Immune or genetic-mediated disruption of CASPR2 causes pain hypersensitivity due to enhanced primary afferent excitability

Human autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with neuropathic pain, and CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized. Human CASPR2 autoantibodies, when injected into mice, were peripherally restricted and resulted in mechanical pain-related hypersensitivity in the absence of neural injury. We therefore investigated the mechanism by which CASPR2 modulates nociceptive function. Mice lacking CASPR2 (Cntnap2(-/-)) demonstrated enhanced pain-related hypersensitivity to noxious mechanical stimuli, heat, and algogens. Both primary afferent excitability and subsequent nociceptive transmission within the dorsal horn were increased in Cntnap2(-/-) mice. Either immune or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of Kv1 channel expression at the soma membrane. This is the first example of passive transfer of an autoimmune peripheral neuropathic pain disorder and demonstrates that CASPR2 has a key role in regulating cell-intrinsic dorsal root ganglion (DRG) neuron excitability

Exercise, Service and Support: Client Experiences of Physical Activity Referral Schemes(PARS)

Physical activity referral schemes (PARS) represent one of the most prevalent interventions in the fight against chronic illness such as coronary heart disease and obesity. Despite this, issues surrounding low retention and adherence continue to hinder the potential effectiveness of such schemes on public health. This article reports on the second stage of a larger investigation into client experiences of PARS focusing specifically on findings from five client-based focus groups and interviews with five Scheme Organisers. The resulting analysis reveals three main factors impacting participant perceptions of the quality of service and support received: the organisation of PARS provision, client engagement with the PARS community and the nature and extent of client support networks. The article demonstrates that staff have a considerable role to play in engaging clients in the PARS system and that Scheme Organisers should give serious thought to ensuring that clients have valuable and sustainable networks of support. Furthermore, it is suggested that Scheme Organisers need to facilitate a system in which staff are genuinely engaged with the needs of clients and are able to provide individualised programmes of physical activity

Amyloid binding and beyond: a new approach for Alzheimer's disease drug discovery targeting Aβo–PrPC binding and downstream pathways

Amyloid β oligomers (Aβo) are the main toxic species in Alzheimer's disease, which have been targeted for single drug treatment with very little success. In this work we report a new approach for identifying functional Aβo binding compounds. A tailored library of 971 fluorine containing compounds was selected by a computational method, developed to generate molecular diversity. These compounds were screened for Aβo binding by a combined 19F and STD NMR technique. Six hits were evaluated in three parallel biochemical and functional assays. Two compounds disrupted Aβo binding to its receptor PrPC in HEK293 cells. They reduced the pFyn levels triggered by Aβo treatment in neuroprogenitor cells derived from human induced pluripotent stem cells (hiPSC). Inhibitory effects on pTau production in cortical neurons derived from hiPSC were also observed. These drug-like compounds connect three of the pillars in Alzheimer's disease pathology, i.e. prion, Aβ and Tau, affecting three different pathways through specific binding to Aβo and are, indeed, promising candidates for further development

Standardized practices for RNA diagnostics using clinically accessible specimens reclassifies 75% of putative splicing variants

