Positive allosteric modulation as a potential therapeutic strategy in anti-NMDA receptor encephalitis

N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors important for synaptic plasticity, memory, and neuropsychiatric health. NMDAR hypofunction contributes to multiple disorders, including anti-NMDAR encephalitis (NMDARE), an autoimmune disease of the CNS associated with GluN1 antibody-mediated NMDAR internalization. Here we characterize the functional/pharmacological consequences of exposure to CSF from female human NMDARE patients on NMDAR function, and we characterize the effects of intervention with recently described positive allosteric modulators (PAMs) of NMDARs. Incubation (48 h) of rat hippocampal neurons of both sexes in confirmed NMDARE patient CSF, but not control CSF, attenuated NMDA-induced current. Residual NMDAR function was characterized by lack of change in channel open probability, indiscriminate loss of synaptic and extrasynaptic NMDARs, and indiscriminate loss of GluN2B-containing and GluN2B-lacking NMDARs. NMDARs tagged with N-terminal pHluorin fluorescence demonstrated loss of surface receptors. Thus, function of residual NMDARs following CSF exposure was indistinguishable from baseline, and deficits appear wholly accounted for by receptor loss. Coapplication of CSF and PAMs of NMDARs (SGE-301 or SGE-550, oxysterol-mimetic) for 24 h restored NMDAR function following 24 h incubation in patient CSF. Curiously, restoration of NMDAR function was observed despite washout of PAMs before electrophysiological recordings. Subsequent experiments suggested that residual allosteric potentiation of NMDAR function explained the persistent rescue. Further studies of the pathogenesis of NMDARE and intervention with PAMs may inform new treatments for NMDARE and other disorders associated with NMDAR hypofunction.SIGNIFICANCE STATEMENTAnti-N-methyl-d-aspartate receptor encephalitis (NMDARE) is increasingly recognized as an important cause of sudden-onset psychosis and other neuropsychiatric symptoms. Current treatment leaves unmet medical need. Here we demonstrate cellular evidence that newly identified positive allosteric modulators of NMDAR function may be a viable therapeutic strategy.</jats:p

The Ursinus Weekly, February 13, 1978

Ursinus news in brief: Two named to raise funds; Killer pot suspected; Anti-white bias charged; College tax break rift; Male, married, healthy • History 101 exam: Investigation continues, two to five suspected • Task force presents preliminary results • Comment • Letters to the editor • Time and testing • Spend Summer in Spain • Students attend New York play • A Painstaking approach • Casino night • As you like it is coming • Kiss: A Musical (?) Extravaganza • More negative comments • Henry\u27s drama group attends grade school • Erroneous zones • Ursinus basketball playoff bound? • Women\u27s b-ball • Censorship • Bad news Bearacudashttps://digitalcommons.ursinus.edu/weekly/1081/thumbnail.jp

Community analysis of dental plaque and endotracheal tube biofilms from mechanically ventilated patients

© 2017 Elsevier Inc. Purpose Mechanically ventilated patients are at risk for developing ventilator-associated pneumonia, and it has been reported that dental plaque provides a reservoir of respiratory pathogens that may aspirate to the lungs and endotracheal tube (ETT) biofilms. For the first time, metataxonomics was used to simultaneously characterize the microbiome of dental plaque, ETTs, and non-directed bronchial lavages (NBLs) in mechanically ventilated patients to determine similarities in respective microbial communities and therefore likely associations. Material and methods Bacterial 16S rRNA gene sequences from 34 samples of dental plaque, NBLs, and ETTs from 12 adult mechanically ventilated patients were analyzed. Results No significant differences in the microbial communities of these samples were evident. Detected bacteria were primarily oral species (e.g., Fusobacterium nucleatum, Streptococcus salivarius, Prevotella melaninogenica) with respiratory pathogens (Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumoniae, and Haemophilus influenzae) also in high abundance. Conclusion The high similarity between the microbiomes of dental plaque, NBLs, and ETTs suggests that the oral cavity is indeed an important site involved in microbial aspiration to the lower airway and ETT. As such, maintenance of good oral hygiene is likely to be highly important in limiting aspiration of bacteria in this vulnerable patient group

