Hypertabastic survival model

A new two-parameter probability distribution called hypertabastic is introduced to model the survival or time-to-event data. A simulation study was carried out to evaluate the performance of the hypertabastic distribution in comparison with popular distributions. We then demonstrate the application of the hypertabastic survival model by applying it to data from two motivating studies. The first one demonstrates the proportional hazards version of the model by applying it to a data set from multiple myeloma study. The second one demonstrates an accelerated failure time version of the model by applying it to data from a randomized study of glioma patients who underwent radiotherapy treatment with and without radiosensitizer misonidazole. Based on the results from the simulation study and two applications, the proposed model shows to be a flexible and promising alternative to practitioners in this field

Implantation of Mouse Embryonic Stem Cell-Derived Cardiac Progenitor Cells Preserves Function of Infarcted Murine Hearts

Stem cell transplantation holds great promise for the treatment of myocardial infarction injury. We recently described the embryonic stem cell-derived cardiac progenitor cells (CPCs) capable of differentiating into cardiomyocytes, vascular endothelium, and smooth muscle. In this study, we hypothesized that transplanted CPCs will preserve function of the infarcted heart by participating in both muscle replacement and neovascularization. Differentiated CPCs formed functional electromechanical junctions with cardiomyocytes in vitro and conducted action potentials over cm-scale distances. When transplanted into infarcted mouse hearts, CPCs engrafted long-term in the infarct zone and surrounding myocardium without causing teratomas or arrhythmias. The grafted cells differentiated into cross-striated cardiomyocytes forming gap junctions with the host cells, while also contributing to neovascularization. Serial echocardiography and pressure-volume catheterization demonstrated attenuated ventricular dilatation and preserved left ventricular fractional shortening, systolic and diastolic function. Our results demonstrate that CPCs can engraft, differentiate, and preserve the functional output of the infarcted heart

Coordinated Movements Prevent Jamming in an Emperor Penguin Huddle

For Emperor penguins (Aptenodytes forsteri), huddling is the key to survival during the Antarctic winter. Penguins in a huddle are packed so tightly that individual movements become impossible, reminiscent of a jamming transition in compacted colloids. It is crucial, however, that the huddle structure is continuously reorganized to give each penguin a chance to spend sufficient time inside the huddle, compared with time spent on the periphery. Here we show that Emperor penguins move collectively in a highly coordinated manner to ensure mobility while at the same time keeping the huddle packed. Every 30–60 seconds, all penguins make small steps that travel as a wave through the entire huddle. Over time, these small movements lead to large-scale reorganization of the huddle. Our data show that the dynamics of penguin huddling is governed by intermittency and approach to kinetic arrest in striking analogy with inert non-equilibrium systems, including soft glasses and colloids

Individual, behavioural and home environmental factors associated with eating behaviours in young adolescents

This study aimed to examine individual, behavioural and home environmental factors associated with frequency of consumption of fruit, vegetables and energy-dense snacks among adolescents. Adolescents aged 11-12 years (n = 521, 48% boys) completed a paper-based questionnaire during class-time which included a Food Frequency Questionnaire assessing their consumption of fruit, vegetables, and energy dense (ED) snacks, and items assessing habits, self-efficacy, eating at the television (TV), eating with parents, parenting practices, and home availability and accessibility of foods. Multiple linear regression analyses showed that eating fruit and vegetables while watching TV and home availability and accessibility of fruit and vegetables were positively associated with frequency of fruit consumption and vegetable consumption, while home accessibility of ED snack foods was negatively associated with frequency of fruit consumption. Habit for eating ED snack foods in front the TV, eating ED snack foods while watching TV, and home availability of ED snacks were positively associated with frequency of ED snack consumption. This study has highlighted the importance of a healthy home environment for promoting fruit and vegetable intake in early adolescents and also suggests that, if snacking while TV viewing occurs, this could be a good opportunity for promoting fruit and vegetable intake. These findings are likely to be useful for supporting the development of multi-faceted interventions and aid us in knowing what advice to give to parents to help them to help their young adolescents to develop and maintain healthy eating habits

