A robust and efficient method for estimating enzyme complex abundance and metabolic flux from expression data

A major theme in constraint-based modeling is unifying experimental data, such as biochemical information about the reactions that can occur in a system or the composition and localization of enzyme complexes, with highthroughput data including expression data, metabolomics, or DNA sequencing. The desired result is to increase predictive capability resulting in improved understanding of metabolism. The approach typically employed when only gene (or protein) intensities are available is the creation of tissue-specific models, which reduces the available reactions in an organism model, and does not provide an objective function for the estimation of fluxes, which is an important limitation in many modeling applications. We develop a method, flux assignment with LAD (least absolute deviation) convex objectives and normalization (FALCON), that employs metabolic network reconstructions along with expression data to estimate fluxes. In order to use such a method, accurate measures of enzyme complex abundance are needed, so we first present a new algorithm that addresses quantification of complex abundance. Our extensions to prior techniques include the capability to work with large models and significantly improved run-time performance even for smaller models, an improved analysis of enzyme complex formation logic, the ability to handle very large enzyme complex rules that may incorporate multiple isoforms, and depending on the model constraints, either maintained or significantly improved correlation with experimentally measured fluxes. FALCON has been implemented in MATLAB and ATS, and can be downloaded from: https://github.com/bbarker/FALCON. ATS is not required to compile the software, as intermediate C source code is available, and binaries are provided for Linux x86-64 systems. FALCON requires use of the COBRA Toolbox, also implemented in MATLAB.Comment: 30 pages, 12 figures, 4 table

External work is deficient in both limbs of patients with unilateral PAD

External work was utilized to measure differences between the unaffected and the affected limb in patients with unilateral peripheral arterial disease compared to healthy controls. Patients with unilateral peripheral arterial disease have shown deficits in peak joint powers during walking in the unaffected and affected legs. However, no research has detailed the amount of work that is being performed by each leg compared to healthy controls even though such an analysis would provide valuable information on the energy output from the affected and the unaffected legs. Two hypotheses were tested: a) the unaffected and affected leg would perform less work than healthy controls in a pain-free state, and b) the onset of symptomatic claudication pain would result in further changes in the external work. Results showed that during a pain-free state, both the unaffected and affected legs perform less work than the healthy controls. After onset of claudication pain, the work output by the affected limb becomes further decreased while the unaffected limb experiences changes in negative external work. These findings combined with recent evidence of decreased peak powers in both legs in unilateral peripheral arterial disease patients reflects altered pathomechanics in both limbs compared to healthy controls

Increased minimum toe clearance variability in patients with peripheral arterial disease

Individuals with peripheral arterial disease (PAD) report difficulty walking and experience 73% more falls than their healthy counterparts, but no studies have investigated functional mechanisms contributing to increased falls. Minimum toe clearance (MTC) is the minimum vertical distance between the toe of the swinging leg and the walking surface when the leg is swinging, and decreased values are associated with an increased risk for falls. This study is the first such analysis in patients with PAD. Eighteen individuals with PAD and eighteen healthy controls walked on a treadmill before and after the onset of claudication pain. Mean MTC and the standard deviation of MTC values across the trial were calculated. Mean MTC was not different between groups in the pain-free (P = 0.244) or pain conditions (P = 0.565). MTC variability was increased for patients with PAD in pain-free (P = 0.048) and pain conditions (P = 0.019). No significant differences existed between conditions for MTC mean (P = 0.134) or MTC variability (P = 0.123). Increased MTC variability is present before and after the onset of claudication pain, and may be a useful assessment for treatment and rehabilitation efficacy in these patients

The effects of extending trust and distrust to the outgroup in Northern Ireland: Intergroup emotions and anticipated intergroup relations

Two studies examined perceptions of risk, threat, and emotions experienced once a community leader has made the decision to extend trust or distrust to the outgroup, in the context of Northern Ireland. Study 1 examined the impact of three factors — the extension of trust or distrust, a social climate of threat or reduced threat, and high/low group identification — on perceived risk and group-level emotion. Study 2 examined the impact of these factors on expected negative intergroup relations and symbolic and realistic outcomes. Results from both studies demonstrated that: (1) evaluation of a community leader’s extension of trust or distrust toward the outgroup under threat/reduced threat was moderated by group identification, and (2) the leader’s extension of distrust toward the outgroup elicited greater anger and less positive emotion, and was seen as more damaging to intergroup relations than was the extension of trust

Patients with peripheral arterial disease exhibit reduced joint powers compared to velocity-matched controls

