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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.

Over the last 12-months during the pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the Centers for Disease Control and Prevention (CDC) have issued public health instructions with the hope of mitigating the spread of the virus. Through existing relationships established by an academic hospital, we established weekly community conference calls to disseminate such critical information on the pandemic and allow community leaders to discuss struggles and successes. From these calls, we were able to collaborate in a more intimate manner with faith-based organizations, whereby we emphasized and planned the role they could undertake during the pandemic. Such emphasis was made between our medical institution and various faith-based organizations through meetings titled "Congregational COVID-19 Conversations." Over the past 12-months, we held virtual meetings with 38 faith-based organizations: 15 Christian congregations, 21 Jewish synagogues, and 2 Islamic masjids. We describe in detail in this report a narrative summary of the meetings. From these meetings, we discussed several COVID-19-related themes that included how to have their place of worship disseminate public health messaging, aid in preparing buildings for public worship, and insight into preparing their regions for aid in both COVID-19 testing and for potential SARS-CoV-2 vaccine sites. This medical-religious partnership has proven feasible and valuable during the pandemic and warrants emphasis in that it has the potential to serve a vital role in mitigating COVID-19-related disparities in certain communities, as well as potentially ending the COVID-19 pandemic completely., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Latinxs have been disproportionately impacted by COVID-19. Latinx immigrants, in particular, face significant barriers to SARS-CoV-2 testing, including lack of insurance, language barriers, stigma, work conflicts, and limited transportation., Methods: In response to a disproportionately high SARS-CoV-2 positivity rate among Latinxs at the Johns Hopkins Health System, investigators implemented free community-based testing by partnering with religious leaders and leveraging the skill of trusted community health workers. Data were extracted from the electronic health record and a Research Electronic Data Capture database. SARS-CoV-2 positivity was evaluated per event stratified by race/ethnicity. Total rates of SARS-CoV-2 positivity and categorical patient characteristics were compared between groups using chi-square tests., Results: Between June 25, 2020 and October 15, 2020, a total of 1,786 patients (57.5% Latinx, 31.2% non-Hispanic White, 5.9% non-Hispanic Black, and 5.3% non-Hispanic other) were tested for SARS-CoV-2 in 18 testing events. Among them, 355 (19.9%) tested positive. The positivity rate was 31.5% for Latinxs, 7.6% for non-Hispanic Blacks, 3.4% for non-Hispanic Whites, and 5.3% for patients of other races/ethnicities. Compared with Latinxs who tested negative, Latinxs who tested positive were more likely to report Spanish as their preferred language (91.6% vs 81.7%, p<0.001), be younger (30.4 vs 33.4 years, p<0.008), and have a larger household size (4.8 vs 4.3 members, p<0.002)., Conclusions: Community-based testing identified high levels of ongoing SARS-CoV-2 transmission among primarily Latinxs with limited English proficiency. During this period, the overall positivity rate at this community testing site was almost 10 times higher among Latinxs than among non-Hispanic Whites., (Copyright © 2021. Published by Elsevier Inc.)

During the pandemic caused by the severe acute respiratory syndrome coronavirus-2, public health instructions were issued with the hope of curbing the virus' spread. In an effort to assure accordance with these instructions, equitable strategies for at-risk and vulnerable populations and communities are warranted. One such strategy was our community conference calls, implemented to disseminate information on the pandemic and allow community leaders to discuss struggles and successes. Over the first 6 weeks, we held 12 calls, averaging 125 (standard deviation 41) participants. Participants were primarily from congregations and faith-based organizations that had an established relationship with the hospital, but also included school leaders, elected officials, and representatives of housing associations. Issues discussed included reasons for quarantining, mental health, social isolation, health disparities, and ethical concerns regarding hospital resources. Concerns identified by the community leaders as barriers to effective quarantining and adherence to precautions included food access, housing density, and access to screening and testing. Through the calls, ways to solve such challenges were addressed, with novel strategies and resources reaching the community. This medical-religious resource has proven feasible and valuable during the pandemic and warrants discussions on reproducing it for other communities during this and future infectious disease outbreaks.

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.)

This study focused on the association between type of community health interventions and lay health educator variables. Lay health educators are volunteers from local faith communities who complete a healthcare training program, taught by physicians in-training. Lay health educators are instructed to implement health-related initiatives in their respective communities after graduation. Of the 72 graduates since 2011, we surveyed 55 lay health educators to gain insight into their involvement with their congregation and the type of health projects they have implemented. We dichotomized the health projects into "raising awareness" and "teaching new health skills." Using adjusted logistic regression models, variables associated with implementing health projects aimed at teaching health skills included length of time as a member of their congregation, current employment, and age. These results may help future programs prepare lay health community educators for the type of health interventions they intend to implement in their respective communities.

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.)

As the older adult population continues to grow, the prevalence of chronic diseases is also increasing, leading to the need for novel ways of managing this large population of patients. One solution is to focus on informal caregivers. These informal caregivers already make a substantial contribution to our nation's healthcare finances and patient health outcomes. Caregivers also derive benefits from caring for their family member or friend; however, it is not uncommon for these individuals to experience negative health consequences, or what is often called "burden of care." Those called to care are not without their own burdens, and they must frequently make significant lifestyle adjustments that impact their own health. Therefore, for caregivers to be effective, caring for the caregivers must be a focus of medicine in the twenty-first century.

