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This paper evaluates the forecasting performance of a Brownian semi-stationary (BSS) process in modelling the volatility of 21 equity indices. We implement a hybrid scheme to simulate BSS processes with high efficiency and precision. These simulations are useful to price derivatives, accounting for rough volatility. We then calibrate the BSS parameters for the realised kernel of 21 equity indices, using data from the Oxford-Man Institute. Finally, we conduct one-step and ten-step ahead forecasts on six indices and find that the BSS outperforms benchmarks, including a Log-HAR specification, in most cases.

Two complementary experiments were conducted to investigate the relationships between the canopy structure of Pennisetum clandestinum (kikuyugrass) pastures created by intermittent stocking strategies and daily herbage intake by cattle. The first experiment (Exp. I) evaluated the relationship between different pre-grazing heights (10, 15, 20, and 25 cm) and a single defoliation intensity (50% reduction in the initial heights). In the second experiment (Exp. II), four defoliation intensities (40, 50, 60, or 70% reduction in height) were combined with a single pre-grazing height (25 cm). The following variables were analyzed: i) plant-part composition, herbage mass, and bulk density of the grazing layer; and ii) daily herbage intake. The data were analyzed using orthogonal polynomial contrasts. The Tukey-Kramer test was used to compare daily herbage intake means so that the differences among treatments could be characterized. In general, herbage intake decreased as the pre-grazing canopy height decreased (Exp. I; P = 0.03) and as defoliation intensity increased (Exp. II; P = 0.02). These response patterns were associated with canopy structure, both that existing before and that created during the stocking period. In conclusion, pre-grazing heights lower than 25 cm or defoliation intensities greater than 40% reduce daily herbage intake by cattle in kikuyugrass pastures under intermittent stocking. RESUMO Dois experimentos complementares foram conduzidos para investigar as relações entre a estrutura do dossel de pastagens de Pennisetum clandestinum (capim-quicuiu) criadas por estratégias de lotação intermitente e o consumo de forragem por bovinos. O primeiro (Exp. I) avaliou o efeito de diferentes alturas em pré-pastejo (10, 15, 20 e 25 cm) associadas com uma única severidade de desfolhação (50% das alturas iniciais). No segundo (Exp. II) quatro severidades de desfolhação (40, 50, 60 ou 70% da altura total) foram combinadas com uma única altura inicial (25 cm). As variáveis analisadas foram: i) composição morfológica, massa e densidade do estrato de pastejo; ii) consumo de forragem. Os dados foram analisados por contrastes de polinômios ortogonais. Entretanto, para uma melhor caracterização das diferenças entre tratamentos, optou-se por comparar as médias de consumo pelo teste de Tukey. De modo geral, o consumo de forragem diminuiu com a redução da altura em pré-pastejo (Exp. I; P=0,03) ou com o aumento da severidade de desfolhação (Exp. II; P=0,02), em resposta as estruturas criadas antes e durante o processo de ocupação. Ademais, houve uma aparente abdicação dos animais em compensar estas condições com ajustes no comportamento ingestivo. Concluiu-se que alturas em pré-pastejo menores que 25 cm ou severidades de desfolhação maiores que 40% reduzem o consumo de forragem por bovinos em pastos de capim-quicuiu sob lotação intermitente.

Two experiments were conducted to assess the effect of pre‐grazing heights and proportions of defoliation on morphological and chemical composition of the grazing layer of two warm‐season perennial grasses of contrasting structures (tall tufted grass—elephant grass, Exp. I; small size stoloniferous grass—kikuyu grass, Exp. II) under intermittent stocking management. The treatments were as follows: Exp. I—factorial arrangement between two pre‐grazing heights (90 and 120 cm) and two proportions of defoliation (removal of 50% or 70% of the initial pre‐grazing heights); Exp. II—four pre‐grazing heights (10, 15, 20 and 25 cm) combined with the same proportion of defoliation (50% of the initial pre‐grazing heights). Forage samples were collected at pre‐grazing heights and clipped into the grazing layer (cutting heights defined by treatments). The following variables were analyzed: (a) forage mass; (b) proportion of leaves, stems, and dead material; (c) crude protein, neutral detergent fiber, and acid detergent fiber contents. In a general way, there were no significant differences in morphological and chemical composition of the grazing layer of treatments with proportions of defoliation of 50%. Although the treatments of 70% (Exp. I) and 10 cm (Exp. II) showed some differences, both targets impaired the grazing process and were considered as unpractical under field situations. It was concluded that forage chemical composition of warm‐season perennial grasses does not change in the upper half of the sward within a range of pre‐grazing heights, provided moderate proportions of defoliation (around 50%) are used.

BACKGROUND total hip arthroplasty (THA) is associated with decreased pain and improved function, including increased walking speed, but it does not always improve overall joint mechanics during activities of daily living such as level walking and stair climbing. The hip's ability to generate power to move and allow for smooth and efficient forward motion is critical to success after surgery. Although osteoarthritis (OA) of the hip limits the power of the affected joint, it is not known whether other joints in the affected limb or in the contralateral limb need to produce more power to compensate. Additionally, it is not known whether alterations in the production of power before and after surgery are gender-specific. QUESTIONS/PURPOSES (1) Is there a change in the power production of the bilateral ankles, knees, and hips during level walking before and after patients undergo unilateral THA, and are there important gender-specific differences in these findings? (2) How do these findings differ for stair climbing? METHODS Three-dimensional motion and ground reaction force data were collected for 13 men and 13 women who underwent primary, unilateral THA. This was a secondary analysis of previously collected data on gait mechanics from 60 patients who underwent THA. In the initial study, patients were included if they were scheduled to undergo a primary, unilateral THA within 4 weeks of the study and were able to walk without an assistive device. Patients were recruited from the practices of four surgeons at a single institution from 2008 to 2011. Patients were included in the current study if they were enrolled in the previous study, attended all three assessment visits (preoperative and 6 weeks and 1 year postoperative), and, during the preoperative visit, were able to walk without using an assistive device and climb stairs without using a handrail. Patients walked and ascended stairs at a self-selected speed at the three assessment visits. The power of each ankle, knee, or hip was calculated in Visual 3D using kinematic and kinetic data collected using motion capture. Power for each joint was normalized to the total power of the bilateral lower limbs by dividing the individual joint power by the total lower-extremity joint power. A mixed-model repeated-measures ANOVA was used to determine differences in normalized joint power for the ankle, knee, and hip, based on gender, limb (surgical-side versus nonsurgical-side) and timepoint (preoperative and 6 weeks and 1 year postoperative). RESULTS Surgical-side absolute (preoperative: -0.2 ± 0.2 [CI, -0.3 to -0.2], 1 year postoperative: -0.5 ± 0.3 [CI, -0.6 to - 0.5]; p < 0.001) and normalized (preoperative: 0.05 ± 0.04 [CI, 0.03-0.06], 1 year postoperative: 0.08 ± 0.04 [CI, 0.06-0.09]; p = 0.020) hip power production increased during walking. Surgical-side absolute (preoperative: 1.1 ± 0.3 [CI, 1.0-1.3], 1 year postoperative: 1.6 ± 0.2 [CI, 1.3-2.0]; p = 0.005) and normalized (preoperative: 0.16 ± 0.04 [CI, 0.14-0.18], 1 year postoperative: 0.21 ± 0.06 [CI, 0.18-0.24]; p = 0.008) hip power production increased during stair climbing, while nonsurgical ankle absolute (preoperative: 0.9 ± 0.5 [CI, 0.6 - 1.2], 1 year postoperative: 0.6 ± 0.3 [CI, 0.4-0.8]; p = 0.064) and normalized (preoperative: 0.13 ± 0.06 [CI, 0.10-0.16], 1 year postoperative: 0.08 ± 0.04 [CI, 0.06-0.10]; p = 0.015) power decreased during stair climbing after THA. No consistent effect of gender was observed. CONCLUSIONS In this gait-analysis study, power was improved in hip joints that were operated on, and power production in the ipsilateral and contralateral ankles and ipsilateral hips was reduced during level walking and stair climbing. The success of surgical intervention must be based on restoring reasonable balance of forces in the lower limb. Patients with OA of the hip lose power production in this joint and must compensate for the loss by producing power in other joints, which then may become arthritic. To determine future interventions, an understanding of whether changes in forces or joint angle affect the change in joint power is needed. Based on these results, THA appeared to effectively increase hip power and reduce the need for compensatory power production in other joints for both men and women in this patient cohort. LEVEL OF EVIDENCE Level I, prognostic study.