Previous studies have shown major deficits in gait for individuals with peripheral arterial disease before and after the onset of pain. However, these studies did not have subjects ambulate at similar velocities and potential exists that the differences in joint powers may have been due to differences in walking velocity. The purpose of this study was to examine the joint moments and powers of peripheral arterial disease limbs for subjects walking at similar self-selected walking velocities as healthy controls prior to onset of any symptoms. Results revealed peripheral arterial disease patients have reduced peak hip power absorption in midstance (p = 0.017), reduced peak knee power absorption in early and late stance (p = 0.037 and p = 0.020 respectively), and reduced peak ankle power generation in late stance (p = 0.021). This study reveals that the gait of patients with peripheral arterial disease walking prior to the onset of any leg symptoms is characterized by failure of specific and identifiable muscle groups needed to perform normal walking and that these gait deficits are independent of reduced gait velocity

Averting HIV Infections in New York City: A Modeling Approach Estimating the Future Impact of Additional Behavioral and Biomedical HIV Prevention Strategies

Background:New York City (NYC) remains an epicenter of the HIV epidemic in the United States. Given the variety of evidence-based HIV prevention strategies available and the significant resources required to implement each of them, comparative studies are needed to identify how to maximize the number of HIV cases prevented most economically.Methods:A new model of HIV disease transmission was developed integrating information from a previously validated micro-simulation HIV disease progression model. Specification and parameterization of the model and its inputs, including the intervention portfolio, intervention effects and costs were conducted through a collaborative process between the academic modeling team and the NYC Department of Health and Mental Hygiene. The model projects the impact of different prevention strategies, or portfolios of prevention strategies, on the HIV epidemic in NYC.Results:Ten unique interventions were able to provide a prevention benefit at an annual program cost of less than $360,000, the threshold for consideration as a cost-saving intervention (because of offsets by future HIV treatment costs averted). An optimized portfolio of these specific interventions could result in up to a 34$106,378; the total cost was in excess of $2 billion (over the 20 year period, or approximately$100 million per year, on average). The cost-savings of prevented infections was estimated at more than $5 billion (or approximately$250 million per year, on average).Conclusions:Optimal implementation of a portfolio of evidence-based interventions can have a substantial, favorable impact on the ongoing HIV epidemic in NYC and provide future cost-saving despite significant initial costs. © 2013 Kessler et al

Force and acceleration characteristics of military foot drill: implications for injury risk in recruits

Background: Foot drill involving marching and drill manoeuvres is conducted regularly during basic military recruit training. Characterising the biomechanical loading of foot drill will improve our understanding of the contributory factors to lower limb overuse injuries in recruits. Aim: Quantify and compare forces, loading rates and accelerations of British Army foot drill, within and between trained and untrained personnel. Methods: 24 trained soldiers (12 men and 12 women; TRAINED) and 12 civilian men (UNTRAINED) performed marching and five drill manoeuvres on force platforms; motion capture recorded tibial position. Peak vertical impact force (PF), peak vertical loading rate (PLR), expressed as multiples of body weight (BW) and peak tibial impact acceleration (PTA) were recorded. Results: Drill manoeuvre PF, PLR and PTA were similar, but higher in TRAINED men (PF, PLR: p<0.01; PTA: p<0.05). Peak values in TRAINED men were shown for the halt (mean (SD); PF: 6.5 (1.5) BW; PLR: 983 (333) BW/s PTA; PTA: 207 (57) m/s2) and left turn (PF: 6.6 (1.7) BW; PLR: 928 (300) BW/s; 184 (62) m/s2). Marching PF, PLR, PTA were similar between groups and lower than all drill manoeuvres (PF: 1.1–1.3 BW; PLR: 42–70 BW/s; p<0.01; PTA: 23–38 m/s2; p<0.05). Conclusions: Army foot drill generates higher forces, loading rates and accelerations than activities such as running and load carriage, while marching is comparable to moderate running (10.8 km/h). The large biomechanical loading of foot drill may contribute to the high rate of overuse injuries during initial military training, and strategies to regulate/reduce this loading should be explored

The SDSS-IV extended Baryon Oscillation Spectroscopic Survey: Quasar Target Selection

As part of the Sloan Digital Sky Survey (SDSS) IV the extended Baryon Oscillation Spectroscopic Survey (eBOSS) will improve measurements of the cosmological distance scale by applying the Baryon Acoustic Oscillation (BAO) method to quasar samples. eBOSS will adopt two approaches to target quasars over 7500 deg^2. First, a "CORE" quasar sample will combine the optical selection in ugriz using a likelihood-based routine called XDQSOz, with a mid-IR-optical color cut. eBOSS CORE selection (to g 2.1 quasars. Second, a selection based on variability in multi-epoch imaging from the Palomar Transient Factory should recover an additional ~3–4 deg^(−2)z > 2.1 quasars to g 2.1 will be used to improve BAO measurements in the Lyα Forest. Beyond its key cosmological goals, eBOSS should be the next-generation quasar survey, comprising >500,000 new quasars and >500,000 uniformly selected spectroscopically confirmed 0.9 < z < 2.2 quasars. At the conclusion of eBOSS, the SDSS will have provided unique spectra for more than 800,000 quasars