Commensurate distances and similar motifs in genetic congruence and protein interaction networks in yeast

BACKGROUND: In a genetic interaction, the phenotype of a double mutant differs from the combined phenotypes of the underlying single mutants. When the single mutants have no growth defect, but the double mutant is lethal or exhibits slow growth, the interaction is termed synthetic lethality or synthetic fitness. These genetic interactions reveal gene redundancy and compensating pathways. Recently available large-scale data sets of genetic interactions and protein interactions in Saccharomyces cerevisiae provide a unique opportunity to elucidate the topological structure of biological pathways and how genes function in these pathways. RESULTS: We have defined congruent genes as pairs of genes with similar sets of genetic interaction partners and constructed a genetic congruence network by linking congruent genes. By comparing path lengths in three types of networks (genetic interaction, genetic congruence, and protein interaction), we discovered that high genetic congruence not only exhibits correlation with direct protein interaction linkage but also exhibits commensurate distance with the protein interaction network. However, consistent distances were not observed between genetic and protein interaction networks. We also demonstrated that congruence and protein networks are enriched with motifs that indicate network transitivity, while the genetic network has both transitive (triangle) and intransitive (square) types of motifs. These results suggest that robustness of yeast cells to gene deletions is due in part to two complementary pathways (square motif) or three complementary pathways, any two of which are required for viability (triangle motif). CONCLUSION: Genetic congruence is superior to genetic interaction in prediction of protein interactions and function associations. Genetically interacting pairs usually belong to parallel compensatory pathways, which can generate transitive motifs (any two of three pathways needed) or intransitive motifs (either of two pathways needed)

A Computational Approach for Deciphering the Organization of Glycosaminoglycans

BACKGROUND. Increasing evidence has revealed important roles for complex glycans as mediators of normal and pathological processes. Glycosaminoglycans are a class of glycans that bind and regulate the function of a wide array of proteins at the cell-extracellular matrix interface. The specific sequence and chemical organization of these polymers likely define function; however, identification of the structure-function relationships of glycosaminoglycans has been met with challenges associated with the unique level of complexity and the nontemplate-driven biosynthesis of these biopolymers. METHODOLOGY/PRINCIPAL FINDINGS. To address these challenges, we have devised a computational approach to predict fine structure and patterns of domain organization of the specific glycosaminoglycan, heparan sulfate (HS). Using chemical composition data obtained after complete and partial digestion of mixtures of HS chains with specific degradative enzymes, the computational analysis produces populations of theoretical HS chains with structures that meet both biosynthesis and enzyme degradation rules. The model performs these operations through a modular format consisting of input/output sections and three routines called chainmaker, chainbreaker, and chainsorter. We applied this methodology to analyze HS preparations isolated from pulmonary fibroblasts and epithelial cells. Significant differences in the general organization of these two HS preparations were observed, with HS from epithelial cells having a greater frequency of highly sulfated domains. Epithelial HS also showed a higher density of specific HS domains that have been associated with inhibition of neutrophil elastase. Experimental analysis of elastase inhibition was consistent with the model predictions and demonstrated that HS from epithelial cells had greater inhibitory activity than HS from fibroblasts. CONCLUSIONS/SIGNIFICANCE. This model establishes the conceptual framework for a new class of computational tools to use to assess patterns of domain organization within glycosaminoglycans. These tools will provide a means to consider high-level chain organization in deciphering the structure-function relationships of polysaccharides in biology.US National Institutes of Health (HL56200, HL088672); the Massachusetts Lions Eye Research Fund, Inc

Design of the ARES Mars Airplane and Mission Architecture

Significant technology advances have enabled planetary aircraft to be considered as viable science platforms. Such systems fill a unique planetary science measurement gap, that of regional-scale, near-surface observation, while providing a fresh perspective for potential discovery. Recent efforts have produced mature mission and flight system concepts, ready for flight project implementation. This paper summarizes the development of a Mars airplane mission architecture that balances science, implementation risk and cost. Airplane mission performance, flight system design and technology maturation are described. The design, analysis and testing completed demonstrates the readiness of this science platform for use in a Mars flight project

Survival after hospital discharge for ST-segment elevation and non-ST-segment elevation acute myocardial infarction: a population-based study

BACKGROUND: Limited recent data are available describing differences in long-term survival, and factors affecting prognosis, after ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI), especially from the more generalizable perspective of a population-based investigation. The objectives of this study were to examine differences in post-discharge prognosis after hospitalization for STEMI and NSTEMI, with a particular focus on factors associated with reduced long-term survival. METHODS: We reviewed the medical records of residents of the Worcester, MA, USA metropolitan area hospitalized at eleven central Massachusetts medical centers for acute myocardial infarction (AMI) during 2001, 2003, 2005, and 2007. RESULTS: A total of 3762 persons were hospitalized with confirmed AMI; of these, 2539 patients (67.5%) were diagnosed with NSTEMI. The average age of study patients was 70.3 years and 42.9% were women. Patients with NSTEMI experienced higher post-discharge death rates with 3-month, 1-year, and 2-year death rates of 12.6%, 23.5%, and 33.2%, respectively, compared to 6.1%, 11.5%, and 16.4% for patients with STEMI. After multivariable adjustment, patients with NSTEMI were significantly more likely to have died after hospital discharge (adjusted hazards ratio 1.28; 95% confidence interval 1.14-1.44). Several demographic (eg, older age) and clinical (eg, history of stroke) factors were associated with reduced long-term survival in patients with NSTEMI and STEMI. CONCLUSIONS: The results of this study in residents of central Massachusetts suggest that patients with NSTEMI are at higher risk for dying after hospital discharge, and several subgroups are at particularly increased risk

