow regimes. Fish assemblage stability was significantly lower in Runoff/Intermittent Flashy than Groundwater Flashy streams in 2002, but did not differ between flow regimes in 2003. Redundancy analysis showed fish species densities were well separated by flow regime in both years. Periodic and opportunistic species were characteristic of Runoff/Intermittent Flashy streams, whereas mainly equilibrium species were characteristic of Groundwater Flashy streams. We found that spatial and temporal variation in hydrology had a strong influence on fish assemblage dynamics in Ozark streams with lower assemblage stability and greater fluctuations in density in more hydrologically variable streams and years. Understanding relationships between fish assemblage structure and hydrologic variation is vital for conservation of fish biodiversity. Future work should consider addressing how alteration of hydrologic variation will affect biotic assemblages.

Osteoblast-like cell attachment to and calcification of novel phosphonate-containing polymeric substrates.

In an attempt to interact natural bone and bone cells with biomaterials and to begin to develop modular tissue engineering scaffolds, substrates containing phosphonate groups were identified to mimic mineral-protein and natural polymer-protein interactions. In this study, we investigated poly(vinyl phosphonic acid) copolymer integration with existing materials as a graft-copolymer surface modification. Phosphonate-containing copolymer-modified surfaces were created and shown to have varying phosphate content within different polymeric surfaces. As the phosphonate content in the monomer feed approached 30% vinyl phosphonic acid, increased osteoblast-like cell adhesion (3- to 8-fold increase in adhesion) and proliferation (2- to 10-fold increase in proliferation rate) was observed. Since surfaces modified with 30% vinyl phosphonic acid in the feed exhibited a maximal cell adhesion and proliferation (9.4 x 10(4) cells/cm(2)/day), it was hypothesized that this copolymer composition was optimal for protein-polymer interactions. Osteoblast-like cells formed confluent layers and were able to differentiate on all surfaces that contained vinyl phosphonic acid. Most importantly, cells interacting with these surfaces were able to significantly mineralize the surface. These results suggest that phosphonate-containing polymers can be used to integrate biomaterials with natural bone and could be used for tissue engineering applications.

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.

DREAMTools: a Python package for scoring collaborative challenges.

UNLABELLED: DREAM challenges are community competitions designed to advance computational methods and address fundamental questions in system biology and translational medicine. Each challenge asks participants to develop and apply computational methods to either predict unobserved outcomes or to identify unknown model parameters given a set of training data. Computational methods are evaluated using an automated scoring metric, scores are posted to a public leaderboard, and methods are published to facilitate community discussions on how to build improved methods. By engaging participants from a wide range of science and engineering backgrounds, DREAM challenges can comparatively evaluate a wide range of statistical, machine learning, and biophysical methods. Here, we describe DREAMTools, a Python package for evaluating DREAM challenge scoring metrics. DREAMTools provides a command line interface that enables researchers to test new methods on past challenges, as well as a framework for scoring new challenges. As of March 2016, DREAMTools includes more than 80% of completed DREAM challenges. DREAMTools complements the data, metadata, and software tools available at the DREAM website http://dreamchallenges.org and on the Synapse platform at https://www.synapse.org. AVAILABILITY:   DREAMTools is a Python package. Releases and documentation are available at http://pypi.python.org/pypi/dreamtools. The source code is available at http://github.com/dreamtools/dreamtools.

Human immunodeficiency virus type 1 Nef-mediated downregulation of CD4 correlates with Nef enhancement of viral pathogenesis.

The nef gene products encoded by human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus type 1 (SIV-1) increase viral loads in infected hosts and accelerate clinical progression to AIDS. Nef exhibits a spectrum of biological activities, including the ability to downregulate surface expression of CD4 and major histocompatibility complex (MHC) class I antigens, to alter the state of T-cell activation, and to enhance the infectivity of viral particles. To determine which of these in vitro functions most closely correlates with the pathogenic effects of Nef in vivo, we constructed recombinant HIV-1 NL4-3 viruses carrying mutations within the nef gene that selectively impair these functions. These mutant viruses were evaluated for pathogenic potential in severe combined immunodeficiency (SCID) mice implanted with human fetal thymus and liver (SCID-hu Thy/Liv mice), in which virus-mediated depletion of thymocytes is known to be Nef dependent. Disruption of the polyproline type II helix (Pxx)4 within Nef (required for binding of Hck and p21-activated kinase-like kinases, downregulation of MHC class I, and enhancement of HIV-1 infectivity in vitro but dispensable for CD4 downregulation) did not impair thymocyte depletion in virus-infected Thy/Liv human thymus implants. Conversely, three separate point mutations in Nef that compromised its ability to downregulate CD4 attenuated thymocyte depletion while not diminishing viral replication. These findings indicate that the functional ability of Nef to downregulate CD4 and not MHC class I downregulation, Hck or PAK binding, or (Pxx)4-associated enhancement of infectivity most closely correlates with Nef-mediated enhancement of HIV-1 pathogenicity in vivo. Nef-mediated CD4 downregulation merits consideration as a new target for the development of small-molecule inhibitors.