Calculation of Forces at Focal Adhesions from Elastic Substrate Data: The Effect of Localized Force and the Need for Regularization

AbstractForces exerted by stationary cells have been investigated on the level of single focal adhesions by combining elastic substrates, fluorescence labeling of focal adhesions, and the assumption of localized force when solving the inverse problem of linear elasticity theory. Data simulation confirms that the inverse problem is ill-posed in the presence of noise and shows that in general a regularization scheme is needed to arrive at a reliable force estimate. Spatial and force resolution are restricted by the smoothing action of the elastic kernel, depend on the details of the force and displacement patterns, and are estimated by data simulation. Corrections arising from the spatial distribution of force and from finite substrate size are treated in the framework of a force multipolar expansion. Our method is computationally cheap and could be used to study mechanical activity of cells in real time

Elastic interactions of active cells with soft materials

Anchorage-dependent cells collect information on the mechanical properties of the environment through their contractile machineries and use this information to position and orient themselves. Since the probing process is anisotropic, cellular force patterns during active mechanosensing can be modelled as anisotropic force contraction dipoles. Their build-up depends on the mechanical properties of the environment, including elastic rigidity and prestrain. In a finite sized sample, it also depends on sample geometry and boundary conditions through image strain fields. We discuss the interactions of active cells with an elastic environment and compare it to the case of physical force dipoles. Despite marked differences, both cases can be described in the same theoretical framework. We exactly solve the elastic equations for anisotropic force contraction dipoles in different geometries (full space, halfspace and sphere) and with different boundary conditions. These results are then used to predict optimal position and orientation of mechanosensing cells in soft material.Comment: Revtex, 38 pages, 8 Postscript files included; revised version, accepted for publication in Phys. Rev.

Foreigners Traveling to the U.S. for Transplantation May Adversely Affect Organ Donation: A National Survey

The aims of this study were (1) to determine attitudes among the American public regarding foreigners coming to the United States for the purposes of transplantation, and (2) to investigate the impact this practice might have on the public's willingness to donate organs. A probability-based national sample of adults age ≥18 was asked whether people should be allowed to travel to the United States to receive a transplant, and whether this practice would discourage the respondents from becoming an organ donor. Among 1049 participants, 30% (95% CI 25–34%) felt that people should not be allowed to travel to the United States to receive a deceased donor transplant, whereas 28% felt this would be acceptable in some cases. Thirty-eight percent (95% CI 33–42%) indicated that this practice might prevent them from becoming an organ donor. In conclusion, deceased-donor transplantation of foreigners is opposed by many Americans. Media coverage of this practice has the potential to adversely affect organ donation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79295/1/j.1600-6143.2010.03111.x.pd

Theoretical description of phase coexistence in model C60

We have investigated the phase diagram of the Girifalco model of C60 fullerene in the framework provided by the MHNC and the SCOZA liquid state theories, and by a Perturbation Theory (PT), for the free energy of the solid phase. We present an extended assessment of such theories as set against a recent Monte Carlo study of the same model [D. Costa et al, J. Chem. Phys. 118:304 (2003)]. We have compared the theoretical predictions with the corresponding simulation results for several thermodynamic properties. Then we have determined the phase diagram of the model, by using either the SCOZA, or the MHNC, or the PT predictions for one of the coexisting phases, and the simulation data for the other phase, in order to separately ascertain the accuracy of each theory. It turns out that the overall appearance of the phase portrait is reproduced fairly well by all theories, with remarkable accuracy as for the melting line and the solid-vapor equilibrium. The MHNC and SCOZA results for the liquid-vapor coexistence, as well as for the corresponding critical points, are quite accurate. All results are discussed in terms of the basic assumptions underlying each theory. We have selected the MHNC for the fluid and the first-order PT for the solid phase, as the most accurate tools to investigate the phase behavior of the model in terms of purely theoretical approaches. The overall results appear as a robust benchmark for further theoretical investigations on higher order C(n>60) fullerenes, as well as on other fullerene-related materials, whose description can be based on a modelization similar to that adopted in this work.Comment: RevTeX4, 15 pages, 7 figures; submitted to Phys. Rev.

KAHRP dynamically relocalizes to remodeled actin junctions and associates with knob spirals in Plasmodium falciparum-infected erythrocytes

The knob-associated histidine-rich protein (KAHRP) plays a pivotal role in the pathophysiology of Plasmodium falciparum malaria by forming membrane protrusions in infected erythrocytes, which anchor parasite-encoded adhesins to the membrane skeleton. The resulting sequestration of parasitized erythrocytes in the microvasculature leads to severe disease. Despite KAHRP being an important virulence factor, its physical location within the membrane skeleton is still debated, as is its function in knob formation. Here, we show by super-resolution microscopy that KAHRP initially associates with various skeletal components, including ankyrin bridges, but eventually colocalizes with remnant actin junctions. We further present a 35 Å map of the spiral scaffold underlying knobs and show that a KAHRP-targeting nanoprobe binds close to the spiral scaffold. Single-molecule localization microscopy detected ~60 KAHRP molecules/knob. We propose a dynamic model of KAHRP organization and a function of KAHRP in attaching other factors to the spiral scaffold

Osteoporosis Treatment Efficacy for Men: A Systematic Review and Meta-Analysis.

