Knee adduction moment and medial contact force - facts about their correlation during gait

The external knee adduction moment is considered a surrogate measure for the medial tibiofemoral contact force and is commonly used to quantify the load reducing effect of orthopedic interventions. However, only limited and controversial data exist about the correlation between adduction moment and medial force. The objective of this study was to examine whether the adduction moment is indeed a strong predictor for the medial force by determining their correlation during gait. Instrumented knee implants with telemetric data transmission were used to measure tibiofemoral contact forces in nine subjects. Gait analyses were performed simultaneously to the joint load measurements. Skeletal kinematics, as well as the ground reaction forces and inertial parameters, were used as inputs in an inverse dynamics approach to calculate the external knee adduction moment. Linear regression analysis was used to analyze the correlation between adduction moment and medial force for the whole stance phase and separately for the early and late stance phase. Whereas only moderate correlations between adduction moment and medial force were observed throughout the whole stance phase (R(2)?=?0.56) and during the late stance phase (R(2)?=?0.51), a high correlation was observed at the early stance phase (R(2)?=?0.76). Furthermore, the adduction moment was highly correlated to the medial force ratio throughout the whole stance phase (R(2)?=?0.75). These results suggest that the adduction moment is a surrogate measure, well-suited to predicting the medial force ratio throughout the whole stance phase or medial force during the early stance phase. However, particularly during the late stance phase, moderate correlations and high inter-individual variations revealed that the predictive value of the adduction moment is limited. Further analyses are necessary to examine whether a combination of other kinematic, kinetic or neuromuscular factors may lead to a more reliable prediction of the force magnitud

Pseudocontingencies – rule based and associative

The present work puts forward a rule-based model for judging the direction of a contingency. A set of “alignment rules” (ARs) is defined, all of which bind frequent observations to frequent observations and infrequent observations to infrequent observations. These rules qualify as possible mechanisms behind pseudocontingencies (PCs, Fiedler, Freytag, & Meiser, 2009). Six experiments, involving social and non-social stimuli, are presented that pit the predictions of the rule-based PCs against associative models for contingency judgments (Van Rooy, Van Overwalle, Vanhoomissen, Labiouse, & French, 2003). Results consistently show that participants associate predictors with criteria that are non-contingent but jointly frequent and rare. Crucially, these illusory contingency judgments are shown to persist (a) in attitude ratings after extended observational learning and (b) at asymptote in operant learning. In sum, the results are evidence for the impact of rule-based PCs under conditions that call for associative learning. In a next step, rational arguments (Anderson, 1990) are used to set the AR apart from other rule-based models with similar empirical predictions. Results of two simulations reveal that the AR performs remarkably well under real-life constraints. Under clearly definable conditions, like strongly skewed base rates and small observational samples, the AR performs even better than other models, like ΔP (Allan, 1993) or the Sum-of-Diagonals (SoD, Inhelder & Piaget, 1958). Finally, the AR is claimed to be a natural by-product of the learning history with strong contingencies. Suggestive evidence from a simulation is provided that shows an increased likelihood of jointly skewed base rates, the precondition for ARs, in the presence of strong contingencies. Thus, ARs might develop from a confusion of the learned above chance probability p ( joint-skew | strong-contingency ) with an above chance probability p ( strong-contingency | joint –skew ) that justifies an AR inference. Possible future research on how joint observations and base-rates interact to influence contingency judgments is outlined

Base-rate neglect based on base-rates in experience-based contingency learning

Predicting criterion events based on probabilistic predictor events, humans often lend excessive weight to predictor event information and insufficient weight to criterion event base-rates. Using the matching-to-sample paradigm established in studies on experience-based contingency learning in animals, Goodie and Fantino (1996) showed that human judges exhibit base-rate neglect when sample cues are associated with response options through similarity relations. In conceptual replications of these studies, we demonstrated similar effects when sample cues resemble the response options in terms of base-rates skewed in the same direction rather than physical similarity. In line with the pseudocontingency illusion (Fiedler & Freytag, 2004), predictions were biased toward the more (less) frequently rewarded response option following the more (less) frequently presented sample cue. Thus, what is a demonstration of base-rate neglect from one perspective turns out to reflect the judges' sensitivity to the alignment of skewed base-rate distributions.

Dissecting SAMHD1´s role in the type I Interferon induced early block to HIV-1 infection and its connection to cancer

