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Ji Eun Song,1 Eunjeong Ji,2 Nak-Hyun Kim,1,3 Jung Hun Ohn,1,3 Yejee Lim,1,3 Jongchan Lee,1,3 Hye Won Kim,1,3 Sun-Wook Kim,1,3 Jiwon Ryu,1,3 Hee-Sun Park,1,3 Eun Sun Kim1,3 1Hospital Medicine Center, Seoul National University Bundang Hospital, Seongnam, Republic of Korea; 2Medical Research Collaborating Center, Seoul National University Bundang Hospital, Seongnam, Republic of Korea; 3Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of KoreaCorrespondence: Eun Sun Kim, Department of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of Korea, Email apolio3700@gmail.comPurpose: Older patients have a higher risk of aspiration pneumonia and mortality if they are hospitalized. We aimed to assess the effectiveness of an aspiration prevention quality improvement (QI) program that utilizes the Gugging Swallowing Screen (GUSS) in older patients.Patients and Methods: This retrospective cohort study was conducted in an acute medical care unit of a tertiary hospital in South Korea. The study used one-to-one propensity matching and included 96 patients who received the QI program and 96 who did not. All patients were aged 65 years or older and had risk factors for aspiration, including neurological and non-neurological disorders, neuromuscular disorders, impaired airway defenses, and dysphagia due to esophageal or gastrointestinal disorders. The primary outcomes included the duration of the fasting period during hospitalization, changes in nutritional status before admission and at discharge, in-hospital mortality, and readmission due to pneumonia within 90 days.Results: Fasting period, changes in weight and albumin levels upon discharge after hospitalization, and length of stay did not differ significantly between patients in the GUSS and non-GUSS groups. However, the risk of readmission within 90 days was significantly lower in patients who underwent the GUSS than in those who did not (hazard ratio, 0.085; 95% confidence interval, 0.025– 0.290; p = 0.001).Conclusion: The GUSS aspiration prevention program effectively prevented readmission due to pneumonia within 90 days in older patients with acute illnesses. This implies that the adoption of efficient aspiration prevention methods in older patients with acute illnesses could play a pivotal role by enhancing patient outcomes and potentially mitigating the healthcare costs linked to readmissions.Keywords: aspiration pneumonia, older patients, gugging swallowing screen, prevention, quality improvement

ObjectivesTo determine whether life expectancy (LE) changes between 2000 and 2019 were associated with race, rural status, local economic prosperity, and changes in local economic prosperity, at the county level.MethodsBetween 12/1/22 and 2/28/23, we conducted a retrospective analysis of 2000 and 2019 data from 3,123 United States counties. For Total, White, and Black populations, we compared LE changes for counties across the rural-urban continuum, the local economic prosperity continuum, and for counties in which local economic prosperity dramatically improved or declined.ResultsIn both years, overall, across the rural-urban continuum, and for all studied populations, LE decreased with each progression from the most to least prosperous quintile (all p < 0.001); improving county prosperity between 2000–2019 was associated with greater LE gains (p < 0.001 for all).ConclusionAt the county level, race, rurality, and local economic distress were all associated with LE; improvements in local economic conditions were associated with accelerated LE. Policymakers should appreciate the health externalities of investing in areas experiencing poor economic prosperity if their goal is to improve population health.

Abstract Background Acute-care interventions that identify patients with substance use disorders (SUDs), initiate treatment, and link patients to community-based services, have proliferated in recent years. Yet, much is unknown about the specific strategies being used to support continuity of care from emergency department (ED) or inpatient hospital settings to community-based SUD treatment. In this scoping review, we synthesize the existing literature on patient transition interventions, and form an initial typology of reported strategies. Methods We searched Pubmed, Embase, CINAHL and PsychINFO for peer-reviewed articles published between 2000 and 2021 that studied interventions linking patients with SUD from ED or inpatient hospital settings to community-based SUD services. Eligible articles measured at least one post-discharge treatment outcome and included a description of the strategy used to promote linkage to community care. Detailed information was extracted on the components of the transition strategies and a thematic coding process was used to categorize strategies into a typology based on shared characteristics. Facilitators and barriers to transitions of care were synthesized using the Consolidated Framework for Implementation Research. Results Forty-five articles met inclusion criteria. 62% included ED interventions and 44% inpatient interventions. The majority focused on patients with opioid (71%) or alcohol (31%) use disorder. The transition strategies reported across studies were heterogeneous and often not well described. An initial typology of ten transition strategies, including five pre- and five post-discharge transition strategies is proposed. The most common strategy was scheduling an appointment with a community-based treatment provider prior to discharge. A range of facilitators and barriers were described, which can inform efforts to improve hospital-to-community transitions of care. Conclusions Strategies to support transitions from acute-care to community-based SUD services, although critical for ensuring continuity of care, vary greatly across interventions and are inconsistently measured and described. More research is needed to classify SUD care transition strategies, understand their components, and explore which lead to the best patient outcomes.