Autophagy is a central eukaryotic catabolic pathway responsible for clearance and recycling of an extensive portfolio of cargoes, which are packed in vesicles, called autophagosomes, and are delivered to lysosomes for degradation. Besides basal autophagy, which constantly degrades cellular material, the pathway is highly responsive to several stress conditions. However, the exact protein content and phospholipid composition of autophagosomes under changing autophagy conditions remain elusive so far. Here, we introduce a FACS-based approach for isolation of native unmanipulated autophagosomes and ensure the quality of the preparations. Employing quantitative proteomics and phospholipidomics, we obtained a profound cargo and lipid profile of autophagosomes purified upon basal autophagy conditions, nutrient deprivation, and proteasome inhibition. Indeed, starvation only mildly affected the content profile, while interference with proteasome activity showed stronger effects and specifically altered autophagosome cargoes. Interestingly, the phospholipid composition of autophagosomes was unaffected by the different treatments. Thus, the novel isolation method enables purification of intact autophagosomes in large quantities and allows protein content and phospholipid profiling without the requirement of exhaustive cellular fractionation or genetic manipulation.

Fragmentation methods based on the many-body expansion offer an attractive approach for the quantum-chemical treatment of large molecular systems, such as molecular clusters and crystals. Conventionally, the many-body expansion is performed for the total energy, but such an energy-based many-body expansion often suffers from a slow convergence with respect to the expansion order. For systems that show strong polarization effects such as water clusters, this can render the energy-based many-body expansion infeasible. Here, we establish a density-based many-body expansion as a promising alternative approach. By performing the many-body expansion for the electron density instead of the total energy and inserting the resulting total electron density into the total energy functional of density-functional theory, one can derive a density-based energy correction, which in principle accounts for all higher order polarization effects. Here, we systematically assess the accuracy of such a density-based many-body expansion for test sets of water clusters. We show that already a density-based two-body expansion is able to reproduce interaction energies per fragment within chemical accuracy, and is able to accurately predict the energetic ordering as well as the relative interaction energies of different isomers of water clusters.

Background and Objectives Total hip arthroplasty (THA) is a common surgical procedure in older adults (65 years or older). THA has high patient satisfaction, but little is known about balance and mobility limitations after surgery and if outcomes are sex-specific. This study was aimed to evaluate post-THA asymmetry during unilateral standing and a dynamic balance and reach test and test the hypotheses that balance performance would be decreased on the surgical limb and that balance deficits would be greater in women than in men. Research Design and Methods Primary, unilateral THA (70 male, 57 female) patients completed a bilateral 10-s single-leg stance test. Sixty male but only 34 female participants could maintain unilateral balance for 10 s or greater. The cohort who successfully completed the 10-s single-limb stance test then completed a Lower Quarter Y-Balance Test in which the maximum anterior (ANT), posteromedial (PM), and posterolateral reach distances were obtained bilaterally and used to calculate the asymmetry score. All variables were compared using a mixed-model repeated-measures analysis of variance (sex by limb), while independent samples t tests were used to assess sex-specific asymmetry. Results Women failed single-leg stance at a higher rate than men (85.7% vs 59.6%; p = .001). Reach distance was different between limbs for all reach directions (p < .004) with greater reach distance on the nonoperative limb for all patients. Men had a greater reach distance in the ANT (p = .004) and PM (p = .006) directions. Discussion and Implications These results indicate that post-THA, the operative limb and female patients have greater balance limitations. These results are novel and reveal sex-specific patterns that emphasize the need for sex-specific postoperative rehabilitation programs to improve long-term outcomes, especially in older adults with muscle weakness and balance deficits.

Background Racial differences in gait mechanics have been recently reported, but we don’t know what factors may drive differences in gait and whether these factors are innate or modifiable. The answers to those questions will inform both basic research and clinical interventions and outcomes. Research question Do anthropometric, strength, and health status measures explain racial differences in gait between African Americans (AA) and white Americans (WA)? Methods Venous blood samples, anthropometric measures, lower extremity strength, and an assessment of health status were collected from 92 participants (18–30 years old) as part of an Institutional Review Board-approved study. 3D motion capture and force plate data were recorded during 7 walking trials at set regular (1.35 m/s) and fast (1.6 m/s) speeds. Racial differences in gait were identified at both speeds. Correlations between anthropometric, strength, and health status independent variables and outcome measures were computed after stratifying data by sex. Stepwise linear regression models evaluated whether the inclusion of anthropometric, strength, and health status independent variables explained racial effects. Results In males, no racial differences in gait were explained by independent variables. Q-angle and ankle dorsiflexion strength accounted for racial differences in self-selected walking speed in females. Racial differences in ankle plantarflexion angle were explained by ankle plantarflexion strength differences. Significance Factors that explain racial differences in gait in females were both innate and modifiable. These data make clear that it is important to include racially diverse normative gait databases in research studies. These results also identify potential intervention targets aimed at reducing racial health disparities.