Human immunodeficiency virus-1 (HIV-1) and all other viruses are known to interact with multiple host cellular proteins during their replication in the target cell. While many of these host cellular proteins facilitate viral replication, a number of them are reported to repress viral replication. These host cellular proteins are known as restriction factors and they represent the host's first line of defense against the viral pathogens. Sterile alpha motif and HD domain containing 1 (SAMHD1) has been identified as a HIV-1 restriction factor that blocks early-stage virus replication in dendritic and other myeloid cells. SAMHD1 is the target of the viral protein x (Vpx) from simian lentiviruses and HIV-2. Vpx mediates the recruitment of the Cullin4-DDB1-DCAF1 ubiquitin ligase machinery to SAMHD1 leading to polyubiquitination and subsequent degradation of SAMHD1. Previous studies on monocyte-derived dendritic cells suggested that the Vpx-induced rescue of HIV-1 infection from early type I IFN-induced blocks was independent of SAMHD1, since Vpx mutant Q76A, which is unable to recruit DCAF1 and to degrade SAMHD1, still increased HIV-1 infection in type I IFN treated cells. The rescue in healthy blood donor cells was not observed when Q76A mutant Vpx virus-like particles were used, suggesting that – in conflict with previous reports – SAMHD1 degradation is required for efficient Vpx-mediated rescue of HIV-1 from the type I IFN-induced early antiviral blocks. To investigate the role of SAMHD1 in the Vpx-mediated rescue of HIV-1 from the type I IFN-induced block in myeloid cells at more detail, we generated CRISPR/Cas9 THP-1 cells, a monocytic acute myeloid leukemia cell line, lacking a functional SAMHD1 gene. In line with previous studies, the lack of SAMHD1 protein had no impact on the level of the type I IFN-induced early block to HIV-1 infection as compared to control or parental THP-1 cells. However, while Vpx was able to rescue HIV-1 infectivity in parental THP-1 or CRISPR/Cas9 control cells from the type I IFN effects, no rescue was observed when SAMHD1 protein was absent. To investigate whether the enzymatic activity of SAMHD1 was required for the Vpx-mediated rescue of HIV-1 infection from the early type I IFN-induced blocks, we reconstituted expression of wild type or different catalytically-inactive SAMHD1 mutants in SAMHD1-/- cells and found that Vpx increased HIV-1 infectivity in the presence of wild type, but not H233A mutant SAMHD1, suggesting that the enzymatic activity of SAMHD1 is required for a Vpx-induced rescue of HIV-1 infection from the type I IFN-induced block. We also generated a CRISPR/Cas9 THP-1 cell clone, which had one disrupted SAMHD1 allele and one allele, in which the entire nuclear localization signal (11KRPR14) was deleted in frame, generating an internally NLS-disrupted endogenously expressed SAMHD1 protein. In these cells, SAMHD1 was predominantly localized to the cytoplasm, although a 5 fraction was also observed in the nucleoplasm, suggesting for an alternative nuclear import pathway, independent of the classical 11KRPR14 NLS. In these cells, Vpx still rescued HIV-1 from the type I IFN-induced early block to infection. Of note, SAMHD1 degradation was profoundly delayed, suggesting that Vpx-induced polyubiquitination of SAMHD1 is sufficient to overcome the early IFN-induced block to HIV-1 in myeloid cells. SAMHD1 not only acts as a host restriction factor against lentiviral, endogenous retroviruses, hepatitis B virus, herpesviruses (HSV-1) and poxviruses, mutations in the SAMHD1 gene have also been linked to the immune disorder Aicardi-Goutières Syndrome (AGS), a genetic disease mimicking congenital virus infection. Recurrent mutations and reduced expression levels of SAMHD1 have been suggested to play a role for the oncogenesis of several cancers such as colon and Rectum Adenocarcinoma (COAD/READ), lung cancer, cutaneous T-cell lymphoma, acute myeloid leukemia (AML), and chronic lymphocytic leukemia (CLL). Interestingly, SAMHD1’s function as a possible tumor suppressor is complexed by its role as a resistance factor in nucleoside analogue-based anti-cancer therapies. Cytarabine (ara-C), a deoxycytidine analog, is the single most important drug in the treatment of AML and other hematological malignancies, exerting its cytotoxic effects through its activated triphosphate (ara-CTP), eventually leading to DNA damage and cell death. We and others demonstrated that SAMHD1 is able to detoxify cells by hydrolytic activity towards ara-CTP. Accordingly, primary AML blasts treated with Vpx to deplete SAMHD1 as well as THP-1 CRISPR/Cas9 SAMHD1 knock-out cells showed increased sensitivity towards ara-C induced cytotoxicity. Using these knock-out cells as a back-bone, we expressed a large panel of SAMHD1 mutants harboring non-synonymous single nucleotide polymorphisms (SNPs) that have been identified in patients with AML, READ, STAD or COAD and performed differential analyses of ara-C sensitivity as well as restriction activity towards HIV-1 infection to unravel possible mechanistic differences in both activities. In this respect neutralization of ara-C induced cytotoxicity was found to be a very good surrogate for the enzymatic dNTPase activity of SAMHD1, and using naturally occurring SAMHD1 variants ensured that these proteins were not artificially defective, hence for the first time a direct comparison of enzymatic activity and anti-HIV-1 activity could be investigated in the same cells. We are currently investigating the effects of these SAMHD1 SNPs on oligomerization and sensitivity for degradation by Vpx. The identification of SAMHD1 SNPs altering the sensitivity to certain anti-cancer chemotherapies could also be a key for future personalized treatment strategies. Furthermore, the ability of our assays to uncouple SAMHD1 enzymatic activity from virus restriction could help to understand the contribution of SAMHD1’s dNTPase activity towards HIV-1 restriction and since the Vpx-induced rescue of HIV-1 infection from the type I IFN induced block was shown to depend on SAMHD1, may help to unravel the IFN-induced early blocks against HIV-1. In Summary, SAMHD1 plays a bigger role in the type I IFN-induced block than currently is appreciated and further investigation of its cellular function may provide insights into the underlying mechanisms and contributing additional factors