Abstract Background Socioeconomic status has long been associated with population health and health outcomes. While ameliorating social determinants of health may improve health, identifying and targeting areas where feasible interventions are most needed would help improve health equity. We sought to identify inequities in health and social determinants of health (SDOH) associated with local economic distress at the county-level. Methods For 3,131 counties in the 50 US states and Washington, DC (wherein approximately 325,711,203 people lived in 2019), we conducted a retrospective analysis of county-level data collected from County Health Rankings in two periods (centering around 2015 and 2019). We used ANOVA to compare thirty-three measures across five health and SDOH domains (Health Outcomes, Clinical Care, Health Behaviors, Physical Environment, and Social and Economic Factors) that were available in both periods, changes in measures between periods, and ratios of measures for the least to most prosperous counties across county-level prosperity quintiles, based on the Economic Innovation Group’s 2015–2019 Distressed Community Index Scores. Results With seven exceptions, in both periods, we found a worsening of values with each progression from more to less prosperous counties, with least prosperous counties having the worst values (ANOVA p

Plant growth requires the integration of internal and external cues, perceived and transduced into a developmental programme of cell division, elongation and wall thickening. Mechanical forces contribute to this regulation, and thigmomorphogenesis typically includes reducing stem height, increasing stem diameter, and a canonical transcriptomic response. We present data on a bZIP transcription factor involved in this process in grasses. Brachypodium distachyon SECONDARY WALL INTERACTING bZIP (SWIZ) protein translocated into the nucleus following mechanostimulation. Classical touch-responsive genes were upregulated in B. distachyon roots following touch, including significant induction of the glycoside hydrolase 17 family, which may be unique to grass thigmomorphogenesis. SWIZ protein binding to an E-box variant in exons and introns was associated with immediate activation followed by repression of gene expression. SWIZ overexpression resulted in plants with reduced stem and root elongation. These data further define plant touch-responsive transcriptomics and physiology, offering insights into grass mechanotranduction dynamics.

While rural-urban disparities in health and health outcomes have been demonstrated, because of their impact on (and intervenability to improve) health and health outcomes, we sought to examine cross-sectional and longitudinal inequities in health, clinical care, health behaviors, and social determinants of health (SDOH) between rural and non-rural counties in the pre-pandemic era (2015 to 2019), and to present a Health Equity Dashboard that can be used by policymakers and researchers to facilitate examining such disparities. Therefore, using data obtained from 2015-2022 County Health Rankings datasets, we used analysis of variance to examine differences in 33 county level attributes between rural and non-rural counties, calculated the change in values for each measure between 2015 and 2019, determined whether rural-urban disparities had widened, and used those data to create a Health Equity Dashboard that displays county-level individual measures or compilations of them. We followed STROBE guidelines in writing the manuscript. We found that rural counties overwhelmingly had worse measures of SDOH at the county level. With few exceptions, the measures we examined were getting worse between 2015 and 2019 in all counties, relatively more so in rural counties, resulting in the widening of rural-urban disparities in these measures. When rural-urban gaps narrowed, it tended to be in measures wherein rural counties were outperforming urban ones in the earlier period. In conclusion, our findings highlight the need for policymakers to prioritize rural settings for interventions designed to improve health outcomes, likely through improving health behaviors, clinical care, social and environmental factors, and physical environment attributes. Visualization tools can help guide policymakers and researchers with grounded information, communicate necessary data to engage relevant stakeholders, and track SDOH changes and health outcomes over time.