The effect of race has rarely been investigated in biomechanics studies despite racial health disparities in the incidence of musculoskeletal injuries and disease, hindering both treatment and assessment of rehabilitation. The purpose of this study was to test the hypothesis that racial differences in gait mechanics exist between African Americans (AA) and white Americans (WA). Ninety-two participants (18–30 years old) were recruited with equal numbers in each racial group and sex. Self-selected walking speed was measured for each participant. 3D motion capture and force plate data were recorded during 7 walking trials at regular and fast set speeds. Step length, step width, peak vertical ground reaction force, peak hip extension, peak knee flexion, and peak ankle plantarflexion were computed for all trials at both set speeds. Multivariate and post-hoc univariate ANOVA models were fit to determine main and interaction effects of sex and race (SPSS V26, α = 0.05). Self-selected walking speed was slower in AA (p = 0.004, ƞp2 = 0.088). No significant interactions between race and sex were identified. Males took longer steps (regular: p

Gaze-tracking techniques have advanced our understanding of visual attention and decision making during walking and athletic events, but little is known about how vision influences behavior during running over common, natural obstacles. This study tested hypotheses about whether runners regularly collect visual information and pre-plan obstacle clearance (feedforward control), make improvisational adjustments (online control), or some combination of both. In this study, the gaze profiles of 5 male and 5 female runners, fitted with a telemetric gaze-tracking device, were used to identify the frequency of fixations on an obstacle during a run. Overall, participants fixated on the obstacle 2.4 times during the run, with the last fixation occurring on average between 40% and 80% of the run, suggesting runners potentially shifted from a feedforward planning strategy to an online control strategy during the late portions of the running trial. A negative association was observed between runner velocity and average number of fixations. Consistent with previous studies on visual strategies used during walking, our results indicate that visual attentiveness is part of an important feedforward strategy for runners allowing them to safely approach an obstacle. Thus, visual obstacle attention is a key factor in the navigation of complex, natural landscapes while running.

Virtual Reality (VR) allows for infinitely large environments. However, the physical traversable space is always limited by real-world boundaries. This discrepancy between physical and virtual dimensions renders traditional locomotion methods used in real world unfeasible. To alleviate these limitations, research proposed various artificial locomotion concepts such as teleportation, treadmills, and redirected walking. However, these concepts occupy the user's hands, require complex hardware or large physical spaces. In this paper, we contribute nine VR locomotion concepts for foot-based locomotion, relying on the 3D position of the user's feet and the pressure applied to the sole as input modalities. We evaluate our concepts and compare them to state-of-the-art point & teleport technique in a controlled experiment with 20 participants. The results confirm the viability of our approaches for foot-based and engaging locomotion. Further, based on the findings, we contribute a wireless hardware prototype implementation.

Fragmentation methods allow for the accuratequantum-chemical treatment of large molecular clusters and materials. Here, we explore the combination of two complementary approaches to the development of such fragmentation methods: the many-body expansion (MBE) on the one hand and subsystem density-functional theory (DFT) or frozen-density embedding (FDE) theory on the other hand. First, we assess potential benefits of using FDE to account of the environmentin the subsystem calculation performed within the MBE. Second, we use subsystem DFT to derive a density-based MBE, in which a many-body expansion of the electron density is used to calculate the systems' total energy. This provides a correctionto the energies calculated with a conventional, energy-based MBE that only depends on the subsystem's electron densities. For the test case of clusters of water and of aspirin, we show that such a density-based MBE converges faster than the conventional energy-based MBE. For our test cases, truncation errors in the interaction energies are below chemical accuracy already with a two-body expansion. The density-based MBE thus provides a promising avenue for accurate quantum-chemical calculation of molecular clusters and materials.

This study evaluated the leaf area index (LAI) recovery mechanisms and forage accumulation rates on the regrowth of different grass species subjected to different defoliation intensities. For that purpose, plots of Pennisetum clandestinum (kikuyugrass), Lolium multiflorum (annual ryegrass), and Avena strigosa (black oats) were defoliated from 20 to 80 % of their initial heights (25, 20, and 25 cm, respectively). At different increments in height, forage samples were collected to ground level and used to estimate tiller population density (TPD), leaf area per tiller (LA), and forage mass. From these data, we calculated the leaf area index (LAI), average leaf area index (aLAI), and average and instantaneous forage accumulation rate (FAR and IFAR, respectively). Data were plotted over time (days) to describe LAI recovery and forage accumulation rates. As the defoliation intensity increased, greater canopy heights were needed for pastures to achieve their maximum forage accumulation rates, which required longer regrowth intervals. The need for high tiller recruitment after defoliation, which delayed canopy LAI recovery, seemed to be one of the main cause. Thus, grazing management strategies that involve costly tiller recruitment could decrease both overall forage production and sward persistence over time. However, the plant ability to recover LAI after successive intense defoliations seems to be species-dependent and related to their phenotypic plasticity.

International audience; As part of the first edition of the Video Mapping Festival, thirteen creators in residence on the Arenberg Creative Mine site, have developed works that will be broadcast during an evening in March 2018 in Lille. These residencies were an opportunity to carry out research on the creative experience, guided by the following questions: can we access the creative dynamics experienced by creators? If so, what can we observe and understand of this creative dynamic? What insights does this understanding offer? By studying the intimate experience of creators during their production activity, we question the modalities of creation in residence.

Two-dimensional video analysis is commonly used to assess kinematics when three-dimensional motion capture is unavailable. However, videos are often assessed using manual digitization, which limits the ability to extract outcomes that require continuous data. Here, we introduced a method to collect continuous kinematic data in 2D using an inexpensive camera and an open-source automated marker tracking program. We tested the validity of this method by comparing 2D video analysis to 3D motion capture for measuring sagittal-plane running kinematics. Twenty uninjured participants ran on a treadmill for 1-min while lower extremity kinematics were collected simultaneously in 3D using a motion capture system and in 2D using a single digital camera, both at 120 Hz. Knee, ankle, and foot angle at contact, peak knee flexion, knee flexion excursion, and knee-ankle flexion vector coding variability were computed using both the 3D and 2D kinematic data, and were compared using intraclass correlation coefficients and Bland-Altman plots. The agreement between collection methods was excellent for foot angle at contact and knee flexion excursion, good for ankle and knee angle at contact and knee-ankle vector coding variability, and moderate for peak knee flexion. However, Bland-Altman plots revealed significant differences between the 2D and 3D collection methods, which varied across study participants. These low-cost methods could be useful for collecting continuous sagittal plane running kinematics in non-laboratory settings.

