Increasing β-catenin/Wnt3A activity levels drive mechanical strain-induced cell cycle progression through mitosis.

Mechanical force and Wnt signaling activate β-catenin-mediated transcription to promote proliferation and tissue expansion. However, it is unknown whether mechanical force and Wnt signaling act independently or synergize to activate β-catenin signaling and cell division. We show that mechanical strain induced Src-dependent phosphorylation of Y654 β-catenin and increased β-catenin-mediated transcription in mammalian MDCK epithelial cells. Under these conditions, cells accumulated in S/G2 (independent of DNA damage) but did not divide. Activating β-catenin through Casein Kinase I inhibition or Wnt3A addition increased β-catenin-mediated transcription and strain-induced accumulation of cells in S/G2. Significantly, only the combination of mechanical strain and Wnt/β-catenin activation triggered cells in S/G2 to divide. These results indicate that strain-induced Src phosphorylation of β-catenin and Wnt-dependent β-catenin stabilization synergize to increase β-catenin-mediated transcription to levels required for mitosis. Thus, local Wnt signaling may fine-tune the effects of global mechanical strain to restrict cell divisions during tissue development and homeostasis

Wind Tunnel Results of the B-52B with the X-43A Stack

A low-speed wind-tunnel test was performed with a three-percent-scale model of a booster rocket mated to an X-43A research vehicle, a combination referred to as the Hyper-X launch vehicle. The test was conducted both in free-stream air and in the presence of a partial model of the B-52B airplane. The objectives of the test were to obtain force and moment data to generate structural loads affecting the pylon of the B-52B airplane and to determine the aerodynamic influence of the B-52B airplane on the Hyper-X launch vehicle to evaluate launch separation characteristics. The wind-tunnel test was conducted at a low-speed wind tunnel in Hampton, Virginia. All moments and forces reported are based either on the aerodynamic influence of the B-52B airplane or are for the Hyper-X launch vehicle in free-stream air. Overall, the test showed that the B-52B airplane imparts a strong downwash onto the Hyper-X launch vehicle, reducing the net lift of the Hyper-X launch vehicle. Also, pitching and rolling moments are imparted onto the booster and are a strong function of the launch-drop angle of attack

Spatial distribution of cell-cell and cell-ECM adhesions regulates force balance while main-taining E-cadherin molecular tension in cell pairs.

Mechanical linkage between cell-cell and cell-extracellular matrix (ECM) adhesions regulates cell shape changes during embryonic development and tissue homoeostasis. We examined how the force balance between cell-cell and cell-ECM adhesions changes with cell spread area and aspect ratio in pairs of MDCK cells. We used ECM micropatterning to drive different cytoskeleton strain energy states and cell-generated traction forces and used a Förster resonance energy transfer tension biosensor to ask whether changes in forces across cell-cell junctions correlated with E-cadherin molecular tension. We found that continuous peripheral ECM adhesions resulted in increased cell-cell and cell-ECM forces with increasing spread area. In contrast, confining ECM adhesions to the distal ends of cell-cell pairs resulted in shorter junction lengths and constant cell-cell forces. Of interest, each cell within a cell pair generated higher strain energies than isolated single cells of the same spread area. Surprisingly, E-cadherin molecular tension remained constant regardless of changes in cell-cell forces and was evenly distributed along cell-cell junctions independent of cell spread area and total traction forces. Taken together, our results showed that cell pairs maintained constant E-cadherin molecular tension and regulated total forces relative to cell spread area and shape but independently of total focal adhesion area

