Null method to estimate the maximal PA at subsaturating concentrations of agonist
(2025) The Journal of General Physiology, 157 (1), .
Germann, A.L., Pierce, S.R., Steinbach, J.H., Akk, G.
Department of Anesthesiology, Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, United States
Abstract
The maximal probability of being in an active state (PA,max) is a measure of gating efficacy for a given agonist acting on a given receptor channel. In macroscopic electrophysiological recordings, PA,max is typically estimated by comparing the amplitude of the current response to a saturating concentration of a test agonist to that of a reference agonist with known PA. Here, we describe an approach to estimate the PA,max for low-efficacy agonists at subsaturating concentrations. In this approach, the amplitude of the response to a high-efficacy control agonist applied alone is compared with the amplitude of the response to a control agonist coapplied with the low-efficacy test agonist that binds to the same site(s). If the response to the combination is larger than the response to the control agonist alone, then the PA,max of the test agonist is greater than the PA of the control response. Conversely, if the response to the control agonist is reduced upon exposure to the test agonist, then the PA,max of the test agonist is smaller than the PA of the control response. The exact PA,max of the test agonist can be determined by testing its effect at different concentrations of the control agonist to estimate the PA at which the effect changes direction. The main advantage of this approach lies in the ability to use low, subsaturating concentrations of the test agonist. The model-based predictions are supported by observations from activation of heteromeric and homomeric GABAA receptors by combinations of high- and low-efficacy orthosteric agonists. © 2024 Germann et al.
Document Type: Article
Publication Stage: Final
Source: Scopus
Fatty acid binding protein 7 plays an important modulatory sex-dependent role on brain endocannabinoid levels and THC metabolism
(2024) PLoS ONE, 19 (12), art. no. e0313091, .
Penman, S.L.a , Senetra, A.S.b , Roeder, N.M.a c , Richardson, B.J.a c , Pareek, O.a , Owada, Y.d , Kagawa, Y.d e , Gold, M.S.f , McCurdy, C.R.b g h , Sharma, A.b g , Thanos, P.K.a c
a Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY, United States
b Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, United States
c Department of Psychology, State University of New York at Buffalo, Buffalo, NY, United States
d Department of Organ Anatomy, Graduate School of Medicine, Tohoku University, Aobaku, Sendai, Japan
e The Florey Institute, The University of Melbourne, Parkville, VIC, Australia
f Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
g Translational Drug Development Core, Clinical and Translational Science Institute, University of Florida, Gainesville, FL, United States
h Department of Medicinal Chemistry, University of Florida, Gainesville, FL, United States
Abstract
Fatty acid binding protein 7 (FABP7) is present in the brain, but its interaction with the endocannabinoid system and phytocannabinoids is still not well understood. FABP7 has been proposed as a shuttle protein for trafficking endogenous cannabinoids, as well as an intracellular carrier of THC. In a mouse model of FABP7 global deletion, we used ultra-high performance liquid chromatography- tandem mass spectrometry (UPLC-MS/MS) to measure brain levels of Δ9 tetrahydrocannabinol (THC) as well as its primary metabolite, 11-hydroxy-THC (11-OH-THC), in male and female mice after acute inhalation of THC, compared to wild-type controls. We also measured brain levels of endogenous cannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) both at baseline and after acute THC inhalation. We found that in females, brain concentrations of 11-OH-THC were significantly reduced in FABP7-/- mice compared to FABP7+/+. Additionally, FABP7-/- females had significantly reduced AEA levels and significantly increased 2-AG levels in brain tissue compared to FABP7+/+. Vaporized THC administration had trending, but not significant, impacts on endocannabinoid concentrations in both males and females. Our findings suggest a sex-specific role of FABP7 in the metabolism of THC as well as the regulation of endocannabinoid levels in the brain. © 2024 Penman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding details
National Institutes of HealthNIH
RIAQ0940
Document Type: Article
Publication Stage: Final
Source: Scopus
Human single cell RNA-sequencing reveals a targetable CD8+ exhausted T cell population that maintains mouse low-grade glioma growth
(2024) Nature Communications, 15 (1), art. no. 10312, .
