Mitochondrial reactive oxygen species (ROS) production and detoxification are tightly balanced. Shifting this balance enables ROS to activate intracellular signaling and/or induce cellular damage and ...cell death. Increased mitochondrial ROS production is observed in a number of pathological conditions characterized by mitochondrial dysfunction. One important hallmark of these diseases is enhanced glycolytic activity and low or impaired oxidative phosphorylation. This suggests that ROS is involved in glycolysis (dys)regulation and vice versa. Here we focus on the bidirectional link between ROS and the regulation of glucose metabolism. To this end, we provide a basic introduction into mitochondrial energy metabolism, ROS generation and redox homeostasis. Next, we discuss the interactions between cellular glucose metabolism and ROS. ROS-stimulated cellular glucose uptake can stimulate both ROS production and scavenging. When glucose-stimulated ROS production, leading to further glucose uptake, is not adequately counterbalanced by (glucose-stimulated) ROS scavenging systems, a toxic cycle is triggered, ultimately leading to cell death. Here we inventoried the various cellular regulatory mechanisms and negative feedback loops that prevent this cycle from occurring. It is concluded that more insight in these processes is required to understand why they are (un)able to prevent excessive ROS production during various pathological conditions in humans.
Abstract Inverse dynamics based simulations on musculoskeletal models is a commonly used method for the analysis of human movement. Due to inaccuracies in the kinematic and force plate data, and a ...mismatch between the model and the subject, the equations of motion are violated when solving the inverse dynamics problem. As a result, dynamic inconsistency will exist and lead to residual forces and moments. In this study, we present and evaluate a computational method to perform inverse dynamics-based simulations without force plates, which both improves the dynamic consistency as well as removes the model׳s dependency on measured external forces. Using the equations of motion and a scaled musculoskeletal model, the ground reaction forces and moments (GRF&Ms) are derived from three-dimensional full-body motion. The method entails a dynamic contact model and optimization techniques to solve the indeterminacy problem during a double contact phase and, in contrast to previously proposed techniques, does not require training or empirical data. The method was applied to nine healthy subjects performing several Activities of Daily Living (ADLs) and evaluated with simultaneously measured force plate data. Except for the transverse ground reaction moment, no significant differences ( P >0.05) were found between the mean predicted and measured GRF&Ms for almost all ADLs. The mean residual forces and moments, however, were significantly reduced ( P >0.05) in almost all ADLs using our method compared to conventional inverse dynamic simulations. Hence, the proposed method may be used instead of raw force plate data in human movement analysis using inverse dynamics.
Musculoskeletal (MS) models should be able to integrate patient-specific MS architecture and undergo thorough validation prior to their introduction into clinical practice. We present a methodology ...to develop subject-specific models able to simultaneously predict muscle, ligament, and knee joint contact forces along with secondary knee kinematics. The MS architecture of a generic cadaver-based model was scaled using an advanced morphing technique to the subject-specific morphology of a patient implanted with an instrumented total knee arthroplasty (TKA) available in the fifth "grand challenge competition to predict in vivo knee loads" dataset. We implemented two separate knee models, one employing traditional hinge constraints, which was solved using an inverse dynamics technique, and another one using an 11-degree-of-freedom (DOF) representation of the tibiofemoral (TF) and patellofemoral (PF) joints, which was solved using a combined inverse dynamic and quasi-static analysis, called force-dependent kinematics (FDK). TF joint forces for one gait and one right-turn trial and secondary knee kinematics for one unloaded leg-swing trial were predicted and evaluated using experimental data available in the grand challenge dataset. Total compressive TF contact forces were predicted by both hinge and FDK knee models with a root-mean-square error (RMSE) and a coefficient of determination (R2) smaller than 0.3 body weight (BW) and equal to 0.9 in the gait trial simulation and smaller than 0.4 BW and larger than 0.8 in the right-turn trial simulation, respectively. Total, medial, and lateral TF joint contact force predictions were highly similar, regardless of the type of knee model used. Medial (respectively lateral) TF forces were over- (respectively, under-) predicted with a magnitude error of M < 0.2 (respectively > -0.4) in the gait trial, and under- (respectively, over-) predicted with a magnitude error of M > -0.4 (respectively < 0.3) in the right-turn trial. Secondary knee kinematics from the unloaded leg-swing trial were overall better approximated using the FDK model (average Sprague and Geers' combined error C = 0.06) than when using a hinged knee model (C = 0.34). The proposed modeling approach allows detailed subject-specific scaling and personalization and does not contain any nonphysiological parameters. This modeling framework has potential applications in aiding the clinical decision-making in orthopedics procedures and as a tool for virtual implant design.