Increased Oxidative Stress in Injured and Ill Elite International Olympic Rowers

Identifying strategies that reduce the risk of illness and injury is an objective of sports science and medicine teams. No studies have examined the relationship between oxidative stress (OS) and illness or injury in international athletes undergoing periods of intensified training and competition. Purpose: We aimed to identify relationships between illness, injury and OS. Methods: A longitudinal, observational study of elite male rowers (n=10) was conducted over 18-weeks leading into World Championships. Following a recovery day and a 12-hour fast, hydroperoxides (FORT) and total anti-oxidant capacity (FORD) were measured in venous blood, with the ratio calculated as the oxidative stress index (OSI). At all study time points, athletes were independently dichotomized as ill or not ill, injured or not injured. OS data were compared between groups using independent t-tests. A Cox proportional hazard model was used to assess the association of OS with injury and illness while adjusting for age and body mass index. Results: FORD was lower (p<0.02) and OSI was higher (p<0.001) with illness than without illness. FORT and OSI were higher with injury than without injury (p<0.001). FORD exerts a protective effect on illness with 0.5 mmol•L-1 increase related to a 30.6% illness risk reduction (p=0.014), and OSI exerts a harmful effect on illness risk with a 0.5 unit increase in OSI related to an 11.3% increased risk (p=0.036). Conclusion: OS is increased in injured and ill athletes. Monitoring OS may be advantageous in assessing recovery from, and in reducing injury and illness risk given the association

Resilience in Virginia: Outlook 2021

VCPC\u27s October webinar included an update on Virginia’s participation in the Regional Greenhouse Gas Initiative and the implementation of Executive Order 24; remarks from the Speaker of the House of Delegates, Eileen Filler -Corn, and a legislative panel discussed resilience issues for the upcoming 2021 Virginia General Assembly session. VCPC was honored to host Governor Ralph Northam for Closing Remarks

Resilience in Virginia: Outlook 2021

VCPC\u27s October webinar included an update on Virginia’s participation in the Regional Greenhouse Gas Initiative and the implementation of Executive Order 24; remarks from the Speaker of the House of Delegates, Eileen Filler -Corn, and a legislative panel discussed resilience issues for the upcoming 2021 Virginia General Assembly session. VCPC was honored to host Governor Ralph Northam for Closing Remarks

Microbial profiling of dental plaque from mechanically ventilated patients

© 2015 The Authors. Micro-organisms isolated from the oral cavity may translocate to the lower airways during mechanical ventilation (MV) leading to ventilator-associated pneumonia (VAP). Changes within the dental plaque microbiome during MV have been documented previously, primarily using culture-based techniques. The aim of this study was to use community profiling by high throughput sequencing to comprehensively analyse suggested microbial changes within dental plaque during MV. Bacterial 16S rDNA gene sequences were obtained from 38 samples of dental plaque sampled from 13 mechanically ventilated patients and sequenced using the Illumina platform. Sequences were processed using Mothur, applying a 97 % gene similarity cut-off for bacterial species level identifications. A significant ‘microbial shift’ occurred in the microbial community of dental plaque during MV for nine out of 13 patients. Following extubation, or removal of the endotracheal tube that facilitates ventilation, sampling revealed a decrease in the relative abundance of potential respiratory pathogens and a compositional change towards a more predominantly (in terms of abundance) oral microbiota including Prevotella spp., and streptococci. The results highlight the need to better understand microbial shifts in the oral microbiome in the development of strategies to reduce VAP, and may have implications for the development of other forms of pneumonia such as community-acquired infection

The Ursinus Weekly, April 28, 1977

Ursinus news in brief: Mattress team takes second; Chemistry delegates tapped; Cub & Key chooses officers; Classes elect officers; Economics Club elects officers; Library announces new hours; Pre-legal Society elections held • SFARC discusses Weekly • Meal popularity surveyed • GRE revised • Food service names liaison • Comment: After orientation, what then? • Curriculum review urged • Letters to the editor • Musical gobs • Perfection personified • Movie attack: Airport 77 • Band holds concert • Presidential memo • Weekly special: Fidel interested in assassination probe • Songfest \u2777 • Faculty promotions announced • More on food • Sum. Eve. School • Baseball team excites fans • Lacrosse undefeated • Tennis times • Women\u27s tennis • Amateur boxing • Track • Golf • Correction • Mexico triphttps://digitalcommons.ursinus.edu/weekly/1070/thumbnail.jp

Managing for ocean biodiversity to sustain marine ecosystem services

Managing a complex ecosystem to balance delivery of all of its services is at the heart of ecosystem-based management. But how can this balance be accomplished amidst the conflicting demands of stakeholders, managers, and policy makers? In marine ecosystems, several common ecological mechanisms link biodiversity to ecosystem functioning and to a complex of essential services. As a result, the effects of preserving diversity can be broadly beneficial to a wide spectrum of important ecosystem processes and services, including fisheries, water quality, recreation, and shoreline protection. A management system that conserves diversity will help to accrue more “ecoservice capital” for human use and will maintain a hedge against unanticipated ecosystem changes from natural or anthropogenic causes. Although maintenance of biodiversity cannot be the only goal for ecosystem-based management, it could provide a common currency for evaluating the impacts of different human activities on ecosystem functioning and can act as a critical indicator of ecosystem status