Barakat, R.a , Chatterjee, J.a , Mu, R.a , Qi, X.a , Gu, X.b , Smirnov, I.b , Cobb, O.a , Gao, K.a , Barnes, A.a , Kipnis, J.b , Gutmann, D.H.a
a Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
In solid cancers, T cells typically function as cytotoxic effectors to limit tumor growth, prompting therapies that capitalize upon this antineoplastic property (immune checkpoint inhibition; ICI). Unfortunately, ICI treatments have been largely ineffective for high-grade brain tumors (gliomas; HGGs). Leveraging several single-cell RNA sequencing datasets, we report greater CD8+ exhausted T cells in human pediatric low-grade gliomas (LGGs) relative to adult and pediatric HGGs. Using several preclinical mouse LGG models (Nf1-OPG mice), we show that these PD1+/TIGIT+ CD8+ exhausted T cells are restricted to the tumor tissue, where they express paracrine factors necessary for OPG growth. Importantly, ICI treatments with α-PD1 and α-TIGIT antibodies attenuate Nf1-OPG tumor proliferation through suppression of two cytokine (Ccl4 and TGFβ)-mediated mechanisms, rather than by T cell-mediated cytotoxicity, as well as suppress monocyte-controlled T cell chemotaxis. Collectively, these findings establish a previously unrecognized function for CD8+ exhausted T cells as specialized regulators of LGG maintenance. © The Author(s) 2024.
Funding details
School of Medicine, Washington University in St. LouisWUSM
Alvin J. Siteman Cancer CenterSCC
Office of Research Infrastructure ProgramsORIP, NIH
National Institutes of HealthNIH
National Center for Research ResourcesNCRR
National Cancer InstituteNCICA261939, P30 CA091842
National Cancer InstituteNCI
St. Louis Children’s HospitalSLCHCDI-CORE-2019-813, CDI-CORE-2015-505
St. Louis Children’s HospitalSLCH
National Eye InstituteNEIP30EY002687
National Eye InstituteNEI
Foundation for Barnes-Jewish HospitalFBJH4642, 3770
Foundation for Barnes-Jewish HospitalFBJH
Genome Technology Access CenterGTAC#P30 CA91842
Genome Technology Access CenterGTAC
NIH Office of the DirectorODOD021629
NIH Office of the DirectorOD
Document Type: Article
Publication Stage: Final
Source: Scopus
Exploring the global impact of obesity and diet on dementia burden: the role of national policies and sex differences
(2024) GeroScience, .
Cao, X.a , Peng, H.b , Hu, Z.c , Xu, C.c , Ning, M.c , Zhou, M.d , Mi, Y.e , Yu, P.f , Fazekas-Pongor, V.g , Major, D.g , Ungvari, Z.h i j , Fekete, M.g , Lehoczki, A.g k , Guo, Y.b
a Department of Occupational Health and Environmental Health, School of Public Health, Hebei Key Laboratory of Environment and Human Health, Hebei Medical University, Hebei, Shijiazhuang, China
b Department of Epidemiology and Statistics, School of Public Health, Hebei Key Laboratory of Environment and Human Health, Hebei Medical University, Hebei, Shijiazhuang, China
c Mingde Innovation Class, School of Public Health, Hebei Key Laboratory of Environment and Human Health, Hebei Medical University, Hebei, Shijiazhuang, China
d Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
e Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States
f School of Arts and Science, Washington University in St. Louis, St. Louis, MO, United States
g Institute of Preventive Medicine and Public Health, Semmelweis University, Budapest, Hungary
h Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
i International Training Program in Geroscience, Doctoral College/Institute of Preventive Medicine and Public Health, Semmelweis University, Budapest, Hungary
j Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
k Doctoral College, Health Sciences Program, Semmelweis University, Budapest, Hungary
Abstract
Obesity is a significant modifiable risk factor for dementia. This study aims to quantify the global impact of obesity on dementia burden and examine how national strategies for managing overweight/obesity and dietary factors influence dementia prevalence and mortality, with a focus on sex-specific differences. We used data from the Global Burden of Disease (GBD) and World Health Organization (WHO) to evaluate the association between obesity age-standardized prevalence rate (ASPR) and dementia age-standardized mortality rate (ASMR) and ASPR across 161 countries. A two-step multivariate analysis adjusted for socioeconomic and lifestyle factors was performed. Temporal