Approximate Analytical Model for the Squeeze-Film Lubrication of the Human Ankle Joint with Synovial Fluid Filtrated by Articular Cartilage

The aim of this article is to propose an analytical approximate squeeze-film lubrication model of the human ankle joint for a quick assessment of the synovial pressure field and the load carrying due to the squeeze motion. The model starts from the theory of boosted lubrication for the human articular joints lubrication (Walker et al., Rheum Dis 27:512–520, 1968; Maroudas, Lubrication and wear in joints. Sector, London, 1969) and takes into account the fluid transport across the articular cartilage using Darcy’s equation to depict the synovial fluid motion through a porous cartilage matrix. The human ankle joint is assumed to be cylindrical enabling motion in the sagittal plane only. The proposed model is based on a modified Reynolds equation; its integration allows to obtain a quick assessment on the synovial pressure field showing a good agreement with those obtained numerically (Hlavacek, J Biomech 33:1415–1422, 2000). The analytical integration allows the closed form description of the synovial fluid film force and the calculation of the unsteady gap thickness

Inhibitors of \u3cem\u3eN\u3csup\u3eα\u3c/sup\u3e\u3c/em\u3e-acetyl-l-ornithine Deacetylase: Synthesis, Characterization and Analysis of their Inhibitory Potency

A series of N α-acyl (alkyl)- and N α-alkoxycarbonyl-derivatives of l- and d-ornithine were prepared, characterized, and analyzed for their potency toward the bacterial enzyme N α-acetyl-l-ornithine deacetylase (ArgE). ArgE catalyzes the conversion of N α-acetyl-l-ornithine to l-ornithine in the fifth step of the biosynthetic pathway for arginine, a necessary step for bacterial growth. Most of the compounds tested provided IC50 values in the μM range toward ArgE, indicating that they are moderately strong inhibitors. N α-chloroacetyl-l-ornithine (1g) was the best inhibitor tested toward ArgE providing an IC50 value of 85 μM while N α-trifluoroacetyl-l-ornithine (1f), N α-ethoxycarbonyl-l-ornithine (2b), and N α-acetyl-d-ornithine (1a) weakly inhibited ArgE activity providing IC50 values between 200 and 410 μM. Weak inhibitory potency toward Bacillus subtilis-168 for N α-acetyl-d-ornithine (1a) and N α-fluoro- (1f), N α-chloro- (1g), N α-dichloro- (1h), and N α-trichloroacetyl-ornithine (1i) was also observed. These data correlate well with the IC50 values determined for ArgE, suggesting that these compounds might be capable of getting across the cell membrane and that ArgE is likely the bacterial enzymatic target

Current Estimates for HIV-1 Production Imply Rapid Viral Clearance in Lymphoid Tissues

It has recently been estimated that a single HIV-1 infected cell produces between and more than viral particles over its life span. Since body-wide estimates of the ratio of free virus to productively infected cells are smaller than and much smaller than , individual virions must be cleared rapidly. This seems difficult to reconcile with the fact that most of the total body virus is trapped on follicular dendritic cells where it can survive for many months. It has also been difficult to reconcile the vast difference in the rates at which the virus is cleared from the blood in rhesus macaques and in chronically infected patients. Here we attempt to reconcile these seemingly contradictory observations by considering the virion clearance rate in various organs and the virion exchange rates between them. The main results are that the per capita clearance rate of free virus in lymphoid tissue should be fast, the virion exchange rate between lymphoid tissue and the blood should be slow, and the comparatively slow previous estimates for the virion clearance rate from the blood correspond to the rate of virion efflux from the blood to other organs where the virus is ultimately cleared

Effectiveness and Safety of Apixaban Versus Warfarin Among Older Patients with Venous Thromboembolism with Different Demographics and Socioeconomic Status

Introduction Impact of demographics and socioeconomic status (SES) on anticoagulant treatment outcomes among patients with venous thromboembolism (VTE) is not well understood. This study evaluated risks of recurrent VTE, major bleeding (MB), and clinically relevant non-major bleeding (CRNMB) among older patients with VTE initiating apixaban or warfarin stratified by demographics and SES. Methods Adult patients (≥ 65 years) who initiated apixaban or warfarin after a VTE event were selected from the US CMS Medicare database (September 2014–December 2017). Stabilized inverse probability treatment weighting (IPTW) was used to balance patient characteristics between treatment cohorts. Patients were stratified by age, gender, race, and SES. For each subgroup, Cox proportional hazard models were used to evaluate if there was a significant interaction (p \u3c 0.10) between treatment and subgroup for recurrent VTE, MB, and CRNMB. Results In total, 22,135 apixaban and 45,840 warfarin patients with VTE were included. Post-IPTW, patient characteristics were balanced between treatment cohorts. In older patients, apixaban treatment was associated with significantly lower risks of recurrent VTE (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.52–0.79), MB (HR 0.65; 95% CI 0.57–0.75), and CRNMB (HR 0.79; 95% CI 0.75–0.85) versus warfarin. When stratified by demographics and SES, higher incidence rates of recurrent VTE, MB, and CRNMB were observed for black vs white patients and patients with lower vs higher SES. Comparison of apixaban with warfarin by different demographic and SES subgroups showed generally consistent results as the overall analysis. For most subgroups, no significant interaction was observed between treatment and subgroup strata for recurrent VTE, MB, and CRNMB. Conclusion Among older patients with VTE initiating apixaban or warfarin, higher rates of recurrent VTE and bleeding were observed in black patients and patients with lower SES. Apixaban had a lower risk of recurrent VTE, MB, and CRNMB compared to warfarin. Analyses of demographic and SES subgroups showed consistent findings

