High Uptake and Series Completion of COVID-19 Vaccine at Community-Based Vaccination for Latinos With Limited English Proficiency.

BACKGROUND: Despite the disproportionate impact of COVID-19 on Latinos, there were disparities in vaccination, especially during the early phase of COVID-19 immunization rollout. METHODS: Leveraging a community-academic partnership established to expand access to SARS-CoV2 testing, we implemented community vaccination clinics with multifaceted outreach strategies and flexible appointments for limited English proficiency Latinos. RESULTS: Between February 26 and May 7 2021, 2250 individuals received the first dose of COVID-19 vaccination during 18 free community events. Among them, 92.4% (95% confidence interval [CI], 91.2%-93.4%) self-identified as Hispanic, 88.7% (95% CI, 87.2%-89.9%) were limited English proficiency Spanish speakers, 23.1% (95% CI, 20.9%-25.2%) reported prior COVID-19 infection, 19.4% (95% CI, 16.9%-22.25%) had a body mass index of more than 35, 35.0% (95% CI, 32.2%-37.8%) had cardiovascular disease, and 21.6% (95% CI, 19.2%-24.0%) had diabetes. The timely second-dose completion rate was high (98.7%; 95% CI, 97.6%-99.2%) and did not vary by outreach method. CONCLUSION: A free community-based vaccination initiative expanded access for Latinos with limited English proficiency at high risk for COVID-19 during the early phase of the immunization program in the US.

Interclass GPCR heteromerization affects localization and trafficking.

Membrane trafficking processes regulate G protein-coupled receptor (GPCR) activity. Although class A GPCRs are capable of activating G proteins in a monomeric form, they can also potentially assemble into functional GPCR heteromers. Here, we showed that the class A serotonin 5-HT2A receptors (5-HT2ARs) affected the localization and trafficking of class C metabotropic glutamate receptor 2 (mGluR2) through a mechanism that required their assembly as heteromers in mammalian cells. In the absence of agonists, 5-HT2AR was primarily localized within intracellular compartments, and coexpression of 5-HT2AR with mGluR2 increased the intracellular distribution of the otherwise plasma membrane-localized mGluR2. Agonists for either 5-HT2AR or mGluR2 differentially affected trafficking through Rab5-positive endosomes in cells expressing each component of the 5-HT2AR-mGluR2 heterocomplex alone, or together. In addition, overnight pharmacological 5-HT2AR blockade with clozapine, but not with M100907, decreased mGluR2 density through a mechanism that involved heteromerization between 5-HT2AR and mGluR2. Using TAT-tagged peptides and chimeric constructs that are unable to form the interclass 5-HT2AR-mGluR2 complex, we demonstrated that heteromerization was necessary for the 5-HT2AR-dependent effects on mGluR2 subcellular distribution. The expression of 5-HT2AR also augmented intracellular localization of mGluR2 in mouse frontal cortex pyramidal neurons. Together, our data suggest that GPCR heteromerization may itself represent a mechanism of receptor trafficking and sorting.

Site-Specific Incorporation of Genetically Encoded Photo-Crosslinkers Locates the Heteromeric Interface of a GPCR Complex in Living Cells.

G protein-coupled receptors (GPCRs) are critical mediators of cell signaling. Although capable of activating G proteins in a monomeric form, numerous studies reveal a possible association of class A GPCRs into dimers/oligomers. The relative location of individual protomers within these GPCR complexes remains a topic of intense debate. We previously reported that class A serotonin 5-HT2A receptor (5-HT2AR) and class C metabotropic glutamate 2 receptor (mGluR2) are able to form a GPCR heterocomplex. By introducing the photoactivatable unnatural amino acid p-azido-L-phenylalanine (azF) at selected individual positions along the transmembrane (TM) segments of mGluR2, we delineate the residues that physically interact at the heteromeric interface of the 5-HT2AR-mGluR2 complex. We show that 5-HT2AR crosslinked with azF incorporated at the intracellular end of mGluR2's TM4, while no crosslinking was observed at other positions along TM1 and TM4. Together, these findings provide important insights into the structural arrangement of the 5-HT2AR-mGluR2 complex.

Fully automated head-twitch detection system for the study of 5-HT2A receptor pharmacology in vivo.

Head-twitch behavior (HTR) is the behavioral signature of psychedelic drugs upon stimulation of the serotonin 5-HT2A receptor (5-HT2AR) in rodents. Following the previous report of a semi-automated detection of HTR based on the dynamics of mouse's head movement, here we present a system for the identification of individual HTR events in a fully automated fashion. The validity of this fully automated HTR detection system was tested with the psychedelic drug DOI in 5-HT2AR-KO mice, and via evaluation of potential sources of false-positive and false-negative HTR events. The increased throughput in data processing achieved via automation afforded the possibility of conducting otherwise time consuming HTR time-course studies. To further assess the versatility of our system, we also explored the pharmacological interactions between 5-HT2AR and the metabotropic glutamate receptor 2 (mGluR2). Our data demonstrate the potentiation effect of the mGluR2/3 antagonist LY341495 on DOI-induced HTR, as well as the HTR-blocking effect of the mGluR2/3 agonist and antipsychotic drug in development LY404039. This fully automated system can contribute to speed up our understanding of 5-HT2AR's pharmacology and its characteristic behavioral outputs in rodents.

Role of mGlu2 in the 5-HT2A receptor-dependent antipsychotic activity of clozapine in mice.

BACKGROUND: Serotonin 5-HT2A and metabotropic glutamate 2 (mGlu2) are neurotransmitter G protein-coupled receptors (GPCRs) involved in the signaling mechanisms underlying psychosis and schizophrenia treatment. Previous findings in mGlu2 knockout (KO) mice suggested that mGlu2 is necessary for head-twitch behavior, a rodent phenotype characteristic of hallucinogenic 5-HT2A receptor agonists. However, the role of mGlu2 in the behavioral effects induced by antipsychotic drugs remains poorly understood. Here, we tested antipsychotic-like behavioral phenotypes induced by the atypical antipsychotic clozapine in mGlu2-KO mice and wild-type control littermates. METHODS: Locomotor activity was tested in mGlu2-KO mice and control littermates injected (i.p.) with clozapine (1.5 mg/kg) or vehicle followed by MK801 (0.5 mg/kg), PCP (7.5 mg/kg), amphetamine (6 mg/kg), scopolamine (2 mg/kg), or vehicle. Using a virally (HSV) mediated transgene expression approach, the role of frontal cortex mGlu2 in the modulation of MK801-induced locomotor activity by clozapine treatment was also evaluated. RESULTS: The effect of clozapine on hyperlocomotor activity induced by the dissociative drugs MK801 and phencyclidine (PCP) was decreased in mGlu2-KO mice as compared to controls. Clozapine treatment, however, reduced hyperlocomotor activity induced by the stimulant drug amphetamine and the deliriant drug scopolamine in both wild-type and mGlu2-KO mice. Virally mediated over-expression of mGlu2 in the frontal cortex of mGlu2-KO mice rescued the ability of clozapine to reduce MK801-induced hyperlocomotion. CONCLUSION: These findings further support the existence of a functionally relevant crosstalk between 5-HT2A and mGlu2 receptors in different preclinical models of antipsychotic activity.