Material properties of the heel fat pad across strain rates

The complex structural and material behaviour of the human heel fat pad determines the transmission of plantar loading to the lower limb across a wide range of loading scenarios; from locomotion to injurious incidents. The aim of this study was to quantify the hyper-viscoelastic material properties of the human heel fat pad across strains and strain rates. An inverse finite element (FE) optimisation algorithm was developed and used, in conjunction with quasi-static and dynamic tests performed to five cadaveric heel specimens, to derive specimen-specific and mean hyper-viscoelastic material models able to predict accurately the response of the tissue at compressive loading of strain rates up to 150 s−1. The mean behaviour was expressed by the quasi-linear viscoelastic (QLV) material formulation, combining the Yeoh material model (C10=0.1MPa, C30=7MPa, K=2GPa) and Prony׳s terms (A1=0.06, A2=0.77, A3=0.02 for τ1=1ms, τ2=10ms, τ3=10s). These new data help to understand better the functional anatomy and pathophysiology of the foot and ankle, develop biomimetic materials for tissue reconstruction, design of shoe, insole, and foot and ankle orthoses, and improve the predictive ability of computational models of the foot and ankle used to simulate daily activities or predict injuries at high rate injurious incidents such as road traffic accidents and underbody blast

Towards More Practical Linear Programming-based Techniques for Algorithmic Mechanism Design

R. Lavy and C. Swamy (FOCS 2005, J. ACM 2011) introduced a general method for obtaining truthful-in-expectation mechanisms from linear programming based approximation algorithms. Due to the use of the Ellipsoid method, a direct implementation of the method is unlikely to be efficient in practice. We propose to use the much simpler and usually faster multiplicative weights update method instead. The simplification comes at the cost of slightly weaker approximation and truthfulness guarantees

Stature and mitigation systems affect the risk of leg injury in vehicles attacked under the body by explosive devices

A finite-element (FE) model, previously validated for underbody blast (UBB) loading, was used here to study the effect of stature and of mitigation systems on injury risk to the leg. A range of potential UBB loadings was simulated. The risk of injury to the leg was calculated when no protection was present, when a combat boot (Meindl Desert Fox) was worn, and when a floor mat (IMPAXXTM), which can be laid on the floor of a vehicle, was added. The risk of injury calculated indicates that the floor mat provided a statistically significant reduction in the risk of a major calcaneal injury for peak impact speeds below 17.5 m/s when compared with the scenarios in which the floor mat was not present. The risk of injury to the leg was also calculated for a shorter and a taller stature compared to that of the nominal, 50th percentile male anthropometry; shorter and taller statures were constructed by scaling the length of the tibia of the nominal stature. The results showed that there is a higher risk of leg injury associated with the short stature compared to the nominal and tall statures, whereas the leg-injury risk between nominal and tall statures was statistically similar. These findings provide evidence that the combat boot and the floor mat tested here have an attenuating effect, albeit limited to a range of possible UBB loads. The effect of stature on injury has implications on how vehicle design caters for all potential anthropometries and indeed gender, as women, on average, are shorter than men. The results from the computational simulations here complement laboratory and field experimental models of UBB, and so they contribute to the improvement of UBB safety technology and strategy

On the Number of Iterations for Dantzig-Wolfe Optimization and Packing-Covering Approximation Algorithms

We give a lower bound on the iteration complexity of a natural class of Lagrangean-relaxation algorithms for approximately solving packing/covering linear programs. We show that, given an input with $m$ random 0/1-constraints on $n$ variables, with high probability, any such algorithm requires $\Omega(\rho \log(m)/\epsilon^2)$ iterations to compute a $(1+\epsilon)$-approximate solution, where $\rho$ is the width of the input. The bound is tight for a range of the parameters $(m,n,\rho,\epsilon)$. The algorithms in the class include Dantzig-Wolfe decomposition, Benders' decomposition, Lagrangean relaxation as developed by Held and Karp [1971] for lower-bounding TSP, and many others (e.g. by Plotkin, Shmoys, and Tardos [1988] and Grigoriadis and Khachiyan [1996]). To prove the bound, we use a discrepancy argument to show an analogous lower bound on the support size of $(1+\epsilon)$-approximate mixed strategies for random two-player zero-sum 0/1-matrix games

Differential regulation of human bone marrow mesenchymal stromal cell chondrogenesis by hypoxia inducible factor-1α hydroxylase inhibitors

The transcriptional profile induced by hypoxia plays important roles in the chondrogenic differentiation of marrow stromal/stem cells (MSC) and is mediated by the Hypoxia Inducible Factor complex. However, various compounds can also stabilise HIF's oxygen-responsive element, HIF-1α, at normoxia and mimic many hypoxia-induced cellular responses. Such compounds may prove efficacious in cartilage tissue engineering, where microenvironmental cues may mediate functional tissue formation. Here, we investigated three HIF stabilising compounds, which each have distinct mechanisms of action, to understand how they differentially influenced the chondrogenesis of human bone marrow-derived MSC (hBM-MSC) in vitro. hBM-MSCs were chondrogenically-induced in TGF-β3 -containing media in the presence of HIF-stabilising compounds. HIF-1α stabilisation was assessed by HIF-1α immunofluorescence staining, expression of HIF target and articular chondrocyte specific genes by qPCR, and cartilage-like extracellular matrix (ECM) production by immunofluorescence and histochemical staining. We demonstrate that all three compounds induced similar levels of HIF-1α nuclear localisation. However, whilst the 2-oxoglutarate analogue Dimethyloxalylglycine (DMOG) promoted upregulation of a selection of HIF target genes, Desferrioxamine (DFX) and Cobalt Chloride (CoCl2 ), compounds that chelate or compete with Fe2+ , respectively, did not. Moreover, DMOG induced a more chondrogenic transcriptional profile, which was abolished by Acriflavine, an inhibitor of HIF-1α-HIF-β binding, whilst the chondrogenic effects of DFX and CoCl2 were more limited. Together, these data suggest that HIF-1α function during hBM-MSC chondrogenesis may be regulated by mechanisms with a greater dependence on 2-oxoglutarate than Fe2+ availability. These results may have important implications for understanding cartilage disease and developing targeted therapies for cartilage repair. This article is protected by copyright. All rights reserved