ABSTRACT Subject-specific musculoskeletal (MS) models of the lower extremity are essential for applications such as predicting the effects of orthopedic surgery. We performed an extensive sensitivity ...analysis to assess the effects of potential errors in Hill muscle-tendon (MT) model parameters for each of the 56 MT parts contained in a state-of-the-art MS model. We used two metrics, namely a Local Sensitivity Index (LSI) and an Overall Sensitivity Index (OSI), to distinguish the effect of the perturbation on the predicted force produced by the perturbed MT parts and by all the remaining MT parts, respectively, during a simulated gait cycle. Results indicated that sensitivity of the model depended on the specific role of each MT part during gait, and not merely on its size and length. Tendon slack length was the most sensitive parameter, followed by maximal isometric muscle force and optimal muscle fiber length, while nominal pennation angle showed very low sensitivity. The highest sensitivity values were found for the MT parts that act as prime movers of gait (Soleus: average OSI = 5.61%, Rectus Femoris: average OSI = 4.47%, Gastrocnemius: average OSI = 3.77%, Vastus Lateralis: average OSI = 1.36%, Biceps Femoris Caput Longum: average OSI = 1.06%) and hip stabilizers (Gluteus Medius: average OSI = 3.10%, Obturator Internus: average OSI = 1.96%, Gluteus Minimus: average OSI = 1.40%, Piriformis: average OSI = 0.98%), followed by the Peroneal muscles (average OSI = 2.20%) and Tibialis Anterior (average OSI = 1.78%) some of which were not included in previous sensitivity studies. Finally, the proposed priority list provides quantitative information to indicate which MT parts and which MT parameters should be estimated most accurately to create detailed and reliable subject-specific MS models.
Abstract When analyzing complex biomechanical problems such as predicting the effects of orthopedic surgery, subject-specific musculoskeletal models are essential to achieve reliable predictions. The ...aim of this paper is to present the Twente Lower Extremity Model 2.0, a new comprehensive dataset of the musculoskeletal geometry of the lower extremity, which is based on medical imaging data and dissection performed on the right lower extremity of a fresh male cadaver. Bone, muscle and subcutaneous fat (including skin) volumes were segmented from computed tomography and magnetic resonance images scans. Inertial parameters were estimated from the image-based segmented volumes. A complete cadaver dissection was performed, in which bony landmarks, attachments sites and lines-of-action of 55 muscle actuators and 12 ligaments, bony wrapping surfaces, and joint geometry were measured. The obtained musculoskeletal geometry dataset was finally implemented in the AnyBody Modeling System™ (AnyBody Technology A/S, Aalborg, Denmark), resulting in a model consisting of 12 segments, 11 joints and 21 degrees of freedom, and including 166 muscle–tendon elements for each leg. The new TLEM 2.0 dataset was purposely built to be easily combined with novel image-based scaling techniques, such as bone surface morphing, muscle volume registration and muscle–tendon path identification, in order to obtain subject-specific musculoskeletal models in a quick and accurate way. The complete dataset, including CT and MRI scans and segmented volume and surfaces, is made available at http://www.utwente.nl/ctw/bw/research/projects/TLEMsafe for the biomechanical community, in order to accelerate the development and adoption of subject-specific models on large scale. TLEM 2.0 is freely shared for non-commercial use only, under acceptance of the TLEM safe Research License Agreement.