International audience; L’observation ethnographique des visiteurs et notamment de la trace photographique des postures et du tracé des parcours des visiteurs a permis d’améliorer les conditions matérielles de la visite, l’accrochage des œuvres et les flux des visiteurs parce que l’interprétation des traces entretenait un lien indiciaire fort avec la physiologie du corps comme la fatigue des visiteurs. En revanche, mobiliser les traces de l’activité corporelle des visiteurs pour identifier leurs stratégies de visite et leurs attentes reste délicat d’un point de vue épistémologique. La question de recherche peut être formulée de la façon suivante : dans un musée, peut-on catégoriser la négociation de sens à partir de l’observation du comportement des visiteurs et en particulier de leur parcours ? Peut-on mobiliser les traces du mouvement du corps des visiteurs pour en inférer des modalités d’activité cognitive ou un arrière plan social ?

portuguesO objetivo deste trabalho foi identificar alturas de manejo para pastos de papua sob lotacao continua em sistemas de integracao lavoura-pecuaria (ILP). Para tanto, doze pastos foram cultivados em uma area de ILP e mantidos em 10, 20, 30 ou 40 cm por meio de lotacao continua com caprinos. As seguintes variaveis foram analisadas: massa; taxa de acumulo e oferta de forragem e de folhas; relacao lâmina:colmo; composicao quimica de amostras de simulacao de pastejo; carga animal; ganho medio diario e producao animal por area. Os dados foram submetidos a analises de regressao e correlacao. A significância adotada foi de 5% (P≤0,05). Os principais resultados foram: i) houve um aumento linear na massa de forragem e folhas com o aumento da altura de manejo e pastos com mais de 20 cm ja apresentavam a quantidade minima recomendada para cobertura de solo em ILP ii) o desempenho animal atingiu um plato assintotico nos pastos manejados entre 30-40 cm e foi altamente correlacionado com a altura de manejo e a disponibilidade de forragem (massa e oferta). Pastos de Papua manejados sob lotacao continua em ILP devem ser mantidos entre 30-40 cm para favorecer a producao de biomassa de cobertura e o desempenho animal. EnglishThe aim of this experiment was to identify grazing height targets for Alexandergrass pastures under continuous stocking in integrated crop-livestock system (ICLS). For this purpose, twelve pastures were cultivated into an ICLS area, and maintained at 10, 20, 30, or 40 cm using grazing goats. The following variables were analyzed: leaf and herbage mass, accumulation rate, and allowance; leaf:stem ratio; chemical composition of hand-plucked samples; stocking rate; average daily gain and gain per area. The data were submitted to regression and correlation analysis. Significance was set at 5% (P≤0.05). The main results were: i) herbage and leaf lamina mass increased linearly with grazing height, and pastures maintained at 20 cm already presented the minimum amount recommended for soil cover in ICLS; ii) animal performance achieved an upper asymptotic plateau in pastures maintained around 30-40 cm and it was highly correlated with both grazing height and forage availability (mass and allowance). Alexandergrass pastures under continuous stocking in ICLS should be maintained between 30-40 cm to improve both cover crop biomass and animal performance

Glycogen synthase kinase-3 beta (GSK-3β), a serine/threonine kinase, has been identified as a potential therapeutic target in human bladder cancer. In the present study, we investigated the antitumor effect of a small molecule GSK-3β inhibitor, 9-ING-41, currently in clinical studies in patients with advanced cancer, in bladder cancer cell lines. We found that treatment with 9-ING-41 leads to cell cycle arrest, autophagy and apoptosis in bladder cancer cells. The autophagy inhibitor chloroquine potentiated the antitumor effects of 9-ING-41 when tested in combination studies. Our findings also demonstrate that 9-ING-41 enhanced the growth inhibitory effects of gemcitabine or cisplatin when used in combination in bladder cancer cells. Finally, we found that 9-ING-41 sensitized bladder cancer cells to the cytotoxic effects of human immune effector cells. Our results provide a rationale for the inclusion of patients with advanced bladder cancer in clinical studies of 9-ING-41.

Gait and movement asymmetries are important variables for assessing locomotor mechanics in humans and other animals and as a predictor of injury risk and success of clinical interventions. The four indices used most often to assess symmetry are not well designed for different variable types, perform poorly when presented with cases of high asymmetry or when variables are of low magnitude, and are easily influenced by small variation in the signal. The purpose of the present study was to test the performance of these indices on previously unpublished data on ACL-R patients and to propose a new index to resolve some of these limitations. The performance of four currently used indices and a new index—the Normalized Symmetry Index (NSI), which is scaled to the range of variables being tested across multiple trials—were compared using force and angular data on participants who had undergone anterior cruciate ligament reconstruction and healthy controls. The NSI performed well compared to all other indices with all variables and had the additional benefit of returning values that range from 0% (full symmetry) to ±100% (full asymmetry). Therefore, the NSI can serve as a universal index for assessing asymmetry in humans, nonhuman animal models, and in a clinical context for assessing risk for injury and clinical outcomes.

L’experience des visiteurs de musee est une expression que l’on rencontre frequemment dans les etudes de public realisees dans le champ des sciences de l’information et de la communication (SIC). Neanmoins, l’experience des visiteurs en tant que dynamique corporelle, cognitive, emotionnelle vecue dans le cours de la visite, reste un objet de recherche quasi inconnu. Nous montrons que les paradigmes epistemologiques qui sous-tendent ces recherches en SIC ne sont pas propices a explorer l’experience situee des visiteurs. En revanche, l’enaction propose un cadre fecond qui rend compte a la fois de l’experience, de l’emergence de l’information et du sens. Plus largement l’enactionnisme1 enrichit le constructivisme et les SIC pourraient se saisir de cette epistemologie pour explorer des nouveaux objets de recherche.

The assumption that the morphology of the human calcaneus reflects high and cyclical impact forces at heel strike during adult human walking has never been experimentally tested. Since a walking step with a heel strike is an emergent behavior in children, an ontogenetic study provides a natural experiment to begin testing the relationship between the mechanics of heel strike and calcaneal anatomy. This study examined the ground reaction forces (GRFs) of stepping in children to determine the location of the center of pressure (COP) relative to the calcaneus and the orientation and magnitude of ground reaction forces during foot contact. Three-dimensional kinematic and kinetic data were analyzed for 18 children ranging in age from 11.5 to 43.1 months. Early steppers used a flat foot contact (FFC) and experienced relatively high vertical and resultant GRFs with COP often anterior to the calcaneus. More experienced walkers used an initial heel contact (IHC) in which GRFs were significantly lower but the center of pressure remained under the heel a greater proportion of time. Thus, during FFC the foot experienced higher loading, but the heel itself was relatively wider and the load was distributed more evenly. In IHC walkers load was concentrated on the anterior calcaneus and a narrower heel, suggesting a need for increased calcaneal robusticity during development to mitigate injury. These results provide new insight into foot loading outside of typical mature contact patterns, inform structure-function relationships during development, and illuminate potential causes of heel injury in young walkers.

