The role of heparan sulfate maturation in cancer: A focus on the 3O-sulfation and the enigmatic 3O-sulfotransferases (HS3STs)

Heparansulfate (HS) modifications are master regulators of the cross-talk between cell and matrix and modulate the biological activity of an array of HS binding proteins, including growth factors and chemokines, morphogens and immunity cell receptors. This review will highlight the importance of HS maturation mediated by N-deactetylase/sulfotransferases, 2O- and 6O-sulfotransferases in cancer biology, and will focus on the 3O-sulfotransferases and on the terminal, rare 3O-sulfation, and their important but still enigmatic impact in cancer progression. The review will also discuss the molecular mechanisms of action of these HS modifications with regards to ligand interactions and signaling in the cancer process and their clinical significance

Comparison of subthalamic unilateral and bilateral theta burst deep brain stimulation in Parkinson’s disease

High-frequency, conventional deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson’s disease (PD) is usually applied bilaterally under the assumption of additive effects due to interhemispheric crosstalk. Theta burst stimulation (TBS-DBS) represents a new patterned stimulation mode with 5 Hz interburst and 200 Hz intraburst frequency, whose stimulation effects in a bilateral mode compared to unilateral are unknown. This single-center study evaluated acute motor effects of the most affected, contralateral body side in 17 PD patients with unilateral subthalamic TBS-DBS and 11 PD patients with bilateral TBS-DBS. Compared to therapy absence, both unilateral and bilateral TBS-DBS significantly improved (p < 0.05) lateralized Movement Disorder Society-Unified Parkinson’s Disease Rating Scale part III (MDS-UPDRS III) scores. Bilateral TBS-DBS revealed only slight, but not significant additional effects in comparison to unilateral TBS-DBS on total lateralized motor scores, but on the subitem lower limb rigidity. These results indicate that bilateral TBS-DBS has limited additive beneficial effects compared to unilateral TBS-DBS in the short term

The heparan sulfate sulfotransferase 3-OST3A (HS3ST3A) is a novel tumor regulator and a prognostic marker in breast cancer

International audienceHeparan sulfate (HS) proteoglycan chains are key components of the breast tumor microenvironment that critically influence the behavior of cancer cells. It is established that abnormal synthesis and processing of HS play a prominent role in tumorigenesis, albeit mechanisms remain mostly obscure. HS function is mainly controlled by sulfotransferases, and here we report a novel cellular and pathophysiological significance for the 3-O-sulfotransferase 3-OST3A (HS3ST3A), catalyzing the final maturation step of HS, in breast cancer. We show that 3-OST3A is epigenetically repressed in all breast cancer cell lines of a panel representative of distinct molecular subgroups, except in human epidermal growth factor receptor 2-positive (HER2+) sloan-kettering breast cancer (SKBR3) cells. Epigenetic mechanisms involved both DNA methylation and histone modifications, producing different repressive chromatin environments depending on the cell molecular signature. Gain and loss of function experiments by cDNA and siRNA transfection revealed profound effects of 3-OST3A expression on cell behavior including apoptosis, proliferation, response to trastuzumab in vitro and tumor growth in xenografted mice. 3-OST3A exerted dual activities acting as tumor-suppressor in lumA-michigan cancer foundation (MCF)-7 and triple negative-MD Anderson (MDA) metastatic breast (MB)-231 cells, or as an oncogenic factor in HER2+-SKBR3 cells. Mechanistically, fluorescence-resonance energy transfer-fluorescence-lifetime imaging microscopy experiments indicated that the effects of 3-OST3A in MCF-7 cells were mediated by altered interactions between HS and fibroblast growth factor-7 (FGF-7). Further, this interplay between HS and FGF-7 modulated downstream ERK, AKT and p38 cascades, suggesting that altering 3-O-sulfation affects FGFR2IIIb-mediated signaling. Corroborating our cellular data, a clinical study conducted in a cohort of breast cancer patients uncovered that, in HER2+ patients, high level expression of 3-OST3A in tumors was associated with reduced relapse-free survival. Our findings define 3-OST3A as a novel regulator of breast cancer pathogenicity, displaying tumor-suppressive or oncogenic activities in a cell-and tumor-dependent context, and demonstrate the clinical value of the HS-O-sulfotransferase 3-OST3A as a prognostic marker in HER2+ patients