Wind-Tunnel Results of the B-52B with the X-43A Stack

A low-speed wind-tunnel test was performed with a 3%-scale model of a booster rocket mated to an X-43A research vehicle, a combination referred to as the Hyper-X launch vehicle. The test was conducted both in freestream air and in the presence of a partial model of the B-52B airplane. The objectives of the test were to obtain force and moment data to generate structural loads affecting the pylon of the B-52B airplane and to determine the aerodynamic influence of the B-52B on the Hyper-X launch vehicle for evaluating launch separation characteristics. The windtunnel test was conducted at a low-speed wind tunnel in Hampton, Virginia. All moments and forces reported are based either on the aerodynamic influence of the B-52B airplane or are for the Hyper-X launch vehicle in freestream air. Overall, the test showed that the B-52B airplane imparts a strong downwash onto the Hyper-X launch vehicle, reducing the net lift of the Hyper-X launch vehicle. Pitching and rolling moments are also imparted onto the booster and are a strong function of the launch-drop angle of attack

Applications of Evolutionary Computation (Part II)

The two volumes LNCS 10199 and 10200 constitute the refereed conference proceedings of the 20th European Conference on the Applications of Evolutionary Computation, EvoApplications 2017, held in Amsterdam, The Netherlands, in April 2017, colocated with the Evo* 2017 events EuroGP, EvoCOP, and EvoMUSART

Laterally Propagating Detonations in Thin Helium Layers on Accreting White Dwarfs

Theoretical work has shown that intermediate mass (0.01Msun<M_He<0.1Msun) Helium shells will unstably ignite on the accreting white dwarf (WD) in an AM CVn binary. For more massive (M>0.8Msun) WDs, these helium shells can be dense enough (5x10^5 g/cc) that the convectively burning region runs away on a timescale comparable to the sound travel time across the shell; raising the possibility for an explosive outcome. The nature of the explosion (i.e. deflagration or detonation) remains ambiguous. In the case of detonation, this causes a laterally propagating front whose properties in these geometrically thin and low density shells we begin to study here. Our calculations show that the radial expansion time of <0.1 s leads to incomplete helium burning, in agreement with recent work by Sim and collaborators, but that the nuclear energy released is still adequate to realize a self-sustaining detonation propagating laterally at slower than the Chapman-Jouguet speed. Our simulations resolve the subsonic region behind the front and are consistent with a direct computation of the reaction structure from the shock strength. The ashes are typically He rich, and consist of predominantly Ti-44, Cr-48, along with a small amount of Fe-52, with very little Ni-56 and with significant Ca-40 in carbon-enriched layers. If this helium detonation results in a Type Ia Supernova, its spectral signatures would appear for the first few days after explosion. (abridged)Comment: 7 pages, 5 figure, accepted to the Astrophysical Journa

Graz. Schloßberg.

Blick zum Schloßberg mit Hauptbrück

A Hyper-Heuristic Ensemble Method for Static Job-Shop Scheduling

We describe a new hyper-heuristic method NELLI-GP for solving job-shop scheduling problems (JSSP) that evolves an ensemble of heuristics. The ensemble adopts a divide-and-conquer approach in which each heuristic solves a unique subset of the instance set considered. NELLI-GP extends an existing ensemble method called NELLI by introducing a novel heuristic generator that evolves heuristics composed of linear sequences of dispatching rules: each rule is represented using a tree structure and is itself evolved. Following a training period, the ensemble is shown to outperform both existing dispatching rules and a standard genetic programming algorithm on a large set of new test instances. In addition, it obtains superior results on a set of 210 benchmark problems from the literature when compared to two state-of-the-art hyper-heuristic approaches. Further analysis of the relationship between heuristics in the evolved ensemble and the instances each solves provides new insights into features that might describe similar instances.</jats:p

Hypoglycemia-Related Hospitalizations and Mortality Among Patients With Diabetes Transitioning to Dialysis.