Photometry of Kuiper belt object (486958) Arrokoth from New Horizons LORRI

On January 1st 2019, the New Horizons spacecraft flew by the classical Kuiper belt object (486958) Arrokoth (provisionally designated 2014 MU69), possibly the most primitive object ever explored by a spacecraft. The I/F of Arrokoth is analyzed and fit with a photometric function that is a linear combination of the Lommel-Seeliger (lunar) and Lambert photometric functions. Arrokoth has a geometric albedo of p_v = 0.21_(−0.04)^(+0.05) at a wavelength of 550 nm and ≈0.24 at 610 nm. Arrokoth's geometric albedo is greater than the median but consistent with a distribution of cold classical Kuiper belt objects whose geometric albedos were determined by fitting a thermal model to radiometric observations. Thus, Arrokoth's geometric albedo adds to the orbital and spectral evidence that it is a cold classical Kuiper belt object. Maps of the normal reflectance and hemispherical albedo of Arrokoth are presented. The normal reflectance of Arrokoth's surface varies with location, ranging from ≈0.10–0.40 at 610 nm with an approximately Gaussian distribution. Both Arrokoth's extrema dark and extrema bright surfaces are correlated to topographic depressions. Arrokoth has a bilobate shape and the two lobes have similar normal reflectance distributions: both are approximately Gaussian, peak at ≈0.25 at 610 nm, and range from ≈0.10–0.40, which is consistent with co-formation and co-evolution of the two lobes. The hemispherical albedo of Arrokoth varies substantially with both incidence angle and location, the average hemispherical albedo at 610 nm is 0.063 ± 0.015. The Bond albedo of Arrokoth at 610 nm is 0.062 ± 0.015

Trends in the medical management of patients with heart failure

BACKGROUND: Despite the availability of effective therapies, heart failure (HF) remains a highly prevalent disease and the leading cause of hospitalizations in the U.S. Few data are available, however, describing changing trends in the use of various cardiac medications to treat patients with HF and factors associated with treatment. The objectives of this population-based study were to examine decade-long trends (1995 - 2004) in the use of several cardiac medications in patients hospitalized with acute decompensated heart failure (ADHF) and factors associated with evidence-based treatment. METHODS: We reviewed the medical records of 9,748 residents of the Worcester, MA, metropolitan area who were hospitalized with ADHF at all 11 central Massachusetts medical centers in 1995, 2000, 2002, and 2004. RESULTS: Between 1995 and 2004, respectively, the prescription upon hospital discharge of beta-blockers (23%; 67%), angiotensin pathway inhibitors (47%; 55%), statins (5%; 43%), and aspirin (35%; 51%) increased markedly, while the use of digoxin (51%; 29%), nitrates (46%; 24%), and calcium channel blockers (33%; 22%) declined significantly; nearly all patients received diuretics. Patients in the earliest study year, those with a history of obstructive pulmonary disease or anemia, incident HF, non-specific symptoms, and women were less likely to receive beta blockers and angiotensin pathway inhibitors than respective comparison groups. In 2004, 82% of patients were discharged on at least one of these recommended agents; however, only 41% were discharged on medications from both recommended classes. CONCLUSIONS: Our data suggest that opportunities exist to further improve the use of HF therapeutics

Gene function prediction from congruent synthetic lethal interactions in yeast

We predicted gene function using synthetic lethal genetic interactions between null alleles in Saccharomyces cerevisiae. Phenotypic and protein interaction data indicate that synthetic lethal gene pairs function in parallel or compensating pathways. Congruent gene pairs, defined as sharing synthetic lethal partners, are in single pathway branches. We predicted benomyl sensitivity and nuclear migration defects using congruence; these phenotypes were uncorrelated with direct synthetic lethality. We also predicted YLL049W as a new member of the dynein–dynactin pathway and provided new supporting experimental evidence. We performed synthetic lethal screens of the parallel mitotic exit network (MEN) and Cdc14 early anaphase release pathways required for late cell cycle. Synthetic lethal interactions bridged genes in these pathways, and high congruence linked genes within each pathway. Synthetic lethal interactions between MEN and all components of the Sin3/Rpd3 histone deacetylase revealed a novel function for Sin3/Rpd3 in promoting mitotic exit in parallel to MEN. These in silico methods can predict phenotypes and gene functions and are applicable to genomic synthetic lethality screens in yeast and analogous RNA interference screens in metazoans

Six-month mortality rates are lower in patients with an acute coronary syndrome treated with the combination of clopidogrel and a statin than in patients treated with either therapy alone: An analysis from the global registry of acute coronary events

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Tracking Single Cells in Live Animals Using a Photoconvertible Near-Infrared Cell Membrane Label

We describe a novel photoconversion technique to track individual cells in vivo using a commercial lipophilic membrane dye, DiR. We show that DiR exhibits a permanent fluorescence emission shift (photoconversion) after light exposure and does not reacquire the original color over time. Ratiometric imaging can be used to distinguish photoconverted from non-converted cells with high sensitivity. Combining the use of this photoconvertible dye with intravital microscopy, we tracked the division of individual hematopoietic stem/progenitor cells within the calvarium bone marrow of live mice. We also studied the peripheral differentiation of individual T cells by tracking the gain or loss of FoxP3-GFP expression, a marker of the immune suppressive function of CD4+ T cells. With the near-infrared photoconvertible membrane dye, the entire visible spectral range is available for simultaneous use with other fluorescent proteins to monitor gene expression or to trace cell lineage commitment in vivo with high spatial and temporal resolution