trends in dementia were analyzed based on the presence of national obesity management strategies and varying dietary scores. A 1% increase in national obesity prevalence was associated with a 0.36% increase in dementia mortality (OR: 1.0036; 95% CI: 1.0028–1.0045) in males and 0.12% in females (OR: 1.0012; 95% CI: 1.0007–1.0018). A 1% increase in national obesity ASPR was associated with an increase in ASPR of dementia by 0.26% for males (OR: 1.0026, 95% CI: 1.0024–1.0028) and 0.05% for females (OR: 1.0005, 95% CI: 1.0004–1.0006). Males exhibited a higher susceptibility to obesity-related dementia. Countries with national obesity management strategies showed a significantly greater reduction in dementia mortality, particularly among females (P = 0.025). Higher dietary scores were associated with a more significant decrease in dementia prevalence across both sexes. Rising obesity prevalence is linked to increased dementia burden globally, with males being more vulnerable to this relationship. National management of overweight/obesity and healthier dietary habits may help mitigate the dementia burden, emphasizing the need for integrated public health interventions. © The Author(s), under exclusive licence to American Aging Association 2024.
Author Keywords
Burden; Dementia; Diet; Obesity; Public health
Funding details
EKÖP-2024–9, 101004093/EUniWell/EAC-A02-2019/EAC-A02-2019–1, ÚNKP-23–3-II-SE-14
Basic and Applied Basic Research Foundation of Guangdong Province2022A1515010957
Basic and Applied Basic Research Foundation of Guangdong Province
National Natural Science Foundation of ChinaNSFC82103727
National Natural Science Foundation of ChinaNSFC
ÚNKP-24–3-II-SE-14
Nemzeti Kutatási, Fejlesztési és Innovaciós AlapNKFIA135784
Nemzeti Kutatási, Fejlesztési és Innovaciós AlapNKFIA
RRF-2.3.1–21–2022–00003
TKP2021-NKTA-47
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
COVID-19 Pandemic-Related Stressors, Distress, and Bodily Pain in Native Americans: Results from the Oklahoma Study of Native American Pain Risk
(2024) Journal of Racial and Ethnic Health Disparities, .
Ventresca, H.M.a , Kell, P.A.a , Toledo, T.A.b , Street, E.N.a , Huber, F.A.c , Hellman, N.M.d , Brown, T.V.a , Vore, C.N.a , Trevino, K.a , Shadlow, J.O.e , Rhudy, J.L.f
a Department of Psychology, The University of Tulsa, Tulsa, OK, United States
b Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, United States
c Department of Anesthesiology, Washington University, St. Louis, MO, United States
d Emory University Veterans Healthcare Program, Atlanta, GA, United States
e Department of Psychology, Oklahoma State University, Tulsa, OK, United States
f Health Promotion Research Center, University of Oklahoma Health Sciences Center, 4502 E. 41St Street, Tulsa, OK, United States
Abstract
The COVID-19 pandemic disproportionately impacted minoritized individuals. This study examined the relationships between pandemic-related stressors/distress and bodily pain in 79 Native American (NA) and 101 non-Hispanic White (NHW) participants from the Oklahoma Study of Native American Pain Risk. Online surveys were administered in May/June 2020 (wave 1), March/April 2021 (wave 2), and Sept/Oct 2021 (wave 3). Pandemic-related stressors (e.g., resource loss and added responsibilities) and distress were assessed from a custom-built questionnaire. Bodily pain was assessed from pain items on the Patient Health Questionnaire-15 (PHQ-15). The results indicate NAs and NHWs reported similar pandemic-related stressors and distress at wave 1, which remained at similar levels across all waves in NHWs. By contrast, stressors and distress increased in NAs at waves 2 and 3. Moreover, bodily pain was higher in NAs than NHWs across all waves. Regression-based multilevel analyses predicting bodily pain found that NHWs with more pandemic-related stressors/distress experienced more bodily pain, but stress/distress did not predict bodily pain in NAs. Findings demonstrated that NAs experienced more bodily pain and pandemic-related stressors/distress than NHWs. However, pandemic-related stressors/distress did not further exacerbate NA pain as observed in NHWs. This implies NAs may have demonstrated resiliency that buffered the pronociceptive effects of pandemic-related stress. © W. Montague Cobb-NMA Health Institute 2024.