Linking Pathological Oscillations With Altered Temporal Processing in Parkinsons Disease: Neurophysiological Mechanisms and Implications for Neuromodulation.

Emerging evidence suggests that Parkinson's disease (PD) results from disrupted oscillatory activity in cortico-basal ganglia-thalamo-cortical (CBGTC) and cerebellar networks which can be partially corrected by applying deep brain stimulation (DBS). The inherent dynamic nature of such oscillatory activity might implicate that is represents temporal aspects of motor control. While the timing of muscle activities in CBGTC networks constitute the temporal dimensions of distinct motor acts, these very networks are also involved in somatosensory processing. In this respect, a temporal aspect of somatosensory processing in motor control concerns matching predicted (feedforward) and actual (feedback) sensory consequences of movement which implies a distinct contribution to demarcating the temporal order of events. Emerging evidence shows that such somatosensory processing is altered in movement disorders. This raises the question how disrupted oscillatory activity is related to impaired temporal processing and how/whether DBS can functionally restore this. In this perspective article, the neural underpinnings of temporal processing will be reviewed and translated to the specific alternated oscillatory neural activity specifically found in Parkinson's disease. These findings will be integrated in a neurophysiological framework linking somatosensory and motor processing. Finally, future implications for neuromodulation will be discussed with potential implications for strategy across a range of movement disorders

Phase-Dependent Suppression of Beta Oscillations in Parkinson's Disease Patients

Synchronized oscillations within and between brain areas facilitate normal processing, but are often amplified in disease. A prominent example is the abnormally sustained beta-frequency (∼20 Hz) oscillations recorded from the cortex and subthalamic nucleus of Parkinson's disease patients. Computational modeling suggests that the amplitude of such oscillations could be modulated by applying stimulation at a specific phase. Such a strategy would allow selective targeting of the oscillation, with relatively little effect on other activity parameters. Here, activity was recorded from 10 awake, parkinsonian patients (6 male, 4 female human subjects) undergoing functional neurosurgery. We demonstrate that stimulation arriving on a particular patient-specific phase of the beta oscillation over consecutive cycles could suppress the amplitude of this pathophysiological activity by up to 40%, while amplification effects were relatively weak. Suppressive effects were accompanied by a reduction in the rhythmic output of subthalamic nucleus (STN) neurons and synchronization with the mesial cortex. While stimulation could alter the spiking pattern of STN neurons, there was no net effect on firing rate, suggesting that reduced beta synchrony was a result of alterations to the relative timing of spiking activity, rather than an overall change in excitability. Together, these results identify a novel intrinsic property of cortico-basal ganglia synchrony that suggests the phase of ongoing neural oscillations could be a viable and effective control signal for the treatment of Parkinson's disease. This work has potential implications for other brain diseases with exaggerated neuronal synchronization and for probing the function of rhythmic activity in the healthy brain

Caractérisation structurale et fonctionnelle de la galactose-bêta1,3-glucuronosyltransférase-I recombinante humaine (GlcAT-I)

