A framework for application of metabolic modeling in yeast to predict the effects of nsSNV in human orthologs

Background We have previously suggested a method for proteome wide analysis of variation at functional residues wherein we identified the set of all human genes with nonsynonymous single nucleotide variation (nsSNV) in the active site residue of the corresponding proteins. 34 of these proteins were shown to have a 1:1:1 enzyme:pathway:reaction relationship, making these proteins ideal candidates for laboratory validation through creation and observation of specific yeast active site knock-outs and downstream targeted metabolomics experiments. Here we present the next step in the workflow toward using yeast metabolic modeling to predict human metabolic behavior resulting from nsSNV. Results For the previously identified candidate proteins, we used the reciprocal best BLAST hits method followed by manual alignment and pathway comparison to identify 6 human proteins with yeast orthologs which were suitable for flux balance analysis (FBA). 5 of these proteins are known to be associated with diseases, including ribose 5-phosphate isomerase deficiency, myopathy with lactic acidosis and sideroblastic anaemia, anemia due to disorders of glutathione metabolism, and two porphyrias, and we suspect the sixth enzyme to have disease associations which are not yet classified or understood based on the work described herein. Conclusions Preliminary findings using the Yeast 7.0 FBA model show lack of growth for only one enzyme, but augmentation of the Yeast 7.0 biomass function to better simulate knockout of certain genes suggested physiological relevance of variations in three additional proteins. Thus, we suggest the following four proteins for laboratory validation: delta-aminolevulinic acid dehydratase, ferrochelatase, ribose-5 phosphate isomerase and mitochondrial tyrosyl-tRNA synthetase. This study indicates that the predictive ability of this method will improve as more advanced, comprehensive models are developed. Moreover, these findings will be useful in the development of simple downstream biochemical or mass-spectrometric assays to corroborate these predictions and detect presence of certain known nsSNVs with deleterious outcomes. Results may also be useful in predicting as yet unknown outcomes of active site nsSNVs for enzymes that are not yet well classified or annotated

Mobile integrated health to reduce post-discharge acute care visits: A pilot study

Background Mobile Integrated Health (MIH) leverages specially trained paramedics outside of emergency response to bridge gaps in local health care delivery. Study objective To evaluate the efficacy of a MIH led transitional care strategy to reduce acute care utilization. Methods This was a retrospective cohort analysis of a quality improvement pilot of patient patients from an urban, single county EMS, MIH transitional care initiative. We utilized a paramedic/social worker (or social care coordinator) dyad to provide in home assessments, medication review, care coordination, and improve access to care. The primary outcome compared acute care utilization (ED visits, observation stays, inpatient visits) 90 days before MIH intervention to 90 days after. Results Of the 203 patients seen by MIH teams, inpatient utilization decreased significantly from 140 hospitalizations pre-MIH to 26 post-MIH (83% reduction, p = 0.00). ED and observation stays, however, increased numerically, but neither was significant. (ED 18 to 19 stays, p = 0.98; observation stays 95 to 106, p = 0.30) Primary care visits increased 15% (p = 0.11). Conclusion In this pilot before/after study, MIH significantly reduces acute care hospitalizations

Molecular Beams

Contains research objectives, summary of research and reports on eight research projects.Joint Services Electronics Programs (U. S. Army, U. S. Navy, and U. S. Air Force) under Contract DAAB07-71-C-030

Imaging and treatment of posttraumatic ankle and hindfoot osteoarthritis

Posttraumatic osteoarthritis of the ankle and hindfoot is a common and frequently debil-itating disorder. 70% to 90% of ankle osteoarthritis is related to prior trauma that encompasses a spectrum of disorders including fractures and ligamentous injuries that either disrupt the articular surface or result in instability of the joint. In addition to clinical evaluation, imaging plays a sub-stantial role in the treatment planning of posttraumatic ankle and hindfoot osteoarthritis. Imaging evaluation must be tailored to specific clinical scenarios and includes weight bearing radiography that utilizes standard and specialty views, computed tomography which can be performed with a standard or a weight bearing technique, magnetic resonance imaging, and ultrasound evaluation. This review article aims to familiarize the reader with treatment rationale, to provide a brief review of surgical techniques and to illustrate expected imaging appearances of common operative procedures performed in the setting of posttraumatic ankle and hindfoot osteoarthritis, such as joint‐preserving procedures, ankle fusion, subtalar fusion, tibiotalarcalcaneal fusion and ankle arthroplasty. Preoperative findings will be discussed along with the expected postoperative ap-pearance of various procedures in order to improve detection of their complications on imaging and to provide optimal patient care