While current thinking posits that insulin signaling to glucose transporter 4 (GLUT4) exocytic translocation and glucose uptake in skeletal muscle and adipocytes is controlled by phosphorylation-based signaling, many proteins in this pathway are acetylated on lysine residues. However, the importance of acetylation and lysine acetyltransferases to insulin-stimulated glucose uptake is incompletely defined. Here, we demonstrate that combined loss of the acetyltransferases E1A binding protein p300 (p300) and cAMP response element binding protein binding protein (CBP) in mouse skeletal muscle caused a complete loss of insulin-stimulated glucose uptake. Similarly, brief (i.e., 1 hour) pharmacological inhibition of p300/CBP acetyltransferase activity recapitulated this phenotype in human and rodent myotubes, 3T3-L1 adipocytes, and mouse muscle. Mechanistically, these effects were due to p300/CBP-mediated regulation of GLUT4 exocytic translocation and occurred downstream of Akt signaling. Taken together, we highlight a fundamental role for acetylation and p300/CBP in the direct regulation of insulin-stimulated glucose transport in skeletal muscle and adipocytes.

Eunhee Ji,1,* Myeong Gyu Kim,2,* Jung Mi Oh3 1College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, Republic of Korea; 2Graduate School of Clinical Pharmacy, CHA University, Pocheon 11160, Republic of Korea; 3College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea *These authors contributed equally to this work Purpose: Liver transplantation is the treatment of choice for patients with end-stage liver disease. Due to the between- and within-individual pharmacokinetic variability in tacrolimus, used to prevent rejection after transplantation, it is difficult to predict the dose needed achieve the target levels in the blood. This study aimed to construct a population pharmacokinetic model of tacrolimus dosage prediction for therapeutic drug monitoring in clinical settings for Korean adult patients receiving living donor liver transplantation (LDLT).Methods: A total of 58 Korean adult patients receiving LDLT with tacrolimus administration were enrolled. Demographic, clinical, and CYP3A5*1/*3 polymorphism data were collected. Population pharmacokinetic modeling of tacrolimus during the first 14 days after transplantation was performed using NONMEM program. Parameters were estimated by the first-order conditional estimation with interaction method. The internal validation of the final model was assessed by the bootstrap and visual predictive check methods using 500 samples from the original data.Results: One-compartmental model was selected as a base model. After the stepwise covariate model building process, postoperative day (POD) and combinational CYP3A5 genotype of the recipient and donor were incorporated into clearance (CL/F). The estimated typical values of CL/F and volume of distribution (V/F) were 6.33 L/h and 465 L, respectively. The final model was CL/F =6.33× POD0.257×2.314 (if CYP3A5 expresser recipient grafted from CYP3A5 expresser donor) ×1.523 (if CYP3A5 expresser recipient grafted from CYP3A5 nonexpresser donor) and V/F =465× POD0.322.Conclusion: A population pharmacokinetic model for tacrolimus was established successfully in Korean adult patients receiving LDLT. This model is expected to contribute to improving patient outcomes by optimizing tacrolimus dose adjustment for liver transplant patients. Keywords: tacrolimus, dosage prediction, living donor liver transplantation, CYP3A5, population pharmacokinetics, nonlinear mixed-effects modeling

Sohyun Jeong, Minhee Lee, Eunhee Ji College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gachon University, Incheon, Republic of Korea Purpose: Diabetes is a chronic lifelong condition, and adherence to medications and self-monitoring of blood glucose are challenging for diabetic patients. The dramatic increase in the prevalence of diabetes is largely due to the incidence of type 2 diabetes in low- and middle-income countries (LMIc) besides high-income countries (HIc). We aimed to evaluate whether pharmacist care (PC) service model in LMIc and HIc could improve clinical outcomes in diabetic patients by performing a meta-analysis. Methods: PubMed, Embase, and ProQuest Dissertations Unlimited Published Literature database were searched to find publications pertaining to pharmacist-led intervention in patients with diabetes. The inclusion criteria were as follows: 1) randomized controlled trials, 2) confirmed diabetic patients (type 1 or type 2), 3) pharmaceutical care intervention by clinical pharmacist or/and multidisciplinary team, and 4) reporting HbA1c at baseline and end of study or the mean change in these values. Results: A total of 37 articles were included in the meta-analysis. The overall result was significant and in favor of PC intervention on HbA1c change (standard difference in mean values [SDM]: 0.379, 95% CI: 0.208–0.550, P