A novel small molecule target in human airway smooth muscle for potential treatment of obstructive lung diseases: a staged high-throughput biophysical screening

<p>Abstract</p> <p>Background</p> <p>A newly identified mechanism of smooth muscle relaxation is the interaction between the small heat shock protein 20 (HSP20) and 14-3-3 proteins. Focusing upon this class of interactions, we describe here a novel drug target screening approach for treating airflow obstruction in asthma.</p> <p>Methods</p> <p>Using a high-throughput fluorescence polarization (FP) assay, we screened a library of compounds that could act as small molecule modulators of HSP20 signals. We then applied two quantitative, cell-based biophysical methods to assess the functional efficacy of these molecules and rank-ordered their abilities to relax isolated human airway smooth muscle (ASM). Scaling up to the level of an intact tissue, we confirmed in a concentration-responsive manner the potency of the cell-based hit compounds.</p> <p>Results</p> <p>Among 58,019 compound tested, 268 compounds caused 20% or more reduction of the polarized emission in the FP assay. A small subset of these primary screen hits, belonging to two scaffolds, caused relaxation of isolated ASM cell <it>in vitro </it>and attenuated active force development of intact tissue <it>ex vivo</it>.</p> <p>Conclusions</p> <p>This staged biophysical screening paradigm provides proof-of-principle for high-throughput and cost-effective discovery of new small molecule therapeutic agents for obstructive lung diseases.</p

Multivariable regression analysis of febrile neutropenia occurrence in early breast cancer patients receiving chemotherapy assessing patient-related, chemotherapy-related and genetic risk factors.

BACKGROUND: Febrile neutropenia (FN) is common in breast cancer patients undergoing chemotherapy. Risk factors for FN have been reported, but risk models that include genetic variability have yet to be described. This study aimed to evaluate the predictive value of patient-related, chemotherapy-related, and genetic risk factors. METHODS: Data from consecutive breast cancer patients receiving chemotherapy with 4-6 cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) or three cycles of FEC and docetaxel were retrospectively recorded. Multivariable logistic regression was carried out to assess risk of FN during FEC chemotherapy cycles. RESULTS: Overall, 166 (16.7%) out of 994 patients developed FN. Significant risk factors for FN in any cycle and the first cycle were lower platelet count (OR = 0.78 [0.65; 0.93]) and haemoglobin (OR = 0.81 [0.67; 0.98]) and homozygous carriers of the rs4148350 variant T-allele (OR = 6.7 [1.04; 43.17]) in MRP1. Other significant factors for FN in any cycle were higher alanine aminotransferase (OR = 1.02 [1.01; 1.03]), carriers of the rs246221 variant C-allele (OR = 2.0 [1.03; 3.86]) in MRP1 and the rs351855 variant C-allele (OR = 2.48 [1.13; 5.44]) in FGFR4. Lower height (OR = 0.62 [0.41; 0.92]) increased risk of FN in the first cycle. CONCLUSIONS: Both established clinical risk factors and genetic factors predicted FN in breast cancer patients. Prediction was improved by adding genetic information but overall remained limited. Internal validity was satisfactory. Further independent validation is required to confirm these findings

Reversible Disassembly of the Actin Cytoskeleton Improves the Survival Rate and Developmental Competence of Cryopreserved Mouse Oocytes

Effective cryopreservation of oocytes is critically needed in many areas of human reproductive medicine and basic science, such as stem cell research. Currently, oocyte cryopreservation has a low success rate. The goal of this study was to understand the mechanisms associated with oocyte cryopreservation through biophysical means using a mouse model. Specifically, we experimentally investigated the biomechanical properties of the ooplasm prior and after cryopreservation as well as the consequences of reversible dismantling of the F-actin network in mouse oocytes prior to freezing. The study was complemented with the evaluation of post-thaw developmental competence of oocytes after in vitro fertilization. Our results show that the freezing-thawing process markedly alters the physiological viscoelastic properties of the actin cytoskeleton. The reversible depolymerization of the F-actin network prior to freezing preserves normal ooplasm viscoelastic properties, results in high post-thaw survival and significantly improves developmental competence. These findings provide new information on the biophysical characteristics of mammalian oocytes, identify a pathophysiological mechanism underlying cryodamage and suggest a novel cryopreservation method