Relationships between Prediction Accuracy, Metacognitive Reflection, and Performance in Introductory Genetics Students

Cognitive scientists have previously shown that students&rsquo; perceptions of their learning and performance on assessments often do not match reality. This process of self-assessing performance is a component of metacognition, which also includes the practice of thinking about one&rsquo;s knowledge and identifying and implementing strategies to improve understanding. We used a mixed-methods approach to investigate the relationship between students&rsquo; perceptions of their performance through grade predictions, their metacognitive reflections after receiving their grades, and their actual performance during a semester-long introductory genetics course. We found that, as a group, students do not display better predictive accuracy nor more metacognitive reflections over the semester. However, those who shift from overpredicting to matching or underpredicting also show improved performance. Higher performers are overall more likely to answer reflection questions than lower-performing peers. Although high-performing students are usually more metacognitive in their reflections, an increase in a student&rsquo;s frequency of metacognitive responses over time does not necessarily predict a grade increase. We illustrate several example trends in student reflections and suggest possible next steps for helping students implement better metacognitive regulation. &nbsp;</p

The clustering of galaxies in the SDSS-III Baryon Oscillation Spectroscopic Survey : cosmological implications of the full shape of the clustering wedges in the data release 10 and 11 galaxy samples

We explore the cosmological implications of the angle-averaged correlation function, ξ(s), and the clustering wedges, ξ⊥(s) and ξ∥(s), of the LOWZ and CMASS galaxy samples from Data Releases 10 and 11 of the Sloan Digital Sky Survey III (SDSS-III) Baryon Oscillation Spectroscopic Survey. Our results show no significant evidence for a deviation from the standard Λ cold dark matter model. The combination of the information from our clustering measurements with recent data from the cosmic microwave background is sufficient to constrain the curvature of the Universe to Ωk = 0.0010 ± 0.0029, the total neutrino mass to ∑mν < 0.23 eV (95 per cent confidence level), the effective number of relativistic species to Neff = 3.31 ± 0.27 and the dark energy equation of state to wDE = −1.051 ± 0.076. These limits are further improved by adding information from Type Ia supernovae and baryon acoustic oscillations from other samples. In particular, this data set combination is completely consistent with a time-independent dark energy equation of state, in which case we find wDE = −1.024 ± 0.052. We explore the constraints on the growth rate of cosmic structures assuming f(z) = Ωm(z)γ and obtain γ = 0.69 ± 0.15, consistent with the predictions of general relativity of γ = 0.55.Publisher PDFPeer reviewe

The clustering of galaxies in the SDSS-III Baryon Oscillation Spectroscopic Survey: single-probe measurements from CMASS anisotropic galaxy clustering

With the largest spectroscopic galaxy survey volume drawn from the SDSS-III Baryon Oscillation Spectroscopic Survey (BOSS), we can extract cosmological constraints from the measurements of redshift and geometric distortions at quasi-linear scales (e.g. above 50 $h^{-1}$Mpc). We analyze the broad-range shape of the monopole and quadrupole correlation functions of the BOSS Data Release 12 (DR12) CMASS galaxy sample, at the effective redshift $z=0.59$, to obtain constraints on the Hubble expansion rate $H(z)$, the angular-diameter distance $D_A(z)$, the normalized growth rate $f(z)\sigma_8(z)$, and the physical matter density $\Omega_mh^2$. We obtain robust measurements by including a polynomial as the model for the systematic errors, and find it works very well against the systematic effects, e.g., ones induced by stars and seeing. We provide accurate measurements $\{D_A(0.59)r_{s,fid}/r_s$ $\rm Mpc$, $H(0.59)r_s/r_{s,fid}$ $km s^{-1} Mpc^{-1}$, $f(0.59)\sigma_8(0.59)$, $\Omega_m h^2\}$ = $\{1427\pm26$, $97.3\pm3.3$, $0.488 \pm 0.060$, $0.135\pm0.016\}$, where $r_s$ is the comoving sound horizon at the drag epoch and $r_{s,fid}=147.66$ Mpc is the sound scale of the fiducial cosmology used in this study. The parameters which are not well constrained by our galaxy clustering analysis are marginalized over with wide flat priors. Since no priors from other data sets, e.g., cosmic microwave background (CMB), are adopted and no dark energy models are assumed, our results from BOSS CMASS galaxy clustering alone may be combined with other data sets, i.e., CMB, SNe, lensing or other galaxy clustering data to constrain the parameters of a given cosmological model. The uncertainty on the dark energy equation of state parameter, $w$, from CMB+CMASS is about 8 per cent. The uncertainty on the curvature fraction, $\Omega_k$, is 0.3 per cent. We do not find deviation from flat $\Lambda$CDM.Comment: 15 pages, 11 figures. The latest version matches and the accepted version by MNRAS. A bug in the first version has been identified and fixed in the new version. We have redone the analysis with newest data (BOSS DR12

