Contributors: O. Kovalchuk Ben-Zaken, I. Nissan, S. Tzaban, A. Taraboulos, E. Zcharia, S. Matzger, I. Shafat, I. Vlodavsky, Y. Tal
... Cellular heparan sulfate (HS) has a dual role in scrapie pathogenesis; it is required for PrPSc (scrapie prion protein) formation and facilitates infection of cells, mediating cellular uptake of prions. We examined the involvement of heparanase, a mammalian endoglycosidase degrading HS, in scrapie infection. In cultured cells, heparanase treatment or over-expression resulted in a profound decrease in PrPSc. Moreover, disease onset and progression were dramatically delayed in scrapie infected transgenic mice over-expressing heparanase. Together, our results provide direct in vivo evidence for the involvement of intact HS in the pathogenesis of prion disease and the protective role of heparanase both in terms of susceptibility to infection and disease progression.
Contributors: Qingsen Li, Ekta Makhija, F.M. Hameed, G.V. Shivashankar
... Cells sense physical cues at the level of focal adhesions and transduce them to the nucleus by biochemical and mechanical pathways. While the molecular intermediates in the mechanical links have been well studied, their dynamic coupling is poorly understood. In this study, fibroblast cells were adhered to micropillar arrays to probe correlations in the physical coupling between focal adhesions and nucleus. For this, we used novel imaging setup to simultaneously visualize micropillar deflections and EGFP labeled chromatin structure at high spatial and temporal resolution. We observed that micropillar deflections, depending on their relative positions, were positively or negatively correlated to nuclear and heterochromatin movements. Our results measuring the time scales between micropillar deflections and nucleus centroid displacement are suggestive of a strong elastic coupling that mediates differential force transmission to the nucleus.
Contributors: John B. Bührdel, Sofia Hirth, Mirjam Keßler, Sören Westphal, Monika Forster, Linda Manta, Gerhard Wiche, Benedikt Schoser, Joachim Schessl, Rolf Schröder
... Myofibrillar myopathies (MFM) are progressive diseases of human heart and skeletal muscle with a severe impact on life quality and expectancy of affected patients. Although recently several disease genes for myofibrillar myopathies could be identified, today most genetic causes and particularly the associated mechanisms and signaling events that lead from the mutation to the disease phenotype are still mostly unknown. To assess whether the zebrafish is a suitable model system to validate MFM candidate genes using targeted antisense-mediated knock-down strategies, we here specifically inactivated known human MFM disease genes and evaluated the resulting muscular and cardiac phenotypes functionally and structurally. Consistently, targeted ablation of MFM genes in zebrafish led to compromised skeletal muscle function mostly due to myofibrillar degeneration as well as severe heart failure. Similar to what was shown in MFM patients, MFM gene-deficient zebrafish showed pronounced gene-specific phenotypic and structural differences. In summary, our results indicate that the zebrafish is a suitable model to functionally and structurally evaluate novel MFM disease genes in vivo.
Contributors: Abdalla Abdal-hay, Abdel Salam Hamdy, Ju Hyun Lim
... Air jet spinning (AJS) method has been successfully used for manufacturing of micro/nanofibers. AJS method offers a fiber production rate that is several times higher than those produced by electrospinning. This paper discusses the preparation of TiO2 in two different morphological structures using a one-step AJS based on sol–gel blends of alkoxide precursor (titanium isopropoxide), Ti(iso) and poly(vinyl acetate) (PVAc) solutions. Our results confirmed that TiO2 fibers and tubular structures can be prepared by controlling the proportions of Ti(iso) precursor. Spinning Ti(iso)/PVAc solutions with low precursor concentrations (25%) yielded fibers with smooth surfaces. Increasing the precursor concentration more than 25% resulted in production of very rough fibers of highly tubular structure. Overall, the AJS technique proved to be a valuable method for future research related to polymer and ceramic fiber processing and fabrication.
Hands On - Safety and prevention of complications during percutaneous epicardial access for the ablation of cardiac arrhythmias
Contributors: Han S. Lim, Frédéric Sacher, Hubert Cochet, Benjamin Berte, Seigo Yamashita, Saagar Mahida, Stephan Zellerhoff, Yuki Komatsu, Arnaud Denis, Nicolas Derval
Review - Allosteric modulation of metabotropic glutamate receptors: Structural insights and therapeutic potential
Contributors: Karen J. Gregory, Elizabeth N. Dong, Jens Meiler, P. Jeffrey Conn
... Allosteric modulation of G protein-coupled receptors (GPCRs) represents a novel approach to the development of probes and therapeutics that is expected to enable subtype-specific regulation of central nervous system target receptors. The metabotropic glutamate receptors (mGlus) are class C GPCRs that play important neuromodulatory roles throughout the brain, as such they are attractive targets for therapeutic intervention for a number of psychiatric and neurological disorders including anxiety, depression, Fragile X Syndrome, Parkinson’s disease and schizophrenia. Over the last fifteen years, selective allosteric modulators have been identified for many members of the mGlu family. The vast majority of these allosteric modulators are thought to bind within the transmembrane-spanning domains of the receptors to enhance or inhibit functional responses. A combination of mutagenesis-based studies and pharmacological approaches are beginning to provide a better understanding of mGlu allosteric sites. Collectively, when mapped onto a homology model of the different mGlu subtypes based on the β2-adrenergic receptor, the previous mutagenesis studies suggest commonalities in the location of allosteric sites across different members of the mGlu family. In addition, there is evidence for multiple allosteric binding pockets within the transmembrane region that can interact to modulate one another. In the absence of a class C GPCR crystal structure, this approach has shown promise with respect to the interpretation of mutagenesis data and understanding structure-activity relationships of allosteric modulator pharmacophores.