Framework for modulating ambulatory load in the context of in vivo mechanosensitivity of articular cartilage

Objective: Different stress modalities have been used to provoke a load induced mechanoresponse in blood markers of articular cartilages. The challenge in in vivo experiments is to alter specific loading characteristics. Here, we aimed to develop a load modification framework that changes ambulatory load magnitude without changing load frequency or joint kinematics. Design: Spatiotemporal parameters, sagittal joint kinematics and vertical ground reaction force (vGRF) of 24 healthy participants were recorded while walking with reduced (80%), normal (100%) and increased (120%) bodyweight (BW) on three separate test days in a block randomized cross-over design. The reduced and increased load conditions were compared to the normal load condition using paired sample t-tests for spatiotemporal pa- rameters and statistical parametric mapping for vGRF and joint kinematics. Results: Load modification resulted in measured vGRF differences of 19.5%BW (reduced) and þ16.8%BW (increased). Spatiotemporal parameters with reduced and increased load did not differ from normal load except of a shorter stance time under reduced load (21 ms). Joint kinematics for both conditions did not differ from normal load except of decreased ankle dorsiflexion (maximum 5.9) and increased knee flexion (maximum þ6.5) for the reduced load condition during pre-swing when the support limb is already unloaded. Conclusion: Overall, we did not observe relevant differences in spatiotemporal parameters or joint kinematics between loading conditions. Mean absolute joint angle deviations below 4.1 demonstrate that the proposed load modification framework changes ambulatory load magnitude without changing load frequency or joint kinematics

Long non-coding RNAs: spatial amplifiers that control nuclear structure and gene expression

Over the past decade, it has become clear that mammalian genomes encode thousands of long non-coding RNAs (lncRNAs), many of which are now implicated in diverse biological processes. Recent work studying the molecular mechanisms of several key examples — including Xist, which orchestrates X chromosome inactivation — has provided new insights into how lncRNAs can control cellular functions by acting in the nucleus. Here we discuss emerging mechanistic insights into how lncRNAs can regulate gene expression by coordinating regulatory proteins, localizing to target loci and shaping three-dimensional (3D) nuclear organization. We explore these principles to highlight biological challenges in gene regulation, in which lncRNAs are well-suited to perform roles that cannot be carried out by DNA elements or protein regulators alone, such as acting as spatial amplifiers of regulatory signals in the nucleus

Overview on Multienzymatic Cascades for the Production of Non-canonical α-Amino Acids

SM-R thanks the University of Granada for the support provided by project PPJI2017-1 and the European Cooperation in Science and Technology (COST Action CA15133). Authors are also grateful to the Andalusian Regional Government through Endocrinology & Metabolism Group (CTS-202).The 22 genetically encoded amino acids (AAs) present in proteins (the 20 standard AAs together with selenocysteine and pyrrolysine), are commonly referred as proteinogenic AAs in the literature due to their appearance in ribosome-synthetized polypeptides. Beyond the borders of this key set of compounds, the rest of AAs are generally named imprecisely as non-proteinogenic AAs, even when they can also appear in polypeptide chains as a result of post-transductional machinery. Besides their importance as metabolites in life, many of D-α- and L-α-“non-canonical” amino acids (NcAAs) are of interest in the biotechnological and biomedical fields. They have found numerous applications in the discovery of new medicines and antibiotics, drug synthesis, cosmetic, and nutritional compounds, or in the improvement of protein and peptide pharmaceuticals. In addition to the numerous studies dealing with the asymmetric synthesis of NcAAs, many different enzymatic pathways have been reported in the literature allowing for the biosynthesis of NcAAs. Due to the huge heterogeneity of this group of molecules, this review is devoted to provide an overview on different established multienzymatic cascades for the production of non-canonical D-α- and L-α-AAs, supplying neophyte and experienced professionals in this field with different illustrative examples in the literature. Whereas the discovery of new or newly designed enzymes is of great interest, dusting off previous enzymatic methodologies by a “back and to the future” strategy might accelerate the implementation of new or improved multienzymatic cascades.University of Granada PPJI2017-1European Cooperation in Science and Technology (COST) CA15133Andalusian Regional Government through Endocrinology & Metabolism Group CTS-20

Dose-Response Relationship of Ambulatory Load and Cartilage Pilot Study

Background: Ambulatory load plays an important role in the initiation and progression of osteoarthritis. It is unknown if load-induced changes in articular cartilage biomarkers depend on the magnitude of ambulatory load. Methods: Serum cartilage oligomeric matrix protein sCOMP was assessed before and after a 30-minute walking stress test performed on three test days by 24 healthy volunteers. In each walking stress test, one of three ambulatory loads was applied: normal body weight (100%BW = normal load); reduced body weight (80%BW = reduced load); increased body weight (120%BW = increased load). Knee kinematics and ground reaction force were measured using an inertial sensor gait analysis system and a pressure plate embedded in the treadmill. Results: Load-induced increases in sCOMP rose with increasing ambulatory load magnitude. Mean sCOMP levels increased immediately after the walking stress test by 26.8 ± 12.8%, 28.0 ± 13.3% and 37.3 ± 18.3% for the reduced, normal or increased load condition, respectively. Knee kinematics did not differ between conditions. Conclusion: The results of this study provide important evidence of a dose-response relationship between ambulatory load magnitude and load-induced changes in sCOMP. Our data suggests that in normal weight persons sCOMP levels are more sensitive to increased than to reduced load

Good vibrations: Itch induction by whole body vibration exercise without the need of a pruritogen

Mechanically induced itch is an important cofactor in many patients with chronic itch. However, studying mechanical itch in a controlled environment is challenging because it is difficult to evoke. We investigated the use of whole body vibration (WBV) exercise, a training method used for musculoskeletal rehabilitation, to experimentally evoke mechanical itch. Mild to severe itch ascending from the soles to the groins was evoked in 16 of 20 healthy participants. We observed a characteristic on/off itch crescendo pattern reflecting the alternating intervals of vibration and no vibration. Wheals or an angioedema was absent, and serum mast cell tryptase was not increased by the exercise. Participants described the evoked sensation primarily as "itching" with some nociceptive components. Itch intensity correlated with the intensity of a concomitant erythema (R = 0.45, P = 0.043) and with the rise in skin temperature (R = 0.54, P = 0.017). Hence, WBV can be used as an easily applicable, noninvasive, investigator- and user-friendly framework for studying mechanical itch. Moreover, WBV allows to "switch itch on and off" rapidly and to simultaneously study interactions between itch, skin blood flow and skin temperature