Nayoung Han,1,* Su Hyun Hong,1,2,* Yon Su Kim,3 Dong Ki Kim,3 In-Wha Kim,1 Eunhee Ji,4 Jung Mi Oh1 1Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 2Pharmaceutical Standardization Division, Drug Evaluation Department, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Chungcheongbuk-do, 3Division of Nephrology, Department of Internal Medicine, Seoul National University Hospital, Seoul, 4College of Pharmacy, Gachon University, Incheon, Republic of Korea *These authors contributed equally to this work Background: The purpose of the present study was to determine the effect of additional calcium carbonate treatment on fibroblast growth factor 23 (FGF23) levels in patients treated with calcitriol.Methods: In this randomized, open-labeled, and parallel-group study, a total of 30 patients with early chronic kidney disease (CKD) and vitamin D deficiency were randomly assigned to two groups and received interventions for 8 weeks: 1) a combination of calcium carbonate and calcitriol group; and 2) calcitriol only group. The primary outcome was the difference in percentage change of serum FGF23 levels from baseline between the two groups. Secondary end points included the changes in serum levels of calcium, phosphate, parathyroid hormone (PTH), and 25-hydroxyvitamin D3 (25(OH)D) from baseline.Results: Serum FGF23 levels were more elevated in the combination group than in the calcitriol-alone group. However, both mean change and percentage change in the serum FGF23 levels during the 8-week period were not significantly different between the two groups. Serum calcium level was increased significantly only in the combination treatment group. There was no significant difference in percentage change of serum calcium levels between the two groups. In addition, changes in serum levels of phosphate, 25(OH)D, or PTH were not significantly different between the two groups. In correlation analysis, changes in serum FGF23 levels were positively correlated with changes in serum calcium and phosphate levels, but not with changes in 25(OH)D or PTH levels. No serious adverse events were observed, however, there was one case of mild gastrointestinal discomfort.Conclusion: This study revealed that additional calcium carbonate treatment significantly increased serum FGF23 levels in patients treated with calcitriol, with their synergistic effect in promoting intestinal calcium absorption. This suggests that serum FGF23 levels should be monitored regularly, especially in those who use combination of vitamin D and calcium carbonate from the early stages of CKD. Keywords: fibroblast growth factor-23, vitamin D deficiency, calcium carbonate, calcitriol, mineral and bone disorder

JiEun Kang,1,2,* Kiyon Rhew,3,* Jung Mi Oh,4 NaYoung Han,4 Iyn-Hyang Lee,5 Nam Kyung Je,6 Eunhee Ji,7 Euni Lee,4 Jeong-Hyun Yoon,6 Sandy Jeong Rhie1 1Division of Life and Pharmaceutical Sciences Graduate School, Ewha Womans University, Seoul, Republic of Korea; 2Department of Pharmacy, National Medical Center, Seoul, Republic of Korea; 3College of Pharmacy, Dongduk Women’s University, Seoul, Republic of Korea; 4College of Pharmacy, Seoul National University, Seoul, Republic of Korea; 5College of Pharmacy, Yeungnam University, Gyeongbuk, Republic of Korea; 6College of Pharmacy, Pusan National University, Busan, Republic of Korea; 7College of Pharmacy, Gachon University, Incheon, Republic of Korea *These authors contributed equally to this work Purpose: To assess the degree of satisfaction and expressed needs of pharmaceutical care services in patients with chronic diseases and explore the factors related to the needs from patients’ perspectives for the further development of pharmaceutical care service models. Patients and methods: A cross-sectional survey of 220 patients (mean age ± SD: 61.3±13.1, male:female: 104:116) was conducted. The questionnaire was structured to measure patients’ degree of satisfaction and expressed needs using a 5-point Likert scale. Additionally, preferred duration, methods of service delivery, and willingness to pay were surveyed. Responses were analyzed using an ordinal regression method to predict factors that were related to pharmaceutical care services. Results: Sixty-seven patients had experienced pharmaceutical care services. Their satisfaction levels were high in all categories; however, there were no significant differences between ­categories. The levels of expressed needs were similar among categories without significant differences. The preferred delivery method was a face-to-face conversation combined with being provided with written information (53.2%). The preferred duration was ≤10 min (70.5%). About 48% of the patients showed willingness to pay for the service. Education level and region influenced patients’ needs. Conclusion: The satisfaction and needs of pharmaceutical care services was very positive; however, noticing only a third of patients experienced pharmaceutical care services, this may indicate a lack of awareness and less appreciation of pharmacists by patients. Details concerning patients’ awareness and the value of pharmaceutical care services require further investigation. Keywords: pharmaceutical care service, satisfaction, needs, patient perspective