Rationale &amp; objectiveDiabetic patients with declining kidney function are at heightened risk for hypoglycemia. We sought to determine whether hypoglycemia-related hospitalizations in the interval before dialysis therapy initiation are associated with post-end-stage renal disease (ESRD) mortality among incident patients with ESRD with diabetes.Study designObservational cohort study.Setting &amp; participantsUS veterans from the national Veterans Affairs database with diabetes and chronic kidney disease transitioning to dialysis therapy from October 2007 to September&nbsp;2011.ExposureHypoglycemia-related hospitalizations during the pre-ESRD period and antidiabetic medication regimens.OutcomeThe outcome of post-ESRD all-cause mortality was evaluated relative to pre-ESRD hypoglycemia. The outcome of pre-ESRD hypoglycemia-related hospitalization was evaluated relative to antidiabetic medication regimens.Analytic approachWe examined whether the&nbsp;occurrence and frequency of pre-ESRD hypoglycemia-related hospitalizations are associated with post-ESRD mortality using Cox regression models adjusted for case-mix covariates. In a subcohort of patients prescribed 0 to 2 oral antidiabetic drugs and/or insulin, we examined the 12 most commonly prescribed antidiabetic medication regimens and risk for pre-ESRD hypoglycemia-related hospitalization using logistic regression models adjusted for case-mix covariates.ResultsAmong 30,156 patients who met eligibility criteria, the occurrence of pre-ESRD hypoglycemia-related hospitalization(s) was associated with higher post-ESRD mortality risk: adjusted HR (aHR), 1.25; 95% CI, 1.17-1.34 (reference group: no hypoglycemia hospitalization). Increasing frequency of hypoglycemia-related hospitalizations was independently associated with incrementally higher mortality risk: aHRs of 1.21 (95% CI, 1.12-1.30), 1.47 (95% CI, 1.19-1.82), and 2.07&nbsp;(95% CI, 1.46-2.95) for 1, 2, and 3 or&nbsp;more&nbsp;hypoglycemia-related hospitalizations, respectively (reference group: no hypoglycemia hospitalization). Compared with patients who were prescribed neither oral antidiabetic drugs nor insulin, medication regimens that included sulfonylureas and/or insulin were associated with higher risk for hypoglycemia.LimitationsResidual confounding cannot be excluded.ConclusionsAmong incident patients with ESRD with diabetes, a dose-dependent relationship between frequency of pre-ESRD hypoglycemia-related hospitalizations and post-ESRD mortality was observed. Further study of diabetic management strategies that prevent hypoglycemia as patients with chronic kidney disease transition to ESRD are warranted

Development and Validation of Prediction Scores for Early Mortality at Transition to Dialysis.

ObjectiveTo develop and validate a risk prediction model that would help individualize treatment and improve the shared decision-making process between clinicians and patients.Patients and methodsWe developed a risk prediction tool for mortality during the first year of dialysis based on pre-end-stage renal disease characteristics in a cohort of 35,878 US veterans with incident end-stage renal disease who transitioned to dialysis treatment between October 1, 2007, and March 31, 2014 and then externally validated this tool among 4284 patients in the Kaiser Permanente Southern California (KPSC) health care system who transitioned to dialysis treatment between January 1, 2007, and September 30,&nbsp;2015.ResultsTo ensure model goodness of fit, 2 separate models were selected for patients whose last estimated glomerular filtration rate (eGFR) before dialysis initiation was less than 15 mL/min per 1.73 m2 or 15 mL/min per 1.73 m2 or higher. Model discrimination in the internal validation cohort of veterans resulted in C statistics of 0.71 (95% CI, 0.70-0.72) and 0.66 (95% CI, 0.65-0.67) among patients with eGFR lower than 15 mL/min per 1.73 m2 and 15 mL/min per 1.73 m2 or higher, respectively. In the KPSC external validation cohort, the developed risk score exhibited C statistics of 0.77 (95% CI, 0.74-0.79) in men and 0.74 (95% CI, 0.71-0.76) in women with eGFR lower than 15 mL/min per 1.73 m2 and 0.71 (95% CI, 0.67-0.74) in men and 0.67 (95% CI, 0.62-0.72) in women with eGFR of 15 mL/min per 1.73 m2 or higher.ConclusionA new risk prediction tool for mortality during the first year after transition to dialysis (available at www.DialysisScore.com) was developed in the large national Veterans Affairs cohort and validated with good performance in the racially, ethnically, and gender diverse KPSC cohort. This risk prediction tool will help identify high-risk populations and guide management strategies at the transition to dialysis