Religious institutions are in regular contact with people who need education about and support with health issues. Creating lay health educators to serve in these communities can promote health initiatives centered on education and accessing resources. This paper is a prospective observational report of the impact of trained lay health community congregation members in two faith communities based on an urban setting. We describe health efforts made in an African-American Methodist church and in a Latino Spanish-speaking Catholic church. We review the intricacies in establishing trust with the community, the training of lay health educators, and the implementation strategies and outcomes of health initiatives for these communities.

The current study sought to explore the measurement invariance of the SATAQ-3 across gender using a single mixed gender sample consisting of 122 men and 268 women. Participants' age ranged from 18 to 36 years (M=19.6, SD=1.9). Preliminary results indicate that the 28 item scale was a poor fit for either gender in the current sample. Reverse scored items were deleted as they formed a unique method factor with low factor loadings. The resulting 21 items were a good fit to the hypothesized four factor model for both males and females and established evidence of both strict factorial invariance and population heterogeneity across groups. Coefficient alpha estimates of internal consistency reliability ranged from .79 to .94. These findings support use of the SATAQ-3 in mixed gender samples and validate previous research that reported analysis of gender-based mean differences., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Purpose: This article reports on the interest within the religious community in a medical-religious partnership model designed to address some of the health challenges communities face as the population continues to age and become more diverse., Design and Methods: A geographically and religiously diverse group of 183 clergy who were attending a continuing education program on theology and preaching were invited to complete a 16-item survey asking about their interest in working with hospitals to offer health-related programs and activities in their congregations. Another sample, this one consisting of 524 individuals from a religiously diverse group of congregations in Florida, was also asked about their interest in having health programs offered in their congregations., Results: Of the 54% of clergy who completed the surveys, 72% said it was "very important" and 28% said it was "somewhat important" to actively address the health needs of their congregations. Support for specific programs was also strong, with at least 80% reporting it was very likely they would support screenings, preventive interventions, and health-related classes in their congregations. Strong support was also found among the laity surveyed, with 85% expressing interest in faith-based health programs and 45% reporting they would be interested in helping organize and promote such programs., Implications: Health care systems and other organizations interested in addressing health needs of older adults can look to religious institutions for assistance in providing the information and support patients and family members need to prevent or minimize the impact of chronic illnesses.

Some investigators have found higher levels of distress in late adulthood, but others have reported no differences between younger and older adults or even lower levels of distress in their older samples. In the present investigation, a sample of adults who had attended the same university and ranged in age from 22 to 86 were asked to complete the Brief Symptom Inventory. Subjects were divided into four age cohorts, and analyses were conducted to determine age-related differences in the reporting of symptomatology. Older adults were more likely than younger adults to report symptoms that reflected distress over physical ailments and memory problems, but young adults were more likely to report symptoms of a primarily psychological nature.

The Generalized Expectancy for Success Scale (GESS; Fibel & Hale, 1978) was revised and assessed for reliability and validity. The revised version was administered to 199 college students along with other conceptually related measures, including the Rosenberg Self-Esteem Scale, the Life Orientation Test, and Rotter's Internal-External Locus of Control Scale. One subsample of students also completed the Eysenck Personality Inventory, while another subsample performed a criterion-related task that involved risk taking. Item analysis yielded 25 items with correlations of .45 or higher with the total score. Results indicated high internal consistency and test-retest reliability.

Administered to 106 married male and female residents of a retirement community the Brief Symptom Inventory (BSI) form of the SCL-90. Although no difference was found between males and females on an overall index of psychological distress, a discriminant function analysis indicated that three (Anxiety, Interpersonal Sensitivity, and Paranoid Ideation) of the nine scales provided maximum separation of the two groups. Results supported the conclusion that with marital status, education, and health controlled, male and female elderly Ss show distinct patterns of distress.

Investigated the relationship between numerous age-related stresses and depression in the elderly. Sixty-eight residents of a retirement center completed a questionnaire that assessed depression and a wide range of possible losses or stresses. Depression was found to be related to poorer financial status, fewer and less satisfying interpersonal relationships, poorer physical health and greater concerns about death for women and to poorer physical health and lack of involvement in activities for men.

The Brief Symptom Inventory was administered to 204 female and 143 male students at a 4-year college. Their mean scores on the nine primary symptom dimensions were compared with means of a normative sample of older adults and younger adolescents. The results indicated that college students reported significantly higher levels of distress than did the adult sample and that they showed a different pattern of distress than the younger adolescents. It was suggested that counselors and clinicians may wish to use college level norms when they are using the Brief Symptom Inventory with college students.

A relationship between locus of control and adjustment has been found in many studies of young adults, with externals generally reporting higher levels of psychological distress. However, studies of locus of control and adjustment in the aged have produced conflicting results. This investigation examined the relationship between locus of control and self-reported psychopathology in a sample of 139 residents of a retirement complex. Correlation coefficients were computed for locus of control and each of the nine symptom dimensions of the Brief Symptom Inventory. These analyses were carried out separately for males and for females to determine if locus of control orientation was associated with adjustment for both males and females. Results indicate that locus of control is correlated with self-reported psychopathology for older women but not for older men. These results and those of related investigations are discussed within the context of Rotter's social learning theory.