Objective Neuropsychiatric symptoms are common in Parkinson’s disease dementia (PDD). Frequent and severe neuropsychiatric symptoms create high levels of distress for patients and caregivers, decreasing their quality of life. The aim of this study was to investigate neuropsychiatric symptoms that may contribute to increased caregiver burden in PDD patients. Methods Forty-eight PDD patients were assessed using the 12-item Neuropsychiatric Inventory (NPI) to determine the frequency and severity of mental and behavioral problems. The Burden Interview and Caregiver Burden Inventory were used to evaluate caregiver burden. Results All but one patient showed one or more neuropsychiatric symptoms. The three most frequent neuropsychiatric symptoms were apathy (70.8%) and anxiety (70.8%), followed by depression (68.7%). More severe neuropsychiatric symptoms were significantly correlated with increased caregiver burden. The domains of delusion, hallucination, agitation and aggression, anxiety, irritability and lability, and aberrant motor behavior were associated with caregiver stress. After controlling for age and other potential confounding variables, total NPI score was significantly associated with caregiver burden. Conclusions The results of this study confirm that neuropsychiatric symptoms are frequent and severe in patients with PDD and are associated with increased caregiver distress. A detailed evaluation and management of neuropsychiatric symptoms in PDD patients appears necessary to improve patient quality of life and reduce caregiver burden.

Background and Purpose We investigated the cognitive profiles in a large sample of patients with multiple system atrophy-cerebellar ataxia (MSA-C) and compared directly them in patients with clinical diagnosis of probable MSA-C without dementia and control subjects with intact cognition. Methods We prospectively enrolled 26 patients with clinical diagnosis of probable MSA-C. All patients underwent a standardized neuropsychological test of the Seoul Neuropsychological Screening Battery. Results The score of Korean version of the Mini- Mental State Examination was significantly lower in patients with MSA-C (27.2 ± 2.5) than in control subjects (28.9 ± 1.0, p = 0.003). Patients with MSA-C showed a significantly worse performance in visuospatial function, 3 words recall, verbal immediate, delayed and recognition memory, visual delayed memory, phonemic and sementic Controlled Oral Word Association Test, and ideomotor praxis (p < 0.05). Conclusions Patients with MSA-C show more severe and more widespread cognitive dysfunctions than controls. Our results also indicate that cognitive dysfunction in patients with MCA-C is suggestive of disruption of the cerebellocortical circuits.

Multiple system atrophy (MSA) is an adult-onset sporadic neurodegenerative disease. Because the prognosis of MSA is fatal, neuroprotective or regenerative strategies may be invaluable in MSA treatment. Previously, we obtained clinical and imaging evidence that mesenchymal stem cell (MSC) treatment could have a neuroprotective role in MSA patients. In the present study, we evaluated the effects of MSC therapy on longitudinal changes in subcortical deep grey matter volumes and cortical thickness and their association with cognitive performance. Clinical and imaging data were obtained from our previous randomized trial of autologous MSC in MSA patients. During 1-year follow-up, we assessed longitudinal differences in subcortical deep grey matter volumes and cortical thickness between placebo (n=15) and MSC groups (n=11). Next, we performed correlation analysis between the changes in cortical thickness and changes in the Korean version of the Montreal Cognitive Assessment (MoCA) scores and detailed cognitive performance. There were no significant differences in age, gender ratio, disease duration, clinical severity, MoCA score, or education level between the groups. The subcortical volumetric analysis revealed that the changes in deep grey matter volumes of the caudate, putamen, and thalamus did not differ significantly between the groups. The areas of cortical thinning over time in the placebo group were more extensive, including the frontal, temporal, and parietal areas, whereas these areas in the MSC group were less extensive. Correlation analysis indicated that declines in MoCA scores and phonemic fluency were significantly correlated with cortical thinning of the frontal and posterior temporal areas and anterior temporal areas in MSA patients, respectively. These results suggest that MSC treatment in patients with MSA may modulate cortical thinning over time and related cognitive performance, inferring a future therapeutic candidate for cognitive disorders.