Hypoxia impacts human MSC response to substrate stiffness during chondrogenic differentiation

Tissue engineering strategies often aim to direct tissue formation by mimicking conditions progenitor cells experience within native tissues. For example, to create cartilage in vitro, researchers often aim to replicate the biochemical and mechanical milieu cells experience during cartilage formation in the developing limb bud. This includes stimulating progenitors with TGF-β1/3, culturing under hypoxic conditions, and regulating mechanosensory pathways using biomaterials that control substrate stiffness and/or cell shape. However, as progenitors differentiate down the chondrogenic lineage, the pathways that regulate their responses to mechanotransduction, hypoxia and TGF-β may not act independently, but rather also impact one another, influencing overall cell response. Here, to better understand hypoxia's influence on mechanoregulatory-mediated chondrogenesis, we cultured human marrow stromal/mesenchymal stem cells (hMSC) on soft (0.167 kPa) or stiff (49.6 kPa) polyacrylamide hydrogels in chondrogenic medium containing TGF-β3. We then compared cell morphology, phosphorylated myosin light chain 2 staining, and chondrogenic gene expression under normoxic and hypoxic conditions, in the presence and absence of pharmacological inhibition of cytoskeletal tension. We show that on soft compared to stiff substrates, hypoxia prompts hMSC to adopt more spread morphologies, assemble in compact mesenchymal condensation-like colonies, and upregulate NCAM expression, and that inhibition of cytoskeletal tension negates hypoxia-mediated upregulation of molecular markers of chondrogenesis, including COL2A1 and SOX9. Taken together, our findings support a role for hypoxia in regulating hMSC morphology, cytoskeletal tension and chondrogenesis, and that hypoxia's effects are modulated, at least in part, by mechanosensitive pathways. Our insights into how hypoxia impacts mechanoregulation of chondrogenesis in hMSC may improve strategies to develop tissue engineered cartilage

Dual Mechanisms of LYN Kinase Dysregulation Drive Aggressive Behavior in Breast Cancer Cells

The SRC-family kinase LYN is highly expressed in triple-negative/basal-like breast cancer (TNBC) and in the cell of origin of these tumors, c-KIT-positive luminal progenitors. Here, we demonstrate LYN is a downstream effector of c-KIT in normal mammary cells and protective of apoptosis upon genotoxic stress. LYN activity is modulated by PIN1, a prolyl isomerase, and in BRCA1 mutant TNBC PIN1 upregulation activates LYN independently of c-KIT. Furthermore, the full-length LYN splice isoform (as opposed to the Δaa25-45 variant) drives migration and invasion of aggressive TNBC cells, while the ratio of splice variants is informative for breast cancer-specific survival across all breast cancers. Thus, dual mechanisms-uncoupling from upstream signals and splice isoform ratios-drive the activity of LYN in aggressive breast cancers

Discarding IVF embryos: reporting on global practices

Purpose: To provide a global scale report on a representative sample of the clinical embryology community depicting the practice of discarding supernumerary IVF embryos. Methods: A web-based questionnaire titled “Anonymous questionnaire on embryo disposal practices” was designed in order to ensure anonymous participation of practicing clinical embryologists around the world. Results: During a data collection period of 8 months, 703 filled-in questionnaires from 65 countries were acquired. According to the data acquired, the majority of practitioners, dispose of embryos by placing them directly in a trash can strictly dedicated for embryo disposal for both fresh and frozen cycles (39% and 36.7% respectively). Moreover, 66.4% of practitioners discard the embryos separately—case by case—at different time points during the day. Over half of embryologists (54%) wait until day 6 to discard the surplus embryos, while 65.5% do not implement a specially allocated incubator space as a designated waiting area prior to disposal. The majority of 63.1% reported that this is a witnessed procedure. The vast majority of embryologists (93%) do not employ different protocols for different groups of patients. Nonetheless, 17.8% reported the request to perform a ceremony for these embryos. Assessing the embryologists’ perspective, 59.5% of participants stated that the embryology practice would benefit from a universally accepted and practiced protocol. Conclusion(s): This study uniquely provides insight into global embryo disposal practices and trends. Results highlight the divergence between reported practices, while indicating the significance on standardization of practice, with embryologists acknowledging the need for a universally accepted protocol implementation

A Nearly Linear-Time PTAS for Explicit Fractional Packing and Covering Linear Programs

We give an approximation algorithm for packing and covering linear programs (linear programs with non-negative coefficients). Given a constraint matrix with n non-zeros, r rows, and c columns, the algorithm computes feasible primal and dual solutions whose costs are within a factor of 1+eps of the optimal cost in time O((r+c)log(n)/eps^2 + n).Comment: corrected version of FOCS 2007 paper: 10.1109/FOCS.2007.62. Accepted to Algorithmica, 201