Acinar-to-ductal metaplasia (ADM) is a reversible epithelial transdifferentiation process that occurs in the pancreas in response to acute inflammation. ADM can rapidly progress towards pre-malignant pancreatic intraepithelial neoplasia (PanIN) lesions in the presence of mutant KRas and ultimately pancreatic adenocarcinoma (PDAC). In the present work, we elucidate the role and related mechanism of glycogen synthase kinase-3beta (GSK-3β) in ADM development using in vitro 3D cultures and genetically engineered mouse models. We show that GSK-3β promotes TGF-α-induced ADM in 3D cultured primary acinar cells, whereas deletion of GSK-3β attenuates caerulein-induced ADM formation and PanIN progression in KrasG12D transgenic mice. Furthermore, we demonstrate that GSK-3β ablation influences ADM formation and PanIN progression by suppressing oncogenic KRas-driven cell proliferation. Mechanistically, we show that GSK-3β regulates proliferation by increasing the activation of S6 kinase. Taken together, these results indicate that GSK-3β participates in early pancreatitis-induced ADM and thus could be a target for the treatment of chronic pancreatitis and the prevention of PDAC progression. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Purpose The purpose of this paper is to deliver further insights into empirical research on corporate governance of state-owned enterprises (SOEs) by systematizing existing knowledge, identifying current investigation backlogs, and deriving specific implications for future empirical research to address the lack of empirical knowledge in this field. Design/methodology/approach The study follows a literature analysis approach through a systematic, quantitative analysis of broad-based database queries from EBSCOhost and Web of Science to derive recommendations for future empirical research on SOE-oriented corporate governance. Findings The results indicate that empirical SOE-oriented corporate governance research is a growing field with wide-ranging opportunities for investigation. Given the lack of qualitative empirical research (representing only 21.7 percent of the studies identified) and the massive focus on regression analyses (69.9 percent) and secondary database data (77.2 percent), future empirical approaches should consider different methods and data sources. More qualitative research is needed for exploratory designs and canonical correlation-based statistical methods seem helpful for confirmatory approaches. In addition, 50.4 percent of the studies identified have a Chinese background, indicating room for studies from different cultural contexts. Research limitations/implications Given the range of the research field and the eclectic nature of the analytical approach, it is unlikely that every relevant scientific publication is included. Originality/value Since this study is the first of its kind, it contributes to SOE-oriented corporate governance research by drawing on a wide-ranging selection of studies and analyzing them to derive straightforward recommendations for future empirical research.

A broad pelvis is characteristic of most, if not all, pre-modern hominins. In at least some early australopithecines, most notably the female Australopithecus afarensis specimen known as "Lucy," it is very broad and coupled with very short lower limbs. In 1991, Rak suggested that Lucy's pelvic anatomy improved locomotor efficiency by increasing stride length through rotation of the wide pelvis in the axial plane. Compared to lengthening strides by increasing flexion and extension at the hips, this mechanism could avoid potentially costly excessive vertical oscillations of the body's center of mass (COM). Here, we test this hypothesis. We examined 3D kinematics of walking at various speeds in 26 adult subjects to address the following questions: Do individuals with wider pelves take longer strides, and do they use a smaller degree of hip flexion and extension? Is pelvic rotation greater in individuals with shorter legs, and those with narrower pelves? Our results support Rak's hypothesis. Subjects with wider pelves do take longer strides for a given velocity, and for a given stride length they flex and extend their hips less, suggesting a smoother pathway of the COM. Individuals with shorter legs do use more pelvic rotation when walking, but pelvic breadth was not related to pelvic rotation. These results suggest that a broad pelvis could benefit any bipedal hominin, but especially a short-legged australopithecine such as Lucy, by improving locomotor efficiency, particularly when carrying an infant or traveling in a foraging group with individuals of varying sizes. Anat Rec, 300:739-751, 2017. © 2017 Wiley Periodicals, Inc.

RESUMO O objetivo deste trabalho foi avaliar o padrão de deslocamento de bovinos em pastos de capim-quicuiu submetidos a diferentes alturas de entrada (10, 15, 20 e 25cm) e mesma proporção de rebaixamento (redução em 50% da altura inicial). O padrão de exploração das estações alimentares foi avaliado com base na observação direta de dois animais (1/observador) por unidade experimental, com concomitante registro de códigos em gravadores de voz dos passos, bocados e outras atividades. As avaliações foram realizadas duas vezes por dia (10 e 15h) durante uma hora, no primeiro e no último dia do período de ocupação dos piquetes. Adicionalmente, foram realizadas avaliações em pré e pós-pastejo da massa de forragem, massa de lâminas foliares e altura do perfilho e da bainha estendida. O experimento foi conduzido de acordo com um delineamento em blocos completos ao acaso, com quatro tratamento e três repetições. Durante a fase inicial de rebaixamento, as variáveis passos por minuto, número de bocados por estação alimentar e taxa de bocados foram maiores nos pastos mais baixos, reduzindo com o aumento da altura em pré-pastejo, sem diferenças significativas durante a fase final de rebaixamento. Ocorrem variações no padrão de deslocamento dos animais em pastos de capim-quicuiu durante a fase inicial de rebaixamento, quando alturas entre 20-25cm apresentam melhores condições para o processo de forrageamento. O rebaixamento em 50% da altura inicial interfere negativamente no padrão de deslocamento dos animais, independentemente das metas de altura em pré-pastejo utilizadas. ABSTRACT The aim of this work was to evaluate the pattern of displacement of cattle grazing kikuyu grass swards at different pre-grazing heights of 10, 15, 20 and 25cm and submitted to grazing down to a same level of defoliation of 50% of initial pre-grazing height. Patterns of exploitation of feed stations were evaluated from direct observation of two animals (1/observer) per experimental unit with recording of codes (steps, bites, and other activities in a portable recorder device. The evaluations were performed twice a day (10 and 15h) during one hour, at the first and the last day of stocking period. Moreover, at pre and post-grazing were evaluated: herbage mass, leaf mass and sheath, and extended tiller height. The experimental design was a complete randomized block design with three replications and four treatments. The variables steps per minute, number of bites per feeding station, and bite rate were higher in lower pastures decreasing as the sward height increased in the initial phase with no difference in the final phase of grazing down. During the initial phase of the grazing down the animals presented differences in displacement patterns, where sward heights of 20 to 25cm in Kikuyu grass presented better conditions for foraging by grazing animals. Grazing down pastures to 50% of initial grazing height negatively affects displacement patterns of animals, irrespective of pre-grazing heights targets.