BACKGROUND: Levodopa treatment in Parkinson's disease (PD) increases in serum homocysteine levels due to its metabolism via catechol O-methyltransferase. Endothelial progenitor cells (EPCs) have the capacity to differentiate into mature endothelial cells and are markers for endothelial functions and cardiovascular risks. Along with traditional vascular risk factors, hyperhomocysteinemia is known to decrease the level of EPCs. In the present study, we hypothesized that that levodopa-induced hyperhomocysteinemia leads to a change in EPC levels. METHODOLOGY/PRINCIPAL FINDINGS: We prospectively enrolled PD patients who had been prescribed either levodopa/carbidopa (PD-L group, n = 28) or levodopa/carbidopa/COMT inhibitor (PD-LC group, n = 25) for more than 1 year. The number of circulating EPCs was measured by flow cytometry using dual staining of anti-CD34 and anti-KDR antibodies. The EPCs were divided into tertiles based on their distributions and a logistic regression analysis was used to estimate independent predictors of the highest tertile of EPCs. The number of endothelial progenitor cells was significantly decreased in PD-L patients (118±99/mL) compared with either PD-LC patients (269±258/mL, p = 0.007) or controls (206±204/mL, p = 0.012). The level of homocysteine was significantly increased in PD-L patients (14.9±5.3 µmol/L) compared with either PD-LC patients (11.9±3.0 µmol/L, p = 0.028) or controls (11.1±2.5 µmol/L, p = 0.012). The level of homocysteine was negatively correlated with endothelial progenitor cell levels (r = -0.252, p = 0.028) and was an independent predictor of the highest tertile of endothelial progenitor cell levels (OR; 0.749 [95% CI: 0.584-0.961]). CONCLUSIONS/SIGNIFICANCE: These data indicate that a higher consumption of EPC for restoration of endothelial damage may be associated with chronic levodopa treatment in PD patients.

Presenilin (PS) is involved in many cellular events under physiological and pathological conditions. Previous reports have revealed that PS deficiency results in hyperproliferation and resistance to apoptotic cell death. In the present study, we investigated the effects of PS on beta-catenin and cell mortality during serum deprivation. Under these conditions, PS1/PS2 double-knockout MEFs showed aberrant accumulation of phospho-beta-catenin, higher ROS generation, and notable cell death. Inhibition of beta-catenin phosphorylation by LiCl reversed ROS generation and cell death in PS deficient cells. In addition, the K19/49R mutant form of beta-catenin, which undergoes normal phosphorylation but not ubiquitination, induced cytotoxicity, while the phosphorylation deficient S37A beta-catenin mutant failed to induce cytotoxicity. These results indicate that aberrant accumulation of phospho-beta-catenin underlies ROS-mediated cell death in the absence of PS. We propose that the regulation of beta-catenin is useful for identifying therapeutic targets of hyperproliferative diseases and other degenerative conditions.

While current thinking posits that insulin signaling to glucose transporter 4 (GLUT4) exocytic translocation and glucose uptake in skeletal muscle and adipocytes is controlled by phosphorylation-based signaling, many proteins in this pathway are acetylated on lysine residues. However, the importance of acetylation and lysine acetyltransferases to insulin-stimulated glucose uptake is incompletely defined. Here, we demonstrate that combined loss of the acetyltransferases E1A binding protein p300 (p300) and cAMP response element binding protein binding protein (CBP) in mouse skeletal muscle caused a complete loss of insulin-stimulated glucose uptake. Similarly, brief (i.e., 1 hour) pharmacological inhibition of p300/CBP acetyltransferase activity recapitulated this phenotype in human and rodent myotubes, 3T3-L1 adipocytes, and mouse muscle. Mechanistically, these effects were due to p300/CBP-mediated regulation of GLUT4 exocytic translocation and occurred downstream of Akt signaling. Taken together, we highlight a fundamental role for acetylation and p300/CBP in the direct regulation of insulin-stimulated glucose transport in skeletal muscle and adipocytes.