Monogenic Mitochondrial Disorders Koopman, Werner J.H; Willems, Peter H.G.M; Smeitink, Jan A.M
The New England journal of medicine,
03/2012, Letnik:
366, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Rare monogenic disorders of mitochondria have shed light on mitochondrial function, and the development of therapeutic agents for these disorders may be applicable to more common sporadic diseases ...characterized by mitochondrial dysfunction.
To function normally, human cells require energy in the form of ATP. In many cell types, ATP is primarily generated by mitochondria, which are also key players in other important cellular processes, such as adaptive thermogenesis,
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ion homeostasis,
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innate immune responses,
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production of reactive oxygen species,
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and programmed cell death (apoptosis).
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Mitochondria contain their own DNA (mtDNA), which encodes 13 mitochondrial proteins, 2 ribosomal RNAs (rRNAs), and 22 transfer RNAs (tRNAs). The replication, transcription, translation, and repair of mtDNA are controlled by proteins encoded by nuclear DNA (nDNA).
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,
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Mitochondrial dysfunction is not only observed in monogenic mitochondrial disorders but . . .
Aedes aegypti mosquitoes are responsible for the transmission of arthropod-borne (arbo)viruses including dengue and chikungunya virus (CHIKV) but in contrast to human hosts, arbovirus-infected ...mosquitoes are able to efficiently control virus replication to sub-pathological levels. Yet, our knowledge of the molecular interactions of arboviruses with their mosquito hosts is incomplete. Here, we aimed to identify and characterize novel host genes that control arbovirus replication in Aedes mosquitoes. RNA binding proteins (RBPs) are well-known to regulate immune signaling pathways in all kingdoms of life. We therefore performed a knockdown screen targeting 461 genes encoding predicted RBPs in Aedes aegypti Aag2 cells and identified 15 genes with antiviral activity against Sindbis virus. Amongst these, the three DEAD-box RNA helicases AAEL004419/Dhx15, AAEL008728, and AAEL004859 also acted as antiviral factors in dengue and CHIKV infections. Here, we explored the mechanism of Dhx15 in regulating an antiviral transcriptional response in mosquitoes by silencing Dhx15 in Aag2 cells followed by deep-sequencing of poly-A enriched RNAs. Dhx15 knockdown in uninfected and CHIKV-infected cells resulted in differential expression of 856 and 372 genes, respectively. Interestingly, amongst the consistently downregulated genes, glycolytic process was the most enriched gene ontology (GO) term as the expression of all core enzymes of the glycolytic pathway was reduced, suggesting that Dhx15 regulates glycolytic function. A decrease in lactate production indicated that Dhx15 silencing indeed functionally impaired glycolysis. Modified rates of glycolytic metabolism have been implicated in controlling the replication of several classes of viruses and strikingly, infection of Aag2 cells with CHIKV by itself also resulted in the decrease of several glycolytic genes. Our data suggests that Dhx15 regulates replication of CHIKV, and possibly other arboviruses, by controlling glycolysis in mosquito cells.
Abstract Subject-specific musculo-skeletal models of the lower extremity are an important tool for investigating various biomechanical problems, for instance the results of surgery such as joint ...replacements and tendon transfers. The aim of this study was to assess the potential effects of errors in musculo-skeletal geometry on subject-specific model results. We performed an extensive sensitivity analysis to quantify the effect of the perturbation of origin, insertion and via points of each of the 56 musculo-tendon parts contained in the model. We used two metrics, namely a Local Sensitivity Index (LSI) and an Overall Sensitivity Index (OSI), to distinguish the effect of the perturbation on the predicted force produced by only the perturbed musculo-tendon parts and by all the remaining musculo-tendon parts, respectively, during a simulated gait cycle. Results indicated that, for each musculo-tendon part, only two points show a significant sensitivity: its origin, or pseudo-origin, point and its insertion, or pseudo-insertion, point. The most sensitive points belong to those musculo-tendon parts that act as prime movers in the walking movement (insertion point of the Achilles Tendon: LSI=15.56%, OSI=7.17%; origin points of the Rectus Femoris: LSI=13.89%, OSI=2.44%) and as hip stabilizers (insertion points of the Gluteus Medius Anterior: LSI=17.92%, OSI=2.79%; insertion point of the Gluteus Minimus: LSI=21.71%, OSI=2.41%). The proposed priority list provides quantitative information to improve the predictive accuracy of subject-specific musculo-skeletal models.
