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Excitatory neurotransmission is principally mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-subtype ionotropic glutamate receptors (AMPARs). Negative allosteric modulators are therapeutic candidates that inhibit AMPAR activation and can compete with positive modulators to control AMPAR function through unresolved mechanisms. Here we show that allosteric inhibition pushes AMPARs into a distinct state that prevents both activation and positive allosteric modulation. We used cryo-electron microscopy to capture AMPARs bound to glutamate, while a negative allosteric modulator, GYKI-52466, and positive allosteric modulator, cyclothiazide, compete for control of the AMPARs. GYKI-52466 binds in the ion channel collar and inhibits AMPARs by decoupling the ligand-binding domains from the ion channel. The rearrangement of the ligand-binding domains ruptures the cyclothiazide site, preventing positive modulation. Our data provide a framework for understanding allostery of AMPARs and for rational design of therapeutics targeting AMPARs in neurological diseases., (© 2024. The Author(s).)

Cardiac deaths account for the largest share of on-duty firefighter deaths. To help ensure duty fitness and minimize injury risk, many fire departments require the passing of an annual physical ability test, consisting of a battery of simulated fire suppression activities (sFSAs). The purpose of the study was to determine the relationship of sFSA performance to acute cardiac and respiratory events (ACREs) and the effect that estimated VO 2 max has on sFSA performance. The study was retrospective. As part of an annual physical ability test, five timed sFSAs were performed, summed for a composite time, and categorized into three performance levels (fast, moderate, and slow). Estimated VO 2 max was determined using the Forestry Step Test. A significant ( p = 0.023) linear trend was observed with higher sFSA performance times being associated with a higher proportion of firefighters going on to suffer an ACRE. The estimated VO 2 max was significantly ( p < 0.001) higher in the fast group compared to the slow group. There was not a significant ( p = 0.70) difference in estimated VO 2 max between the moderate and slow groups. Estimated VO 2 max performance and sFSA performance were significantly correlated, with r s (488) = -0.272 and p < 0.001. Poorer sFSA performance was found to be associated with a higher proportion of ACREs. The results suggest that sFSA performance may be a valid indicator of ACRE injury risk and aerobic capacity.

In multicellular organisms, cell-adhesion molecules connect cells into tissues and mediate intercellular signaling between these cells. In vertebrate brains, synaptic cell-adhesion molecules (SAMs) guide the formation, specification, and plasticity of synapses. Some SAMs, when overexpressed in cultured neurons or in heterologous cells co-cultured with neurons, drive formation of synaptic specializations onto the overexpressing cells. However, genetic deletion of the same SAMs from neurons often has no effect on synapse numbers, but frequently severely impairs synaptic transmission, suggesting that most SAMs control the function and plasticity of synapses (i.e., organize synapses) instead of driving their initial establishment (i.e., make synapses). Since few SAMs were identified that mediate initial synapse formation, it is difficult to develop methods that enable experimental control of synaptic connections by targeted expression of these SAMs. To overcome this difficulty, we engineered novel SAMs from bacterial proteins with no eukaryotic homologues that drive synapse formation. We named these engineered adhesion proteins "Barnoligin" and "Starexin" because they were assembled from parts of Barnase and Neuroligin-1 or of Barstar and Neurexin3β, respectively. Barnoligin and Starexin robustly induce the formation of synaptic specializations in a specific and directional manner in cultured neurons. Synapse formation by Barnoligin and Starexin requires both their extracellular Barnase- and Barstar-derived interaction domains and their Neuroligin- and Neurexin-derived intracellular signaling domains. Our findings support a model of synapse formation whereby trans-synaptic interactions by SAMs drive synapse organization via adhesive interactions that activate signaling cascades.

Rehospitalizations in the Medicare population may be influenced by many diverse social factors, such as, but not limited to, access to food, social isolation, and housing safety. Rehospitalizations result in significant cost in this population, with an expected increase as Medicare enrollment grows. We designed a pilot study based upon a partnership between a hospital and a local Meals on Wheels agency to support patients following an incident hospitalization to assess impact on hospital utilization. Patients from an urban medical center who were 60 years or older, had a prior hospitalization in the past 12 months, and had a diagnosis of diabetes, hypertension, heart failure, and/or chronic obstructive pulmonary disease were recruited. Meals on Wheels provided interventions over 3 months of the patient's transition to home: food delivery, home safety inspection, social engagement, and medical supply allocation. Primary outcome was reduction of hospital expenditure. In regard to the results, 84 participants were included in the pilot cohort, with the majority (54) having COPD. Mean age was 74.9 ± 10.5 years; 33 (39.3%) were female; 62 (73.8%) resided in extreme socioeconomically disadvantaged neighborhoods. Total hospital expenditures while the cohort was enrolled in the transition program were $435,258 ± 113,423, a decrease as compared to $1,445,637 ± 325,433 ( p < 0.01) of the cohort's cost during the three months prior to enrollment. In conclusion, the initiative for patients with advanced chronic diseases resulted in a significant reduction of hospitalization expenditures. Further investigations are necessary to define the impact of this intervention on a larger cohort of patients as well as its generalizability across diverse geographic regions.