Effectiveness and safety of apixaban vs warfarin among venous thromboembolism patients at high-risk of bleeding

This study evaluated effectiveness and safety of apixaban versus warfarin among venous thromboembolism patients at high-risk of bleeding (defined as having at least one of the following bleeding risk factors: ≥75 years; used antiplatelet, NSAIDs, or corticosteroids; had prior gastrointestinal bleeding or gastrointestinal-related conditions; late stage chronic kidney disease). Adult venous thromboembolism patients initiating apixaban or warfarin with ≥1 bleeding risk factor were identified from Medicare and four commercial claims databases in the United States. To balance characteristics between apixaban and warfarin patients, stabilized inverse probability treatment weighting was conducted. Cox proportional hazards models were used to estimate the risk of recurrent venous thromboembolism, major bleeding, and clinically relevant non-major bleeding. In total, 88,281 patients were identified. After inverse probability treatment weighting, the baseline patient characteristics were well-balanced between the two cohorts. Among venous thromboembolism patients at high-risk of bleeding, apixaban was associated with significantly lower risk of recurrent venous thromboembolism, major bleeding and clinically relevant non-major bleeding. No significant interactions were observed between treatment and number of risk factors on major bleeding and clinically relevant non-major bleeding or between treatment and type of bleeding risk factors on any of the outcomes. In conclusion, apixaban was associated with significantly lower risk of recurrent venous thromboembolism and bleeding among venous thromboembolism patients at high-risk of bleeding. Effects were generally consistent across subgroups of patients with different number or type of bleeding risk factors

Tunable kinetic proofreading in a model with molecular frustration

In complex systems, feedback loops can build intricate emergent phenomena, so that a description of the whole system cannot be easily derived from the properties of the individual parts. Here we propose that inter-molecular frustration mechanisms can provide non trivial feedback loops which can develop nontrivial specificity amplification. We show that this mechanism can be seen as a more general form of a kinetic proofreading mechanism, with an interesting new property, namely the ability to tune the specificity amplification by changing the reactants concentrations. This contrasts with the classical kinetic proofreading mechanism in which specificity is a function of only the reaction rate constants involved in a chemical pathway. These results are also interesting because they show that a wide class of frustration models exists that share the same underlining kinetic proofreading mechanisms, with even richer properties. These models can find applications in different areas such as evolutionary biology, immunology and biochemistry

Signals: I. Survey description

SIGNALS, the Star formation, Ionized Gas, and Nebular Abundances Legacy Survey, is a large observing programme designed to investigate massive star formation and H II regions in a sample of local extended galaxies. The programme will use the imaging Fourier transform spectrograph SITELLE at the Canada–France–Hawaii Telescope. Over 355 h (54.7 nights) have been allocated beginning in fall 2018 for eight consecutive semesters. Once completed, SIGNALS will provide a statistically reliable laboratory to investigate massive star formation, including over 50 000 resolved H II regions: the largest, most complete, and homogeneous data base of spectroscopically and spatially resolved extragalactic H II regions ever assembled. For each field observed, three datacubes covering the spectral bands of the filters SN1 (363–386 nm), SN2 (482–513 nm), and SN3 (647–685 nm) are gathered. The spectral resolution selected for each spectral band is 1000, 1000, and 5000, respectively. As defined, the project sample will facilitate the study of small-scale nebular physics and many other phenomena linked to star formation at a mean spatial resolution of ∼20 pc. This survey also has considerable legacy value for additional topics, including planetary nebulae, diffuse ionized gas, and supernova remnants. The purpose of this paper is to present a general outlook of the survey, notably the observing strategy, galaxy sample, and science requirements

Rule-based modeling of biochemical systems with BioNetGen

Totowa, NJ. Please cite this article when referencing BioNetGen in future publications. Rule-based modeling involves the representation of molecules as structured objects and molecular interactions as rules for transforming the attributes of these objects. The approach is notable in that it allows one to systematically incorporate site-specific details about proteinprotein interactions into a model for the dynamics of a signal-transduction system, but the method has other applications as well, such as following the fates of individual carbon atoms in metabolic reactions. The consequences of protein-protein interactions are difficult to specify and track with a conventional modeling approach because of the large number of protein phosphoforms and protein complexes that these interactions potentially generate. Here, we focus on how a rule-based model is specified in the BioNetGen language (BNGL) and how a model specification is analyzed using the BioNetGen software tool. We also discuss new developments in rule-based modeling that should enable the construction and analyses of comprehensive models for signal transduction pathways and similarly large-scale models for other biochemical systems. Key Words: Computational systems biology; mathematical modeling; combinatorial complexity; software; formal languages; stochastic simulation; ordinary differential equations; protein-protein interactions; signal transduction; metabolic networks. 1