In Vivo Determination of Fluctuating Forces during Endosome Trafficking Using a Combination of Active and Passive Microrheology

BACKGROUND: Regulation of intracellular trafficking is a central issue in cell biology. The forces acting on intracellular vesicles (endosomes) can be assessed in living cells by using a combination of active and passive microrheology. METHODOLOGY/PRINCIPAL FINDINGS: This dual approach is based on endosome labeling with magnetic nanoparticles. The resulting magnetic endosomes act both as probes that can be manipulated with external magnetic fields to infer the viscoelastic modulus of their surrounding microenvironment, and as biological vehicles that are trafficked along the microtubule network by means of forces generated by molecular motors. The intracellular viscoelastic modulus exhibits power law dependence with frequency, which is microtubule and actin-dependent. The mean square displacements of endosomes do not follow the predictions of the fluctuation-dissipation theorem, which offers evidence for active force generation. Microtubule disruption brings the intracellular medium closer to thermal equilibrium: active forces acting on the endosomes depend on microtubule-associated motors. The power spectra of these active forces, deduced through the use of a generalized Langevin equation, show a power law decrease with frequency and reveal an actin-dependent persistence of the force with time. Experimental spectra have been reproduced by a simple model consisting in a series of force steps power-law distributed in time. This model enlightens the role of the cytoskeleton dependent force exerted on endosomes to perform intracellular trafficking. CONCLUSIONS/SIGNIFICANCE: In this work, the influence of cytoskeleton components and molecular motors on intracellular viscoelasticity and transport is addressed. The use of an original probe, the magnetic endosome, allows retrieving the power spectrum of active forces on these organelles thanks to interrelated active and passive measures. Finally a computational model gives estimates of the force itself and hence of the number of the motors pulling on endosomes

Cadherin-Dependent Cell Morphology in an Epithelium: Constructing a Quantitative Dynamical Model

Cells in the Drosophila retina have well-defined morphologies that are attained during tissue morphogenesis. We present a computer simulation of the epithelial tissue in which the global interfacial energy between cells is minimized. Experimental data for both normal cells and mutant cells either lacking or misexpressing the adhesion protein N-cadherin can be explained by a simple model incorporating salient features of morphogenesis that include the timing of N-cadherin expression in cells and its temporal relationship to the remodeling of cell-cell contacts. The simulations reproduce the geometries of wild-type and mutant cells, distinguish features of cadherin dynamics, and emphasize the importance of adhesion protein biogenesis and its timing with respect to cell remodeling. The simulations also indicate that N-cadherin protein is recycled from inactive interfaces to active interfaces, thereby modulating adhesion strengths between cells

Reinforcement versus Fluidization in Cytoskeletal Mechanoresponsiveness

Every adherent eukaryotic cell exerts appreciable traction forces upon its substrate. Moreover, every resident cell within the heart, great vessels, bladder, gut or lung routinely experiences large periodic stretches. As an acute response to such stretches the cytoskeleton can stiffen, increase traction forces and reinforce, as reported by some, or can soften and fluidize, as reported more recently by our laboratory, but in any given circumstance it remains unknown which response might prevail or why. Using a novel nanotechnology, we show here that in loading conditions expected in most physiological circumstances the localized reinforcement response fails to scale up to the level of homogeneous cell stretch; fluidization trumps reinforcement. Whereas the reinforcement response is known to be mediated by upstream mechanosensing and downstream signaling, results presented here show the fluidization response to be altogether novel: it is a direct physical effect of mechanical force acting upon a structural lattice that is soft and fragile. Cytoskeletal softness and fragility, we argue, is consistent with early evolutionary adaptations of the eukaryotic cell to material properties of a soft inert microenvironment