De novo GRIN variants in M3 helix associated with neurological disorders control channel gating of NMDA receptor.

N-methyl-D-aspartate receptors (NMDARs) are members of the glutamate receptor family and participate in excitatory postsynaptic transmission throughout the central nervous system. Genetic variants in GRIN genes encoding NMDAR subunits are associated with a spectrum of neurological disorders. The M3 transmembrane helices of the NMDAR couple directly to the agonist-binding domains and form a helical bundle crossing in the closed receptors that occludes the pore. The M3 functions as a transduction element whose conformational change couples ligand binding to opening of an ion conducting pore. In this study, we report the functional consequences of 48 de novo missense variants in GRIN1, GRIN2A, and GRIN2B that alter residues in the M3 transmembrane helix. These de novo variants were identified in children with neurological and neuropsychiatric disorders including epilepsy, developmental delay, intellectual disability, hypotonia and attention deficit hyperactivity disorder. All 48 variants in M3 for which comprehensive testing was completed produce a gain-of-function (28/48) compared to loss-of-function (9/48); 11 variants had an indeterminant phenotype. This supports the idea that a key structural feature of the M3 gate exists to stabilize the closed state so that agonist binding can drive channel opening. Given that most M3 variants enhance channel gating, we assessed the potency of FDA-approved NMDAR channel blockers on these variant receptors. These data provide new insight into the structure-function relationship of the NMDAR gate, and suggest that variants within the M3 transmembrane helix produce a gain-of-function.

The SelfSTarT intervention for low back pain patients presenting to first contact physiotherapists: A mixed methods service evaluation.

INTRODUCTION: Globally, back pain is the leading cause of years of disability. In the United Kingdom, over 20 million people live with musculoskeletal (MSK) pain, with low back pain being one of the most common causes. National strategies promote self-management and the use of digital technologies to empower populations. AIMS: To evaluate the uptake and impact of providing the SelfSTart approach (STarT Back and SelfBACK App) when delivered by a First Contact Physiotherapist (FCP) to people presenting with low back pain in primary care. METHODS: Patients presenting with a new episode of low back pain underwent routine assessment and completion of a STarT Back questionnaire. Patients with low/medium scores were offered the SelfBACK App. A control population was provided by the MIDAS-GP study. Patient Experience, outcome measures, healthcare utilisation and retention were captured through the app and clinical systems (EMIS). Interviews with five FCPs explored the experiences of using the SelfSTart approach. RESULTS: SelfSTarT was taken up by almost half (48%) of those to whom it was offered. Compared to MIDAS-GP, users were more likely to be younger, male, in work, and with higher health literacy. SelfSTarT users reported significant improved experiences relating to receiving an agreed care plan and receiving sufficient information. There were no significant differences in treatments offered. FCPs were positive about the app and felt it had value but wanted feedback on patient progress. They recognised that a digital solution would not be suitable for all. CONCLUSION: This approach offers an opportunity to empower and support self-management, using robustly evaluated digital technology.

Type specimens on deposit in the United States department of agriculture nematode collection, beltsville, Maryland.

A list of the deposited type specimens with references, a detailed historical background, importance, and maintenance procedures are given for the type collection of the United States Department of Agriculture Nematode Collection (USDANC). The type specimen section is considered one of the largest and most valuable in existence. It contains 1,430 species mounted and preserved on 5,177 metal and glass slides and 404 vials. Also, a brief description of the other constituent divisions of the collection is given, which, including the type collection, consists of 34,000 permanent slides and vials and 19,500 species entries. The list of deposited types is a type specimen location reference only and should not be used for the status of type species. The generic and specific names are arranged in alphabetical order and are given as indicated by the author(s) or depositor(s) when the types were deposited in the type section of the USDANC. The complete title of the reference is not given for each species, only the author's date, and source and slide number(s). Also, included are authors of designated types other than those of the original type series, e.g. paralectotype, allolectotype, neotype.