Effects of Post-Translational Modifications of Fibrinogen on Clot Formation, Clot Structure, and Fibrinolysis: A Systematic Review

OBJECTIVE: Post-translational modifications of fibrinogen influence the occurrence and progression of thrombotic diseases. In this systematic review, we assessed the current literature on post-translational modifications of fibrinogen and their effects on fibrin formation and clot characteristics. Approach and Results: A systematic search of Medline, Embase, Cochrane Library, and Web of Science was performed to find studies reporting post-translational modifications of fibrinogen and the effects on clot formation and structure. Both in vitro studies and ex vivo studies using patient material were included. One hundred five articles were included, describing 11 different modifications of fibrinogen. For the best known and studied modifications, conclusions could be drawn about their effect on clot formation and structure. Oxidation, high levels of nitration, and glycosylation inhibit the rate of polymerization, resulting in dense clots with thinner fibers, while low levels of nitration increase the rate of polymerization. Glycation showed different results for polymerization, but f

Assessment of Daily Life Physical Activities in Pulmonary Arterial Hypertension

Background: In pulmonary arterial hypertension (PAH), the six-minute walk test (6MWT) is believed to be representative of patient’s daily life physical activities (DLPA). Whether DLPA are decreased in PAH and whether the 6MWT is representative of patient’s DL PA remain unknown. Methods: 15 patients with idiopathic PAH (IPAH) and 10 patients with PAH associated with limited systemic sclerosis (PAH-SSc) were matched with 15 healthy control subjects and 10 patients with limited systemic sclerosis without PAH. Each subject completed a 6MWT. The mean number of daily steps and the mean energy expenditure and duration of physical activities.3 METs were assessed with a physical activity monitor for seven consecutive days and used as markers of DLPA. Results: The mean number of daily steps and the mean daily energy expenditure and duration of physical activities.3 METs were all reduced in PAH patients compared to their controls (all p,0.05). The mean number of daily steps correlated with the 6MWT distance for both IPAH and PAH-SSc patients (r = 0.76, p,0.01 and r = 0.85, p,0.01), respectively. Conclusion: DLPA are decreased in PAH and correlate with the 6MWT distance. Functional exercise capacity may thus be a useful surrogate of DL PA in PAH

Shading Beats Binocular Disparity in Depth from Luminance Gradients: Evidence against a Maximum Likelihood Principle for Cue Combination

Perceived depth is conveyed by multiple cues, including binocular disparity and luminance shading. Depth perception from luminance shading information depends on the perceptual assumption for the incident light, which has been shown to default to a diffuse illumination assumption. We focus on the case of sinusoidally corrugated surfaces to ask how shading and disparity cues combine defined by the joint luminance gradients and intrinsic disparity modulation that would occur in viewing the physical corrugation of a uniform surface under diffuse illumination. Such surfaces were simulated with a sinusoidal luminance modulation (0.26 or 1.8 cy/deg, contrast 20%-80%) modulated either in-phase or in opposite phase with a sinusoidal disparity of the same corrugation frequency, with disparity amplitudes ranging from 0’-20’. The observers’ task was to adjust the binocular disparity of a comparison random-dot stereogram surface to match the perceived depth of the joint luminance/disparitymodulated corrugation target. Regardless of target spatial frequency, the perceived target depth increased with the luminance contrast and depended on luminance phase but was largely unaffected by the luminance disparity modulation. These results validate the idea that human observers can use the diffuse illumination assumption to perceive depth from luminance gradients alone without making an assumption of light direction. For depth judgments with combined cues, the observers gave much greater weighting to the luminance shading than to the disparity modulation of the targets. The results were not well-fit by a Bayesian cue-combination model weighted in proportion to the variance of the measurements for each cue in isolation. Instead, they suggest that the visual system uses disjunctive mechanisms to process these two types of information rather than combining them according to their likelihood ratios

Testing of a Model with Latino Patients That Explains the Links Among Patient-Perceived Provider Cultural Sensitivity, Language Preference, and Patient Treatment Adherence

Introduction Disparities in treatment adherence based on race and ethnicity are well documented but poorly understood. Specifically, the causes of treatment nonadherence among Latino patients living in the USA are complex and include cultural and language barriers. Purpose The purpose of this study was to examine whether patients’ perceptions in patient-provider interactions (i.e., trust in provider, patient satisfaction, and patient sense of interpersonal control in patient-provider interactions) mediate any found association between patient-perceived provider cultural sensitivity (PCS) and treatment adherence among English-preferred Latino (EPL) and Spanish-preferred Latino (SPL) patients. Methods Data from 194 EPL patients and 361 SPL patients were obtained using questionnaires. A series of language-specific structural equation models were conducted to test the relationship between patient-perceived PCS and patient treatment adherence and the examined mediators of this relationship among the Latino patients. Results No significant direct effects of patient-perceived PCS on general treatment adherence were found. However, as hypothesized, several significant indirect effects emerged. Preferred language appeared to have moderating effects on the relationships between patient-perceived PCS and general treatment adherence. Conclusion These results suggest that interventions to promote treatment adherence among Latino patients should likely include provider training to foster patient-defined PCS, trust in provider, and patient satisfaction with care. Furthermore, this training needs to be customized to be suitable for providing care to Latino patients who prefer speaking Spanish and Latino patients who prefer speaking English

Multiple populations in globular clusters. Lessons learned from the Milky Way globular clusters