Purpose: Genetic variants causing aberrant premessenger RNA splicing are increasingly being recognized as causal variants in genetic disorders. In this study, we devise standardized practices for polymerase chain reaction (PCR)-based RNA diagnostics using clinically accessible specimens (blood, fibroblasts, urothelia, biopsy). Methods: A total of 74 families with diverse monogenic conditions (31% prenatal-congenital onset, 47% early childhood, and 22% teenage-adult onset) were triaged into PCR-based RNA testing, with comparative RNA sequencing for 19 cases. Results: Informative RNA assay data were obtained for 96% of cases, enabling variant reclassification for 75% variants that can be used for genetic counseling (71%), to inform clinical care (32%) and prenatal counseling (41%). Variant-associated mis-splicing was highly reproducible for 28 cases with samples from ≥2 affected individuals or heterozygotes and 10 cases with ≥2 biospecimens. PCR amplicons encompassing another segregated heterozygous variant was vital for clinical interpretation of 22 of 79 variants to phase RNA splicing events and discern complete from partial mis-splicing. Conclusion: RNA diagnostics enabled provision of a genetic diagnosis for 64% of recruited cases. PCR-based RNA diagnostics has capacity to analyze 81.3% of clinically significant genes, with long amplicons providing an advantage over RNA sequencing to phase RNA splicing events. The Australasian Consortium for RNA Diagnostics (SpliceACORD) provide clinically-endorsed, standardized protocols and recommendations for interpreting RNA assay data.Field, Ron Fleischer, Chiara Folland, Lucy Fox, Mary- Louise Freckmann, Clara Gaff, Melanie Galea, Roula Ghaoui, Himanshu Goel, Ilias Gornanitis, Thuong Ha, Bernadette Hanna, James Harraway, Rippei Hayashi, Ian Hayes, Alex Henderson, Luke Hesson, Erin Heyer, Michael Hildebrand, Michael Hipwell, Gladys Ho, Ari E. Horton, Cass Hoskins, Matthew F. Hunter, Matilda Jackson, Paul James, Kristi J. Jones, Justin Jong-Leong Wong, Sarah Josephi-Taylor, Himanshu Joshi, Karin Kassahn, Peter Kaub, Lucy Kevin, Edwin Kirk, Emma Krzesinski, Smitha Kumble, Sarah Kummerfeld, Nigel Laing, Chiyan Lau, Eric Lee, Sarah Leighton, Ben Lundie, Sebastian Lunke, Amali Mallawaarachchi, Chelsea Mayoh, Julie McGaughran, Ali- son McLean, Mary McPhillips, Cliff Meldrum, Edwina Middleton, Di Milnes, Kym Mina, David Mowat, Amy Nisselle, Emily Oates, Alicia Oshlack, Elizabeth E. Palmer, Gayathri Parasivam, Michael Parsons, Chirag Patel, Jason R. Pinner, Michael Quinn, John Rasko, Gina Ravenscroft, Anja Ravine, Krista Recsei, Matthew Regan, Jacqueline Rehn, Lisa G. Riley, Stephen Robertson, Anne Ronan, Tony Roscioli, Georgina Ryland, Simon Sadedin, Sarah A. San- daradura, Andreas Schreiber, Hamish Scott, Rodney Scott, Christopher Semsarian, Cas Simons, Emma Singer, Janine M. Smith, Renee Smyth, Amanda Spurdle, Zornitza Stark, Patricia Sullivan, Samantha Sundercombe, Tiong Y. Tan, Michel C. Tchan, Bryony A. Thompson, David Thorburn, John Toubia, Ronald Trent, Emma Tudini, Irina Voneague, Leigh Waddell, Logan Walker, Mathew Wallis, Nick War- nock, Robert Weatheritt, Deborah White, Susan M. White, Mark G. Williams, Meredith J. Wilson, Ingrid Winship, Lisa Worgan, Dale C. Wright, Kathy Wu, Alison Yeung, Andrew Ziolowski. Additional Information The online version of this article, https, doi.org, ., j. gim., ., ., contains supplementary material, which is available to authorized users. Authors Adam M. Bournazos, Lisa G. Riley, Shobhana Bommireddipalli, Lesley Ades, Lauren S. Akesson, Mohammad Al-Shinnag, Stephen I. Alexander, Alison D. Archibald, Shanti Balasubramaniam, Yemima Berman, Victoria Beshay, Kirsten Boggs, Jasmina Bojadzieva, Natasha J. Brown, Samantha J. Bryen, Michael F. Buckley, Belinda Chong, Mark R. Davis, Ruebena Dawes, Martin Delatycki, Liz Donaldson, Lilian Downie, Caitlin Edwards, Matthew Edwards, Amanda Engel, Lisa J. Ewans, Fathimath Faiz, Andrew Fennell, Michael Field, Mary-Louise Freckmann, Lyndon Gallacher, Russell Gear, Himanshu Goel, Shuxiang Goh, Linda Goodwin, Bernadette Hanna, James Harraway, Megan Higgins, Gladys Ho, Bruce K. Hopper, Ari E. Horton, Matthew F. Hunter, Aamira J. Huq, Sarah Josephi-Taylor, Himanshu Joshi, Edwin Kirk, Emma Krzesinski, Kishore R. Kumar, Frances Lemckert, Richard J. Leventer, Suzanna E. Lindsey-Temple, Sebastian Lunke, Alan Ma, Steven Macaskill, Amali Mallawaarachchi, Melanie Marty, Justine E. Marum, Hugh J. McCarthy, Manoj P. Menezes, Alison McLean, Di Milnes, Shekeeb Mohammad, David Mowat, Aram Niaz, Elizabeth E. Palmer, Chirag Patel, Shilpan G. Patel, Dean Phelan, Jason R. Pinner, Sulekha Rajagopalan, Matthew Regan, Jonathan Rodgers, Miriam Rodrigues, Richard H. Roxburgh, Rani Sachdev, Tony Roscioli, Ruvishani Samarasekera, Sarah A. Sandaradura, Elena Savva, Tim Schindler, Margit Shah, Ingrid B. Sinnerbrink, Janine M. Smith, Richard J. Smith, Amanda Springer, Zornitza Stark, Samuel P. Strom, Carolyn M. Sue, Kenneth Tan, Tiong Y. Tan, Esther Tantsis, Michel C. Tchan, Bryony A. Thompson, Alison H. Trainer, Karin van Spaendonck-Zwarts, Rebecca Walsh, Linda Warwick, Stephanie White, Susan M. White, Mark G. Williams, Meredith J. Wilson, Wui Kwan Wong, Dale C. Wright, Patrick Yap, Alison Yeung, Helen Young, Kristi J. Jones, Bruce Bennetts, Sandra T. Cooper, on behalf of the Australasian Consortium for RNA Diagnostic