Best bang for your buck: GPU nodes for GROMACS biomolecular simulations

The molecular dynamics simulation package GROMACS runs efficiently on a wide variety of hardware from commodity workstations to high performance computing clusters. Hardware features are well exploited with a combination of SIMD, multi-threading, and MPI-based SPMD/MPMD parallelism, while GPUs can be used as accelerators to compute interactions offloaded from the CPU. Here we evaluate which hardware produces trajectories with GROMACS 4.6 or 5.0 in the most economical way. We have assembled and benchmarked compute nodes with various CPU/GPU combinations to identify optimal compositions in terms of raw trajectory production rate, performance-to-price ratio, energy efficiency, and several other criteria. Though hardware prices are naturally subject to trends and fluctuations, general tendencies are clearly visible. Adding any type of GPU significantly boosts a node's simulation performance. For inexpensive consumer-class GPUs this improvement equally reflects in the performance-to-price ratio. Although memory issues in consumer-class GPUs could pass unnoticed since these cards do not support ECC memory, unreliable GPUs can be sorted out with memory checking tools. Apart from the obvious determinants for cost-efficiency like hardware expenses and raw performance, the energy consumption of a node is a major cost factor. Over the typical hardware lifetime until replacement of a few years, the costs for electrical power and cooling can become larger than the costs of the hardware itself. Taking that into account, nodes with a well-balanced ratio of CPU and consumer-class GPU resources produce the maximum amount of GROMACS trajectory over their lifetime

More Bang for Your Buck: Improved use of GPU Nodes for GROMACS 2018

We identify hardware that is optimal to produce molecular dynamics trajectories on Linux compute clusters with the GROMACS 2018 simulation package. Therefore, we benchmark the GROMACS performance on a diverse set of compute nodes and relate it to the costs of the nodes, which may include their lifetime costs for energy and cooling. In agreement with our earlier investigation using GROMACS 4.6 on hardware of 2014, the performance to price ratio of consumer GPU nodes is considerably higher than that of CPU nodes. However, with GROMACS 2018, the optimal CPU to GPU processing power balance has shifted even more towards the GPU. Hence, nodes optimized for GROMACS 2018 and later versions enable a significantly higher performance to price ratio than nodes optimized for older GROMACS versions. Moreover, the shift towards GPU processing allows to cheaply upgrade old nodes with recent GPUs, yielding essentially the same performance as comparable brand-new hardware.Comment: 41 pages, 13 figures, 4 tables. This updated version includes the following improvements: - most notably, added benchmarks for two coarse grain MARTINI systems VES and BIG, resulting in a new Figure 13 - fixed typos - made text clearer in some places - added two more benchmarks for MEM and RIB systems (E3-1240v6 + RTX 2080 / 2080Ti

Conditions of Organization and Performance of the Training Services Companies

The aim of this study is to present the results of the research of the author, which aimed at: recognition of the training services market, the entities creating it, the characterization of the structure of employment (their quality, quantity, their education, qualification, age). In addition, the author presented in the form of tabulation the changes that are taking place in the modern world and have an impact on the functioning of the organization. The author defined a new category of a worker, which appears in the organization – an external knowledge worker along with its characteristics. The basic research methods used in the work are: literature studies, empirical analysis using secondary research and own empirical research conducted for the scheduled process research. The paper consists of six components, with description of the functions performed by the service sector in the economy, the characteristics of the training services market, as well as the impact of the new economy on the organization, function and shape of small business training services and employees who are the organization's most important asset

Standardized loads acting in knee implants

The loads acting in knee joints must be known for improving joint replacement, surgical procedures, physiotherapy, biomechanical computer simulations, and to advise patients with osteoarthritis or fractures about what activities to avoid. Such data would also allow verification of test standards for knee implants. This work analyzes data from 8 subjects with instrumented knee implants, which allowed measuring the contact forces and moments acting in the joint. The implants were powered inductively and the loads transmitted at radio frequency. The time courses of forces and moments during walking, stair climbing, and 6 more activities were averaged for subjects with I) average body weight and average load levels and II) high body weight and high load levels. During all investigated activities except jogging, the high force levels reached 3,372–4,218N. During slow jogging, they were up to 5,165N. The peak torque around the implant stem during walking was 10.5 Nm, which was higher than during all other activities including jogging. The transverse forces and the moments varied greatly between the subjects, especially during non-cyclic activities. The high load levels measured were mostly above those defined in the wear test ISO 14243. The loads defined in the ISO test standard should be adapted to the levels reported here. The new data will allow realistic investigations and improvements of joint replacement, surgical procedures for tendon repair, treatment of fractures, and others. Computer models of the load conditions in the lower extremities will become more realistic if the new data is used as a gold standard. However, due to the extreme individual variations of some load components, even the reported average load profiles can most likely not explain every failure of an implant or a surgical procedure