Author Keywords
COVID-19 pandemic; Indigenous; Mental health; Native American; Pain; Pandemic stress; Psychology; Stress and pain; Stressors
Funding details
National Institute on Minority Health and Health DisparitiesNIMHD
National Institutes of HealthNIHR01MD007807
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Dementia Risk and Social Determinants of Health Among Adults Racialized as Black: A Community-Based System Dynamics Perspective
(2024) Journal of Racial and Ethnic Health Disparities, .
Trani, J.-F.a b c d , Hart, R.e , Walker, A.I.B.f , Safi, M.a , Singh, R.K.g , Zhu, Y.f g , Babulal, G.M.b g c g
a Brown School of Social Work, Washington University in St. Louis, St. Louis, MO, United States
b Department of Psychology, University of Johannesburg, Johannesburg, South Africa
c Institute of Public Health, Washington University School of Medicine, St. Louis, MO, United States
d National Conservatory of Arts and Crafts, Paris, France
e William L. Brown Center, Missouri Botanical Garden, St. Louis, MO, United States
f School of Social Work, Adelphi University, Garden City, NY, United States
g Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: The aging population in the USA is projected to increase significantly, with a corresponding rise in dementia cases, particularly among racial minorities. This study examines the key drivers of racial disparities in dementia risk among older Black adults in the St. Louis area, a region characterized by entrenched structural racism. Utilizing a Community-Based System Dynamics (CBSD) approach, we engaged cognitively normal Black adults (age ≥ 45) to explore the complex interplay of social and structural determinants of health (S/SDOH) affecting dementia risk. Methods: Eight CBSD workshops were conducted, during which participants identified and analyzed various factors influencing dementia risk through group model-building techniques. These workshops revealed multiple reinforcing and balancing feedback loops, highlighting the intricate relationships between trauma, health literacy, social isolation, education, healthcare access, and systemic racism. Results: There were 59 participants with an average age of 64, a majority of women (88%) and college-educated (15.9 years) residing in areas with moderately severe deprivation. The resulting Causal Loop Diagrams underscored the impact of poverty, discrimination, and limited access to quality education and healthcare on dementia risk across the lifespan. Participants proposed actionable interventions, including health information campaigns, community mobilization, and improvements in public transportation and healthcare accessibility. Conclusion: This study emphasizes the necessity of addressing S/SDOH to mitigate dementia risk among Black Americans. The findings call for targeted public health initiatives and policy changes to improve socioeconomic conditions and reduce racial disparities in dementia outcomes. © The Author(s) 2024.
Author Keywords
Community-Based System Dynamics; Dementia; Racial disparities; Social and structural determinants of health; Structural racism
Funding details
National Institutes of HealthNIH
National Institute on AgingNIAR01AG074302
National Institute on AgingNIA
Alzheimer’s AssociationAASG-22–968620-ARCHES
Alzheimer’s AssociationAA
Document Type: Article
Publication Stage: Article in Press
Source: Scopus