Recent progress in studies of globular clusters has shown that they are not simple stellar populations, being rather made of multiple generations. Evidence stems both from photometry and spectroscopy. A new paradigm is then arising for the formation of massive star clusters, which includes several episodes of star formation. While this provides an explanation for several features of globular clusters, including the second parameter problem, it also opens new perspectives about the relation between globular clusters and the halo of our Galaxy, and by extension of all populations with a high specific frequency of globular clusters, such as, e.g., giant elliptical galaxies. We review progress in this area, focusing on the most recent studies. Several points remain to be properly understood, in particular those concerning the nature of the polluters producing the abundance pattern in the clusters and the typical timescale, the range of cluster masses where this phenomenon is active, and the relation between globular clusters and other satellites of our Galaxy.Comment: In press (The Astronomy and Astrophysics Review

Increasing Costs Due to Ocean Acidification Drives Phytoplankton to Be More Heavily Calcified: Optimal Growth Strategy of Coccolithophores

Ocean acidification is potentially one of the greatest threats to marine ecosystems and global carbon cycling. Amongst calcifying organisms, coccolithophores have received special attention because their calcite precipitation plays a significant role in alkalinity flux to the deep ocean (i.e., inorganic carbon pump). Currently, empirical effort is devoted to evaluating the plastic responses to acidification, but evolutionary considerations are missing from this approach. We thus constructed an optimality model to evaluate the evolutionary response of coccolithophorid life history, assuming that their exoskeleton (coccolith) serves to reduce the instantaneous mortality rates. Our model predicted that natural selection favors constructing more heavily calcified exoskeleton in response to increased acidification-driven costs. This counter-intuitive response occurs because the fitness benefit of choosing a better-defended, slower growth strategy in more acidic conditions, outweighs that of accelerating the cell cycle, as this occurs by producing less calcified exoskeleton. Contrary to the widely held belief, the evolutionarily optimized population can precipitate larger amounts of CaCO3 during the bloom in more acidified seawater, depending on parameter values. These findings suggest that ocean acidification may enhance the calcification rates of marine organisms as an adaptive response, possibly accompanied by higher carbon fixation ability. Our theory also provides a compelling explanation for the multispecific fossil time-series record from ∼200 years ago to present, in which mean coccolith size has increased along with rising atmospheric CO2 concentration

Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer

ASA404 (5,6-dimethylxanthenone-4-acetic acid or DMXAA) is a small-molecule tumour-vascular disrupting agent (Tumour-VDA). This randomised phase II study evaluated ASA404 plus standard therapy of carboplatin and paclitaxel in patients with histologically confirmed stage IIIb or IV non-small cell lung cancer (NSCLC) not previously treated with chemotherapy. Patients were randomised to receive ⩽6 cycles of carboplatin area under the plasma concentration–time curve 6 mg ml−1 min and paclitaxel 175 mg m−2 (CP, n=36) or standard therapy plus ASA404 1200 mg m−2 (ASA404-CP, n=37). There was little change in the systemic exposure of either total or free carboplatin or paclitaxel on addition of ASA404. Safety profiles were similar and manageable in both groups, with most adverse effects attributed to standard therapy. Tumour response rate (31 vs 22%), median time to tumour progression (5.4 vs 4.4 months) and median survival (14.0 vs 8.8 months, hazard ratio 0.73, 95% CI 0.39, 1.38) were improved in the ASA404 combination group compared with the standard therapy group. In conclusion, this study establishes the feasibility of combining ASA404 with carboplatin and paclitaxel in patients with previously untreated, advanced NSCLC, demonstrating a manageable safety profile and lack of adverse pharmacokinetic interactions. The results indicate that there may be a benefit associated with ASA404, but this needs to be evaluated in a larger trial

Non-Linear Elasticity of Extracellular Matrices Enables Contractile Cells to Communicate Local Position and Orientation

Most tissue cells grown in sparse cultures on linearly elastic substrates typically display a small, round phenotype on soft substrates and become increasingly spread as the modulus of the substrate increases until their spread area reaches a maximum value. As cell density increases, individual cells retain the same stiffness-dependent differences unless they are very close or in molecular contact. On nonlinear strain-stiffening fibrin gels, the same cell types become maximally spread even when the low strain elastic modulus would predict a round morphology, and cells are influenced by the presence of neighbors hundreds of microns away. Time lapse microscopy reveals that fibroblasts and human mesenchymal stem cells on fibrin deform the substrate by several microns up to five cell lengths away from their plasma membrane through a force limited mechanism. Atomic force microscopy and rheology confirm that these strains locally and globally stiffen the gel, depending on cell density, and this effect leads to long distance cell-cell communication and alignment. Thus cells are acutely responsive to the nonlinear elasticity of their substrates and can manipulate this rheological property to induce patterning

Combinatorial Development of Biomaterials for Clonal Growth of Human Pluripotent Stem Cells

July 3, 2012Both human embryonic stem cells and induced pluripotent stem cells can self-renew indefinitely in culture; however, present methods to clonally grow them are inefficient and poorly defined for genetic manipulation and therapeutic purposes. Here we develop the first chemically defined, xeno-free, feeder-free synthetic substrates to support robust self-renewal of fully dissociated human embryonic stem and induced pluripotent stem cells. Material properties including wettability, surface topography, surface chemistry and indentation elastic modulus of all polymeric substrates were quantified using high-throughput methods to develop structure–function relationships between material properties and biological performance. These analyses show that optimal human embryonic stem cell substrates are generated from monomers with high acrylate content, have a moderate wettability and employ integrin α[subscript v]β[subscript 3] and α[subscript v]β[subscript 5] engagement with adsorbed vitronectin to promote colony formation. The structure–function methodology employed herein provides a general framework for the combinatorial development of synthetic substrates for stem cell culture.National Institutes of Health (U.S.) (Grant R37-CA084198)National Institutes of Health (U.S.) (Grant RO1-CA087869)National Institutes of Health (U.S.) (Grant RO1-HD045022)National Institutes of Health (U.S.) (Grant DE016516)Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies (Contract W911NF-07-D-0004