Variation in the Large-Scale Organization of Gene Expression Levels in the Hippocampus Relates to Stable Epigenetic Variability in Behavior

Despite sharing the same genes, identical twins demonstrate substantial variability in behavioral traits and in their risk for disease. Epigenetic factors-DNA and chromatin modifications that affect levels of gene expression without affecting the DNA sequence-are thought to be important in establishing this variability. Epigenetically-mediated differences in the levels of gene expression that are associated with individual variability traditionally are thought to occur only in a gene-specific manner. We challenge this idea by exploring the large-scale organizational patterns of gene expression in an epigenetic model of behavioral variability.To study the effects of epigenetic influences on behavioral variability, we examine gene expression in genetically identical mice. Using a novel approach to microarray analysis, we show that variability in the large-scale organization of gene expression levels, rather than differences in the expression levels of specific genes, is associated with individual differences in behavior. Specifically, increased activity in the open field is associated with increased variance of log-transformed measures of gene expression in the hippocampus, a brain region involved in open field activity. Early life experience that increases adult activity in the open field also similarly modifies the variance of gene expression levels. The same association of the variance of gene expression levels with behavioral variability is found with levels of gene expression in the hippocampus of genetically heterogeneous outbred populations of mice, suggesting that variation in the large-scale organization of gene expression levels may also be relevant to phenotypic differences in outbred populations such as humans. We find that the increased variance in gene expression levels is attributable to an increasing separation of several large, log-normally distributed families of gene expression levels. We also show that the presence of these multiple log-normal distributions of gene expression levels is a universal characteristic of gene expression in eurkaryotes. We use data from the MicroArray Quality Control Project (MAQC) to demonstrate that our method is robust and that it reliably detects biological differences in the large-scale organization of gene expression levels.Our results contrast with the traditional belief that epigenetic effects on gene expression occur only at the level of specific genes and suggest instead that the large-scale organization of gene expression levels provides important insights into the relationship of gene expression with behavioral variability. Understanding the epigenetic, genetic, and environmental factors that regulate the large-scale organization of gene expression levels, and how changes in this large-scale organization influences brain development and behavior will be a major future challenge in the field of behavioral genomics

Discovery, Characterization, and Structure–Activity Relationships of an Inhibitor of Inward Rectifier Potassium (Kir) Channels with Preference for Kir2.3, Kir3.X, and Kir7.1

The inward rectifier family of potassium (Kir) channels is comprised of at least 16 family members exhibiting broad and often overlapping cellular, tissue, or organ distributions. The discovery of disease-causing mutations in humans and experiments on knockout mice has underscored the importance of Kir channels in physiology and in some cases raised questions about their potential as drug targets. However, the paucity of potent and selective small-molecule modulators targeting specific family members has with few exceptions mired efforts to understand their physiology and assess their therapeutic potential. A growing body of evidence suggests that G protein-coupled inward rectifier K (GIRK) channels of the Kir3.X subfamily may represent novel targets for the treatment of atrial fibrillation. In an effort to expand the molecular pharmacology of GIRK, we performed a thallium (Tl+) flux-based high-throughput screen of a Kir1.1 inhibitor library for modulators of GIRK. One compound, termed VU573, exhibited 10-fold selectivity for GIRK over Kir1.1 (IC50 = 1.9 and 19 μM, respectively) and was therefore selected for further study. In electrophysiological experiments performed on Xenopus laevis oocytes and mammalian cells, VU573 inhibited Kir3.1/3.2 (neuronal GIRK) and Kir3.1/3.4 (cardiac GIRK) channels with equal potency and preferentially inhibited GIRK, Kir2.3, and Kir7.1 over Kir1.1 and Kir2.1.Tl+ flux assays were established for Kir2.3 and the M125R pore mutant of Kir7.1 to support medicinal chemistry efforts to develop more potent and selective analogs for these channels. The structure–activity relationships of VU573 revealed few analogs with improved potency, however two compounds retained most of their activity toward GIRK and Kir2.3 and lost activity toward Kir7.1. We anticipate that the VU573 series will be useful for exploring the physiology and structure–function relationships of these Kir channels

Colorectal Cancer Screening in Vulnerable Patients

Low-income, low-literacy, limited English–proficient populations have low colorectal cancer (CRC) screening rates and experience poor patient–provider communication and decision-making processes around screening. The purpose of this study was to test the effect of a CRC screening decision aid on screening-related communication and decision making in primary care visits