Maintenance of cell integrity and cell-to-cell communication are fundamental biological processes. Filamentous fungi, such as Neurospora crassa, depend on communication to locate compatible cells, coordinate cell fusion, and establish a robust hyphal network. Two MAP kinase (MAPK) pathways are essential for communication and cell fusion in N. crassa: the cell wall integrity/MAK-1 pathway and the MAK-2 (signal response) pathway. Previous studies have demonstrated several points of cross-talk between the MAK-1 and MAK-2 pathways, which is likely necessary for coordinating chemotropic growth toward an extracellular signal, and then mediating cell fusion. Canonical MAPK pathways begin with signal reception and end with a transcriptional response. Two transcription factors, ADV-1 and PP-1, are essential for communication and cell fusion. PP-1 is the conserved target of MAK-2, but it is unclear what targets ADV-1. We did RNA sequencing on Δadv-1, Δpp-1, and wild-type cells and found that ADV-1 and PP-1 have a shared regulon including many genes required for communication, cell fusion, growth, development, and stress response. We identified ADV-1 and PP-1 binding sites across the genome by adapting the in vitro method of DNA-affinity purification sequencing for N. crassa To elucidate the regulatory network, we misexpressed each transcription factor in each upstream MAPK deletion mutant. Misexpression of adv-1 was sufficient to fully suppress the phenotype of the Δpp-1 mutant and partially suppress the phenotype of the Δmak-1 mutant. Collectively, our data demonstrate that the MAK-1/ADV-1 and MAK-2/PP-1 pathways form a tight regulatory network that maintains cell integrity and mediates communication and cell fusion.

Objectives: To determine whether life expectancy (LE) changes between 2000 and 2019 were associated with race, rural status, local economic prosperity, and changes in local economic prosperity, at the county level. Methods: Between 12/1/22 and 2/28/23, we conducted a retrospective analysis of 2000 and 2019 data from 3,123 United States counties. For Total, White, and Black populations, we compared LE changes for counties across the rural-urban continuum, the local economic prosperity continuum, and for counties in which local economic prosperity dramatically improved or declined. Results: In both years, overall, across the rural-urban continuum, and for all studied populations, LE decreased with each progression from the most to least prosperous quintile (all p < 0.001); improving county prosperity between 2000-2019 was associated with greater LE gains (p < 0.001 for all). Conclusion: At the county level, race, rurality, and local economic distress were all associated with LE; improvements in local economic conditions were associated with accelerated LE. Policymakers should appreciate the health externalities of investing in areas experiencing poor economic prosperity if their goal is to improve population health. [ABSTRACT FROM AUTHOR]

The median eminence (ME) of the hypothalamus comprises the hypothalamic nerve terminals, glia (especially tanycytes) and the portal capillary vasculature that transports hypothalamic neurohormones to the anterior pituitary gland. The ultrastructure of the ME is dynamically regulated by hormones and undergoes organizational changes during development and reproductive cycles in adult females, but relatively little is known about the ME during aging, especially in nonhuman primates. Therefore, we used a novel transmission scanning electron microscopy technique to examine the cytoarchitecture of the ME of young and aged female rhesus macaques in a preclinical monkey model of menopausal hormone treatments. Rhesus macaques were ovariectomized and treated for 2 years with vehicle, estradiol (E2), or estradiol + progesterone (E2 + P4). While the overall cytoarchitecture of the ME underwent relatively few changes with age and hormones, changes to some features of neural and glial components near the portal capillaries were observed. Specifically, large neuroterminal size was greater in aged compared to young adult animals, an effect that was mitigated or reversed by E2 alone but not by E2 + P4 treatment. Overall glial size and the density and tissue fraction of the largest subset of glia were greater in aged monkeys, and in some cases reversed by E2 treatment. Mitochondrial size was decreased by E2, but not E2 + P4, only in aged macaques. These results contrast substantially with work in rodents, suggesting that the ME of aging macaques is less vulnerable to age-related disorganization, and that the effects of E2 on monkeys' ME are age specific.