International audience; L’action culturelle a eu pour ambition de « libérer » les citoyens des cadres inconscients auxquels ils pouvaient être soumis. Dans les musées, l’idée était d’interroger les valeurs sous-jacentes à la production artistique. Il s’agissait de créer des prises de conscience quant aux systèmes socio-historiques dominants. Les relations interpersonnelles humaines, animateurs, artistes, visiteurs étaient au cœur de la dynamique de l’action culturelle. Aujourd’hui l’éducation non-formelle tend à remplacer l’action culturelle et valorise davantage la créativité individuelle et l’autonomie par l’intermédiaire de « dispositifs ». En quoi l’éducation non-formelle partage-t-elle des intentions communes avec l’action culturelle et en quoi introduit-elle une rupture conceptuelle majeure ?

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with a median survival of 3 years after diagnosis. Although the etiology of IPF is unknown, it is characterized by extensive alveolar epithelial cell apoptosis and proliferation of myofibroblasts in the lungs. While the origins of these myofibroblast appear to be diverse, fibroblast differentiation contributes to expansion of myofibroblasts and to disease progression. We found that agents that contribute to neomatrix formation and remodeling in pulmonary fibrosis (PF); TGF-β, Factor Xa, thrombin, plasmin and uPA all induced fibroblast/myofibroblast differentiation. These same mediators enhanced GSK-3β activation via phosphorylation of tyrosine-216 (p-Y216). Inhibition of GSK-3β signaling with the novel inhibitor 9-ING-41 blocked the induction of myofibroblast markers; α-SMA and Col-1 and reduced morphological changes of myofibroblast differentiation. In in vivo studies, the progression of TGF-β and bleomycin mediated PF was significantly attenuated by 9-ING-41 administered at 7 and 14 days respectively after the establishment of injury. Specifically, 9-ING-41 treatment significantly improved lung function (compliance and lung volumes; p ex vivo and pulmonary fibrosis in vivo. The results offer a strong premise supporting the continued investigation of the GSK-3β signaling pathway in the control of fibroblast-myofibroblast differentiation and fibrosing lung injury. These data provide a strong rationale for extension of clinical trials of 9-ING-41 to patients with IPF.

Animals can amplify the mechanical power output of their muscles as they jump to escape predators or strike to capture prey. One mechanism for amplification involves muscle–tendon unit (MT) systems in which a spring element (series elastic element [SEE]) is pre-stretched while held in place by a “latch” that prevents immediate transmission of muscle (or contractile element, CE) power to the load. In principle, this storage phase is followed by a triggered release of the latch, and elastic energy released from the SEE enables power amplification (PRATIO=PLOAD/PCE,max >1.0), whereby the peak power delivered from MT to the load exceeds the maximum power limit of the CE in isolation. Latches enable power amplification by increasing the muscle work generated during storage and reducing the duration over which that stored energy is released to power a movement. Previously described biological “latches” include: skeletal levers, anatomical triggers, accessory appendages, and even antagonist muscles. In fact, many species that rely on high-powered movements also have a large number of muscles arranged in antagonist pairs. Here, we examine whether a decaying antagonist force (e.g., from a muscle) could be useful as an active latch to achieve controlled energy transmission and modulate peak output power. We developed a computer model of a frog hindlimb driven by a compliant MT. We simulated MT power generated against an inertial load in the presence of an antagonist force “latch” (AFL) with relaxation time varying from very fast (10 ms) to very slow (1000 ms) to mirror physiological ranges of antagonist muscle. The fastest AFL produced power amplification (PRATIO=5.0) while the slowest AFL produced power attenuation (PRATIO=0.43). Notably, AFLs with relaxation times shorter than ∼300 ms also yielded greater power amplification (PRATIO>1.20) than the system driving the same inertial load using only an agonist MT without any AFL. Thus, animals that utilize a sufficiently fast relaxing AFL ought to be capable of achieving greater power output than systems confined to a single agonist MT tuned for maximum PRATIO against the same load.

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BackgroundPrevious analyses of factors influencing footfall timings and gait selection in quadrupeds have focused on the implications for energetic cost or gait mechanics separately. Here we present a model for symmetrical walking gaits in quadrupedal mammals that combines both factors, and aims to predict the substrate contexts in which animals will select certain ranges of footfall timings that (1) minimize energetic cost, (2) minimize rolling and pitching moments, or (3) balance the two. We hypothesize that energy recovery will be a priority on all surfaces, and will be the dominant factor determining footfall timings on flat, ground-like surfaces. The ability to resist pitch and roll, however, will play a larger role in determining footfall choice on narrower and more complex branch-like substrates. As a preliminary test of the expectations of the model, we collected sample data on footfall timings in a primate with relatively high flexibility in footfall timings – the squirrel monkey (Saimiri sciureus) – walking on a flat surface, straight pole, and a pole with laterally-projecting branches to simulate simplified ground and branch substrates. We compare limb phase values on these supports to the expectations of the model.ResultsAs predicted, walking steps on the flat surface tended towards limb phase values that promote energy exchange. Both pole substrates induced limb phase values predicted to favor reduced pitching and rolling moments.ConclusionsThese data provide novel insight into the ways in which animals may choose to adjust their behavior in response to movement on flat versus complex substrates and the competing selective factors that influence footfall timing in mammals. These data further suggest a pathway for future investigations using this perspective.

O objetivo deste estudo foi descrever a estrutura do dossel e o comportamento ingestivo de caprinos em pastos de papuã manejados sob lotação contínua. Os tratamentos corresponderam a quatro alturas de manejo (10, 20, 30 e 40 cm) mantidas através de taxa de lotação variável. As variáveis analisadas foram: composição morfológica, massa e densidade dos componentes; comprimento de lâminas foliares; valor nutritivo por simulação de pastejo; tempos de pastejo, ruminação e atividades complementares. Os dados foram submetidos à análise de variância e teste de contrastes de polinômios ortogonais. Os principais resultados foram: i) com o aumento da altura de manejo, houve um aumento da massa (total e dos componentes morfológicos) e uma inversão na composição morfológica (redução na proporção de lâminas foliares e aumento na de colmos + material morto); ii) o comprimento de lâminas foliares aumentou com a altura de manejo; iii) os animais dedicaram mais tempo ao pastejo com a redução da altura de manejo, embora aparentemente tenham abdicado do pastejo no tratamento 10 cm ao final do experimento. Baseado nos dados de estrutura do dossel e comportamento ingestivo, concluiu-se que pastos de papuã sob lotação contínua devem ser manejados próximos de 40 cm. As razões são discutidas ao longo do artigo. Palavras-chave: Brachiaria; integração lavoura-pecuária; manejo; Urochloa plantaginea; valor nutritivo.