Sex differences and heavy load carriage may contribute to the high rate of musculoskeletal injury in military recruits, particularly within the female population. Thus, the purposes of this study were to determine if load influenced landing quality differently in females compared to males and if load carried per kg body mass was associated to quality of landing. Twenty-eight participants were recruited for this study (males: n = 14; females: n = 14). Participants were grouped by sex. All twenty-eight participants performed three drop-jumps (DJ) under unloaded and loaded conditions. The loaded condition included a combat helmet, tactical vest, and rucksack (22 kg). Two cameras recorded in the frontal and sagittal directions during the three DJ trials. DJ trials were scored using the LESS. There was no significant difference in LESS difference scores between males and females, t(26) = -1.014, p = 0.320, 95% CI = -2.01 to 0.68. Load carried per kg body mass ( r s = 0.401, p = 0.034) was significantly correlated to LESS rank order. The results suggest load does not significantly alter landing quality as measured by the LESS. However, participant body mass and load per kg of body may play a role in a person's ability to adapt to heavy loads.

Neuroligins, postsynaptic cell adhesion molecules that are linked to neuropsychiatric disorders, are extensively studied, but fundamental questions about their functions remain. Using in vivo replacement strategies in quadruple conditional knockout mice of all neuroligins to avoid heterodimerization artifacts, we show, in hippocampal CA1 pyramidal neurons, that neuroligin-1 performs two key functions in excitatory synapses by distinct molecular mechanisms. N-methyl-D-aspartate (NMDA) receptor-dependent LTP requires trans-synaptic binding of postsynaptic neuroligin-1 to presynaptic β-neurexins but not the cytoplasmic sequences of neuroligins. In contrast, postsynaptic NMDA receptor (NMDAR)-mediated responses involve a neurexin-independent mechanism that requires the neuroligin-1 cytoplasmic sequences. Strikingly, deletion of neuroligins blocked the spine expansion associated with LTP, as monitored by two-photon imaging; this block involved a mechanism identical to that of the role of neuroligin-1 in NMDAR-dependent LTP. Our data suggest that neuroligin-1 performs two mechanistically distinct signaling functions and that neurolign-1-mediated trans-synaptic cell adhesion signaling critically regulates LTP., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In human patients, loss-of-function mutations of the postsynaptic cell-adhesion molecule neuroligin-4 were repeatedly identified as monogenetic causes of autism. In mice, neuroligin-4 deletions caused autism-related behavioral impairments and subtle changes in synaptic transmission, and neuroligin-4 was found, at least in part, at glycinergic synapses. However, low expression levels precluded a comprehensive analysis of neuroligin-4 localization, and overexpression of neuroligin-4 puzzlingly impaired excitatory but not inhibitory synaptic function. As a result, the function of neuroligin-4 remains unclear, as does its relation to other neuroligins. To clarify these issues, we systematically examined the function of neuroligin-4, focusing on excitatory and inhibitory inputs to defined projection neurons of the mouse brainstem as central model synapses. We show that loss of neuroligin-4 causes a profound impairment of glycinergic but not glutamatergic synaptic transmission and a decrease in glycinergic synapse numbers. Thus, neuroligin-4 is essential for the organization and/or maintenance of glycinergic synapses., (© 2018 Zhang et al.)

Neuroligins are evolutionarily conserved postsynaptic cell adhesion molecules that interact with presynaptic neurexins. Neurons express multiple neuroligin isoforms that are targeted to specific synapses, but their synaptic functions and mechanistic redundancy are not completely understood. Overexpression or RNAi-mediated knockdown of neuroligins, respectively, causes a dramatic increase or decrease in synapse density, whereas genetic deletions of neuroligins impair synapse function with only minor effects on synapse numbers, raising fundamental questions about the overall physiological role of neuroligins. Here, we have systematically analyzed the effects of conditional genetic deletions of all major neuroligin isoforms (i.e., NL1, NL2, and NL3), either individually or in combinations, in cultured mouse hippocampal and cortical neurons. We found that conditional genetic deletions of neuroligins caused no change or only a small change in synapses numbers, but strongly impaired synapse function. This impairment was isoform specific, suggesting that neuroligins are not functionally redundant. Sparse neuroligin deletions produced phenotypes comparable to those of global deletions, indicating that neuroligins function in a cell-autonomous manner. Mechanistically, neuroligin deletions decreased the synaptic levels of neurotransmitter receptors and had no effect on presynaptic release probabilities. Overexpression of neuroligin-1 in control or neuroligin-deficient neurons increased synaptic transmission and synapse density but not spine numbers, suggesting that these effects reflect a gain-of-function mechanism; whereas overexpression of neuroligin-3, which, like neuroligin-1 is also targeted to excitatory synapses, had no comparable effect. Our data demonstrate that neuroligins are required for the physiological organization of neurotransmitter receptors in postsynaptic specializations and suggest that they do not play a major role in synapse formation. SIGNIFICANCE STATEMENT Human neuroligin genes have been associated with autism, but the cellular functions of different neuroligins and their molecular mechanisms remain incompletely understood. Here, we performed comparative analyses in cultured mouse neurons of all major neuroligin isoforms, either individually or in combinations, using conditional knockouts. We found that neuroligin deletions did not affect synapse numbers but differentially impaired excitatory or inhibitory synaptic functions in an isoform-specific manner. These impairments were due, at least in part, to a decrease in synaptic distribution of neurotransmitter receptors upon deletion of neuroligins. Conversely, the overexpression of neuroligin-1 increased synapse numbers but not spine numbers. Our results suggest that various neuroligin isoforms perform unique postsynaptic functions in organizing synapses but are not essential for synapse formation or maintenance., (Copyright © 2017 the authors 0270-6474/17/376816-21$15.00/0.)