Les glycosaminoglycanes (GAGs) sont des hétéropolysaccharides linéaires pour la plupart liés à des protéines pour former des macromolécules appelées protéoglycanes (PGs). Composants structuraux majoritaires de la matrice extracellulaire cartilagineuse, les PGs contribuent avx propriétés biomécaniques et fonctionnelles de l'articulation. Les glycosyltransférases (GTs) impliquées dans la biosynthèse des GAGs ont suscité un intérêt croissant ces dernières années en raison de l'importance biologique des PGs et de leurs implications dans divers mécanismes de régulation cellulaire majeurs. Nous nous sommes plus particulièrement intéressés dans ce travail à la galactose-131,3-glucuronosyltransférase-I (GlcAT-I) qui catalyse la dernière étape de formation de l'amorce tétrassacharidique à partir de laquelle s'effectue la polymérisation des GAGs sur la protéine centrale des PGs et dont le rôle limitant a été suggéré dans cette étape. La caractérisation moléculaire de la GlcAT-I devrait donc s'avérer importante en terme de physiopathologie articulaire. Notre travail a été consacré à la caractérisation structurale et fonctionnelle de la GlcAT-I. Nous avons cherché à analyser son organisation membranaire, en particulier son état d'oligomérisation, et à définir les bases moléculaires de sa spécificité vis-à-vis de substrats donneurs et accepteurs par la recherche et l'identification des motifs peptidiques et/ou acides aminés structuraux et catalytiques. Notre travail a permis de démontrer que l'organisation homodimérique de la GlcAT-I résulte de l'établissement d'un pont disulfure impliquant les Cys33 de chaque monomère. Nous avons parallèlement mis en évidence le rôle crucial d'une autre cystéine (Cys301) dans l'activité de l'enzyme par des approches combinées de mutagenèse dirigée et de modification chimique. De la même manière, l'étude des acides aminés conservés de cette GT a permis de démontrer l'implication des résidus His308 et Arg277 dans la reconnaissance et la prise en charge du substrat donneur par l'enzyme. L'analyse du rôle des résidus acides carboxyliques du site actif a conduit à la mise en évidence du rôle catalytique du résidu Glu281, avancé suite à la première description de la structure cristalline de la GlcAT-I. De façon complémentaire, l'étude du motif DXD, une séquence signature des GTs, souligne l'importance de l'intégrité de ce motif acide pour la fixation du substrat donneur, en relation avec la présence des cations manganèse, indispensables à l'activité de la GlcAT-I. Les études cinétiques ont de plus permis de proposer un modèle d'interaction séquentiel associant l'enzyme au complexe [substrat donneur -cofacteur métallique]. La connaissance et le contrôle des étapes précoces de la biosynthèse des GAGs, en particulier celle catalysée par la GlcAT-I, contribuent à la caractérisation de nouvelles cibles pharmacologiques. Ces informations devraient conduire à la mise en place de nouveaux concepts thérapeutiques, en particulier dans le cadre du traitement des atteintes dégénératives du cartilage comme l'arthrose.NANCY1-SCD Pharmacie-Odontologie (543952101) / SudocSudocFranceF

Walking In Virtual Reality: Effects Of Manipulated Visual Self-Motion On Walking Biomechanics

Walking constitutes the predominant form of self-propelled movement from one geographic location to another in our real world. Likewise, walking in virtual environments (VEs) is an essential part of a users experience in many application domains requiring a high degree of interactivity. However, researchers and practitioners often observe that basic implementations of virtual walking, in which head-tracked movements are mapped isometrically to a VE are not estimated as entirely natural. Instead, users estimate a virtual walking velocity as more natural when it is slightly increased compared to the users physical body movement. In this article, we investigate the effects of such nonisometric mappings between physical movements and virtual motions in the VE on walking velocity and biomechanics of the gait cycle. Therefore, we performed an experiment in which we measured and analyzed parameters of the biomechanics of walking under conditions with isometric as well as nonisometric mappings. Our results show significant differences in most gait parameters when walking in the VE in the isometric mapping condition compared to the corresponding parameters in the real world. For nonisometric mappings we found an increased divergence of gait parameters depending on the velocity of visual self-motion feedback. The results revealed a symmetrical effect of gait detriments for up-or down-scaled virtual velocities, which we discuss in the scope of the previous findings