Background: Breast cancer (BC) with a low hormone receptor (HR) expression (1-9%), although qualifying for endocrine therapy, very often have a molecular phenotype similar to triple-negative BC. In this study we evaluated the clinical behavior of low HR-expressing tumors in a multiparametric cohort of 9027 patients. Methods: We analyzed neoadjuvant clinical trial cohorts (n=4366) and a cancer registry cohort (n=5138). We compared patients with negative [oestrogen (ER) and progesterone receptor (PR)

Der vorliegende Beitrag stellt die wesentlichen Ergebnisse umfangreicher experimenteller Untersuchungen zur Analyse von Stahlbetonplatten unter Impaktbelastung dar. Die vorgestellten Arbeiten erfolgten in Zusammenarbeit zwischen dem Fraunhofer Institut für Kurzzeitdynamik - Ernst‐Mach‐Institut (EMI) und der Technischen Universität Dresden (TUD), innerhalb des durch die DFG geförderten nationalen Forschungsprojekts ""Impakt auf Betonstrukturen - Experiment und Simulation"". In den durchgeführten Experimenten wurde die Einwirkung eines sogenannten harten Stoßes, bei dem die kinetische Energie nahezu vollends in die Struktur eingeleitet wird, für unterschiedliche Geschwindigkeitsbereiche (4,2-6,0 m/s; 44-67 m/s und 200-274 m/s) studiert. Die hervorgerufenen Versagensphänomene und die dynamische Strukturantwort wurden über entsprechend umfangreiche Messtechnik (Dehnungsmessstreifen, Drucksensoren, Lasermesstechnik und Hochgeschwindigkeitskameras) erfasst. Die somit gewonnene Datengrundlage für Bereiche niedriger wie auch hoher Verzerrungsraten dient sowohl dem Verständnis der Zusammenhänge zwischen lokaler Schädigung und globaler Strukturantwort, als auch zur Adaption bestehender Materialmodelle, der Entwicklung von Ingenieurmodellen und der Validierung numerischer Berechnungen.

Some recent papers have recommended moderate intensities of defoliation in order to maximize herbage intake at different time-scales. Most of them, however, did not assess the grazing dynamics of individual tillers during the stocking period. Therefore, the objective of this work was to describe the defoliation dynamics of kikuyugrass (Pennisetum clandestinum Hochst ex. Chiov) pastures subjected to different intensities of defoliation (40, 50, 60, and 70% of the initial height). Twelve 1500 m2 plots were strip-grazed over 24 h, and the frequency and severity of defoliation of individual tillers were assessed in 40 tagged tillers per experimental unit. From these data (n = 1920), we calculated the grazed area in the upper, second, and third horizon, and the total grazed area. We found that the frequency of defoliation by leaf category (expanding, mature, and senescent) increased linearly with the intensity of defoliation, and that reductions in extended tillers could not be used as a proxy to estimate the frequency of defoliation. Moreover, 22% of the second and third horizons were already exploited with intensities of defoliation of 40%, raising the possibility that the exploitation of lower grazing horizons could be more related to stocking density and relatively independent of the grazed area.

Das Verstandnis von Impaktvorgangen auf Stahlbetonstrukturen ist von grundlegender Bedeutung fur die Auslegung von Bauwerken in Hinblick auf die Bewertung ausergewohnlicher Belastungssituationen, wie beispielsweise Steinschlag oder aber Fahrzeug- oder Flugzeuganprall. Bei hohen Verzerrungsraten, die sich bei derartigen Belastungen im Bauteil einstellen, wird ein anderes Material- und Werkstoffverhalten beobachtet als unter quasi-statischen Einwirkungen. Dieses ausert sich zum Beispiel durch eine Zunahme der Festigkeit bei steigender Verzerrungsrate. Daher ist eine Analyse und Bewertung des Tragverhaltens von Bauteilen unter derartigen Belastungszustanden geboten, um das Tragverhalten auf Material- und Bauteilebene zu ermitteln und Tragreserven erkennen zu konnen. Eine entsprechende Methodik und der Einsatz geeigneter Messtechnik sind dafur essentielle Voraussetzungen. Der vorliegende Aufsatz richtet seinen Fokus auf die messtechnischen Methoden und die Herausforderungen bei schnell ablaufenden Belastungsvorgangen. Am Beispiel der experimentellen Untersuchung von Stahlbetonplatten unter Impakt, bei denen Belastungszeiten von wenigen Mikro- und Millisekunden auftreten, werden der Versuchsaufbau und die Mess- und Analysesysteme in Hinblick auf die Messmethoden und die erzielten Messergebnisse beschrieben. Die Ermittlung von Zeitverlaufen bzgl. der Impaktgeschwindigkeit, den Reaktionskraften, dem Verformungsverhalten, sowie auch die Bestimmung von Schallwellengeschwindigkeiten innerhalb des Bauteils, erfordert eine entsprechend hohe Abtastrate bei der Signalaufzeichnung. Diese Ergebnisse ermoglichen letztlich eine ganzheitliche Bewertung des Strukturverhaltens und der Schadigungsphanomene.

Objectives Previous studies suggest that the postures habitually adopted by an animal influence the mechanical loading of its long bones. Relatively extended limb postures in larger animals should preferentially reduce anteroposterior (A-P) relative to mediolateral (M-L) bending of the limb bones and therefore decrease A-P/M-L rigidity. We test this hypothesis by examining growth-related changes in limb bone structure in two primate taxa that differ in ontogenetic patterns of joint posture. Materials and Methods Knee and elbow angles of adult and immature vervets (Chlorocebus aethiops, n = 16) were compared to published data for baboons (Papio hamadryas ursinus, n = 33, Patel et al., 2013). Ontogenetic changes in ratios of A-P/M-L bending rigidity in the femur and humerus were compared in skeletal samples (C. aethiops, n = 28; P. cynocephalus, n = 39). Size changes were assessed with linear regression, and age group differences tested with ANOVA. Results Only the knee of baboons shows significant postural change, becoming more extended with age and mass. A-P/M-L bending rigidity of the femur decreases during ontogeny in immature and adult female baboons only. Trends in the humerus are less marked. Adult male baboons have higher A-P/M-L bending rigidity of the femur than females. Conclusions The hypothesized relationship between more extended joints and reduced A-P/M-L bending rigidity is supported by our results for immature and adult female baboon hind limbs, and the lack of significant age changes in either parameter in forelimbs and vervets. Adult males of both species depart from general ontogenetic trends, possibly due to socially mediated behavioral differences between sexes. Am J Phys Anthropol, 2016. © 2016 Wiley Periodicals, Inc.