OBJECTIVES: To evaluate the efficacy of treatment options to reduce osteoporotic fracture risk in men. DESIGN: Systematic review and meta-analysis. SETTING: Randomized clinical trials that evaluated the efficacy of a treatment for osteoporosis or low bone mineral density for adult men and reported fracture outcomes. PARTICIPANTS: Men. MEASUREMENTS: PubMed, Embase, and the Cochrane Library databases were searched for relevant studies. Information was extracted from included studies on participant sociodemographic characteristics, number of male participants, treatment evaluated, comparator for evaluated treatment, study duration, and fracture outcomes. Risk of bias of individual studies was assessed using measures recommended by the Cochrane Collaboration. RESULTS: Twenty-four articles reporting results for 22 studies (including 4,868 male participants) met strict inclusion criteria. Fixed-effects meta-analyses using the Mantel-Haenszel method demonstrated significantly lower risk of vertebral fractures with alendronate (relative risk (RR) = 0.328, 95% confidence interval (CI) = 0.155-0.692) and risedronate (RR = 0.428, 95% CI = 0.245-0.746) but not with calcitonin (RR = 0.272, 95% CI = 0.046-1.608) or denosumab (RR = 0.256, 95% CI = 0.029-2.238) than in controls. For bisphosphonates as a treatment category, meta-analyses demonstrated significantly lower risk of vertebral fractures (RR = 0.368, 95% CI = 0.252-0.537) and nonvertebral fractures (RR = 0.604, 95% CI = 0.404-0.904) than in controls. The meta-analysis finding that bisphosphonates significantly reduce nonvertebral fracture risk was not robust to sensitivity analysis. CONCLUSION: Bisphosphonates reduce the risk of vertebral and possibly nonvertebral fractures for men with osteoporosis. Further studies are needed to evaluate the efficacy of bisphosphonates for reducing nonvertebral fracture risk and the efficacy of nonbisphosphonates for reducing vertebral and nonvertebral fracture risk in men with osteoporosis

Advancing Research on Racial–Ethnic Health Disparities: Improving Measurement Equivalence in Studies with Diverse Samples

To conduct meaningful, epidemiologic research on racial–ethnic health disparities, racial–ethnic samples must be rendered equivalent on other social status and contextual variables via statistical controls of those extraneous factors. The racial–ethnic groups must also be equally familiar with and have similar responses to the methods and measures used to collect health data, must have equal opportunity to participate in the research, and must be equally representative of their respective populations. In the absence of such measurement equivalence, studies of racial–ethnic health disparities are confounded by a plethora of unmeasured, uncontrolled correlates of race–ethnicity. Those correlates render the samples, methods, and measures incomparable across racial–ethnic groups, and diminish the ability to attribute health differences discovered to race–ethnicity vs. to its correlates. This paper reviews the non-equivalent yet normative samples, methodologies and measures used in epidemiologic studies of racial–ethnic health disparities, and provides concrete suggestions for improving sample, method, and scalar measurement equivalence

Multilineage hematopoietic recovery with concomitant antitumor effects using low dose Interleukin-12 in myelosuppressed tumor-bearing mice

<p>Abstract</p> <p>Background</p> <p>Interleukin-12 (IL-12) is a cytokine well known for its role in immunity. A lesser known function of IL-12 is its role in hematopoiesis. The promising data obtained in the preclinical models of antitumor immunotherapy raised hope that IL-12 could be a powerful therapeutic agent against cancer. However, excessive clinical toxicity, largely due to repeat dose regimens, and modest clinical response observed in the clinical trials have pointed to the necessity to design protocols that minimize toxicity without affecting the anti-tumor effect of IL-12. We have focused on the lesser known role of IL-12 in hematopoiesis and hypothesized that an important clinical role for IL-12 in cancer may be as an adjuvant hematological cancer therapy. In this putative clinical function, IL-12 is utilized for the prevention of cancer therapy-related cytopenias, while providing concomitant anti-tumor responses over and above responses observed with the primary therapy alone. This putative clinical function of IL-12 focuses on the dual role of IL-12 in hematopoiesis and immunity.</p> <p>Methods</p> <p>We assessed the ability of IL-12 to facilitate hematopoietic recovery from radiation (625 rad) and chemotherapy (cyclophosphamide) in two tumor-bearing murine models, namely the EL4 lymphoma and the Lewis lung cancer models. Antitumor effects and changes in bone marrow cellularity were also assessed.</p> <p>Results</p> <p>We show herein that carefully designed protocols, in mice, utilizing IL-12 as an adjuvant to radiation or chemotherapy yield facile and consistent, multilineage hematopoietic recovery from cancer therapy-induced cytopenias, as compared to vehicle and the clinically-utilized cytokine granulocyte colony-stimulating factor (G-CSF) (positive control), while still providing concomitant antitumor responses over and above the effects of the primary therapy alone. Moreover, our protocol design utilizes single, low doses of IL-12 that did not yield any apparent toxicity.</p> <p>Conclusion</p> <p>Our results portend that despite its past failure, IL-12 appears to have significant clinical potential as a hematological adjuvant cancer therapy.</p