Objective
There are marked mitochondrial abnormalities in parkin‐knock‐out Drosophila and other model systems. The aim of our study was to determine mitochondrial function and morphology in ...parkin‐mutant patients. We also investigated whether pharmacological rescue of impaired mitochondrial function may be possible in parkin‐mutant human tissue.
Methods
We used three sets of techniques, namely, biochemical measurements of mitochondrial function, quantitative morphology, and live cell imaging of functional connectivity to assess the mitochondrial respiratory chain, the outer shape and connectivity of the mitochondria, and their functional inner connectivity in fibroblasts from patients with homozygous or compound heterozygous parkin mutations.
Results
Parkin‐mutant cells had lower mitochondrial complex I activity and complex I–linked adenosine triphosphate production, which correlated with a greater degree of mitochondrial branching, suggesting that the functional and morphological effects of parkin are related. Knockdown of parkin in control fibroblasts confirmed that parkin deficiency is sufficient to explain these mitochondrial effects. In contrast, 50% knockdown of parkin, mimicking haploinsufficiency in human patient tissue, did not result in impaired mitochondrial function or morphology. Fluorescence recovery after photobleaching assays demonstrated a lower level of functional connectivity of the mitochondrial matrix, which further worsened after rotenone exposure. Treatment with experimental neuroprotective compounds resulted in a rescue of the mitochondrial membrane potential.
Interpretation
Our study demonstrates marked abnormalities of mitochondrial function and morphology in parkin‐mutant patients and provides proof‐of‐principle data for the potential usefulness of this new model system as a tool to screen for disease‐modifying compounds in genetically homogenous parkinsonian disorders. Ann Neurol 2008;64:555–565
Ambulatory Assessment of Ankle and Foot Dynamics Schepers, H. Martin; Koopman, H. F. J. M.; Veltink, Peter H.
IEEE transactions on biomedical engineering,
05/2007, Letnik:
54, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Ground reaction force (GRF) measurement is important in the analysis of human body movements. The main drawback of the existing measurement systems is the restriction to a laboratory environment. ...This paper proposes an ambulatory system for assessing the dynamics of ankle and foot, which integrates the measurement of the GRF with the measurement of human body movement. The GRF and the center of pressure (CoP) are measured using two six-degrees-of-freedom force sensors mounted beneath the shoe. The movement of foot and lower leg is measured using three miniature inertial sensors, two rigidly attached to the shoe and one on the lower leg. The proposed system is validated using a force plate and an optical position measurement system as a reference. The results show good correspondence between both measurement systems, except for the ankle power estimation. The root mean square (RMS) difference of the magnitude of the GRF over 10 evaluated trials was (0.012 plusmn 0.001) N/N (mean plusmn standard deviation), being (1.1 plusmn 0.1)% of the maximal GRF magnitude. It should be noted that the forces, moments, and powers are normalized with respect to body weight. The CoP estimation using both methods shows good correspondence, as indicated by the RMS difference of (5.1 plusmn 0.7) mm, corresponding to (1.7 plusmn 0.3)% of the length of the shoe. The RMS difference between the magnitudes of the heel position estimates was calculated as (18 plusmn 6) mm, being (1.4 plusmn 0.5)% of the maximal magnitude. The ankle moment RMS difference was (0.004 plusmn 0.001) Nm/N, being (2.3 plusmn 0.5)% of the maximal magnitude. Finally, the RMS difference of the estimated power at the ankle was (0.02 plusmn 0.005) W/N, being (14 plusmn 5)% of the maximal power. This power difference is caused by an inaccurate estimation of the angular velocities using the optical reference measurement system, which is due to considering the foot as a single segment. The ambulatory system considers separate heel and forefoot segments, thus allowing an additional foot moment and power to be estimated. Based on the results of this research, it is concluded that the combination of the instrumented shoe and inertial sensing is a promising tool for the assessment of the dynamics of foot and ankle in an ambulatory setting
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