For single-molecule localization based superresolution, the concentration of fluorescent labels has to be thinned out. This is commonly achieved by photophysically or photochemically deactivating subsets of molecules. Alternatively, apparent switching of molecules can be achieved by transient binding of fluorescent labels. Here, a diffusing dye yields bright fluorescent spots when binding to the structure of interest. As the binding interaction is weak, the labeling is reversible and the dye ligand construct diffuses back into solution. This approach of achieving superresolution by transient binding (STB) is reviewed in this manuscript. Different realizations of STB are discussed and compared to other localization-based superresolution modalities. We propose the development of labeling strategies that will make STB a highly versatile tool for superresolution microscopy at highest resolution.

International audience; During their visit of a museum, visitors show a surprising creativity to be able to bind, to connect themselves to a reality that they largely construct themselves. Succeeding in analyzing the articulation of these links is of a scientific interest that goes beyond the museum field because these links inform the construction modalities of knowledge in ecological situation. The theory of enaction provides a fruitful conceptual framework to study museology as an operative relationship between visitors and reality.; Au cours de leur visite dans un musée, les visiteurs font preuve d’une créativité surprenante pour pouvoir se lier, se relier à un réel qu’ils construisent en grande partie eux-mêmes. Réussir à saisir l’articulation de ces liaisons est d’un intérêt scientifique qui dépasse le cadre du musée, car ces liaisons renseignent sur les modalités de construction des connaissances en situation écologique. La théorie de l’énaction offre un cadre conceptuel fécond pour étudier la muséologie en tant que relation opérative entre les visiteurs et le réel.

Objectives Many primates exhibit a suite of characteristics that distinguish their quadrupedal gaits from non-primate mammals including the use of a diagonal sequence gait, a relatively protracted humerus at touchdown, and relatively high peak vertical forces on the hindlimbs compared to the forelimbs. These characteristics are thought to have evolved together in early, small-bodied primates possibly in response to the mechanical demands of navigating and foraging in a complex arboreal environment. It remains unclear, however, whether primates that employ quadrupedalism only rarely demonstrate the common primate pattern of quadrupedalism or instead use the common non-primate pattern or an entirely different mechanical pattern from either group. Materials and Methods This study compared the kinematics and kinetics of two habitually quadrupedal primates (Lemur catta and Varecia variegata) to those of a dedicated vertical clinger and leaper (Propithecus coquereli) during bouts of quadrupedal walking. Results All three species employed diagonal sequence gaits almost exclusively, displayed similar degrees of humeral protraction, and exhibited lower vertical peak forces in the forelimbs compared to the hindlimb. Discussion From the data in this study, it is possible to reject the idea that P. coquereli uses a non-primate pattern of quadrupedal walking mechanics. Nor do they use an entirely different mechanical pattern from either most primates or most non-primates during quadrupedal locomotion. These findings provide support for the idea that this suite of characteristics is adaptive for the challenges of arboreal locomotion in primates and that these features of primate locomotion may be basal to the order or evolved independently in multiple lineages including indriids. Am J Phys Anthropol, 2016. © 2016 Wiley Periodicals, Inc.

Glycogen synthase kinase-3 (GSK-3) is overexpressed and accumulates in the nucleus in several human malignancies including pancreatic cancer. We recently demonstrated that GSK-3 inhibition sensitizes pancreatic cancer cells to chemotherapy by abrogating the TopBP1/ATR-mediated DNA damage response. Specifically, GSK-3 kinase activity is required to stabilize TopBP1 protein. Herein, we investigated the mechanism by which GSK-3 phosphorylation of TopBP1 prevents its degradation. Interestingly, GSK-3 inhibition not only decreased the total levels of TopBP1, but also reduced the ability of TopBP1 to bind chromatin following gemcitabine treatment. Mutation of a putative GSK-3 phosphorylation site in TopBP1 (S860A) resulted in decreased TopBP1 stability and chromatin recruitment, whereas a phosphomimetic mutant (S860E) had the opposite effect. Furthermore, we found enhanced TopBP1 ubiquitination after GSK-3 inhibition as well as an increased interaction between TopBP1 and hHYD, an ubiquitin ligase that has been shown to ubiquitylate TopBP1 resulting in its degradation. Significantly, the S860A mutation showed a stronger interaction with hHYD compared to WT or the S860E mutant of TopBP1. In conclusion, our study identifies GSK-3 phosphorylation of TopBP1 as a mechanism to prevent the interaction with and ultimate ubiquitylation-mediated degradation by hHYD. Citation Format: Li Ding, Kaely R. Roeck, Olga Alekhina, Daniel M. Schmitt, Daniel D. Billadeau. Glycogen synthase kinase-3 inhibition impairs DNA damage response through ubiquitin ligase hHYD-mediated TopBP1 degradation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4138.

The initiation of a walking step with a heel strike is a defining characteristic of humans and great apes but is rarely found in other mammals. Despite the considerable importance of heel strike to an understanding of human locomotor evolution, no one has explicitly tested the fundamental mechanical question of why great apes use a heel strike. In this report, we test two hypotheses (1) that heel strike is a function of hip protraction and/or knee extension and (2) that short-legged apes with a midfoot that dorsiflexes at heel lift and long digits for whom digitigrady is not an option use heel-strike plantigrady. This strategy increases hip translation while potentially moderating the cost of redirecting the center of mass ('collisional costs') during stance via rollover along the full foot from the heel to toes. We quantified hind limb kinematics and relative hip translation in ten species of primates, including lemurs, terrestrial and arboreal monkeys, chimpanzees, and gorillas. Chimpanzees and gorillas walked with relatively extended knees but only with moderately protracted hips or hind limbs, partially rejecting the first hypothesis. Nonetheless, chimpanzees attained relative hip translations comparable with those of digitigrade primates. Heel-strike plantigrady may be a natural result of a need for increased hip translations when forelimbs are relatively long and digitigrady is morphologically restricted. In addition, foot rollover from the heel to toe in large, short-legged apes may reduce energetic costs of redirecting the center of mass at the step-to-step transition as it appears to do in humans. Heel strike appears to have been an important mechanism for increasing hip translation, and possibly reducing energetic costs, in early hominins and was fundamental to the evolution of the modern human foot and human bipedalism.