Geriatrics Commons^™

Tfeb Degradation Is Regulated By An Ikk/Β-Trcp2 Phosphorylation-Ubiquitination Cascade, Yan Xiong, Jaiprakash Sharma, Meggie N Young, Wen Xiong, Ali Jazayeri, Karl F Poncha, Ma Xenia G Ilagan, Qing Wang, Bei Gao, Hui Zheng, Nicolas L Young, Marco Sardiello

Center on Aging Staff Publications

Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and cellular clearance pathways. TFEB activity is tightly controlled by multiple post-translational mechanisms, but the exact molecular mechanism controlling its stability has remained elusive. Here, we identify the IκB kinase (IKK) complex as a key regulator of TFEB protein stability through a phosphorylation-ubiquitination cascade. A high-content kinase inhibitor screen reveals that IKK inhibition increases TFEB protein levels, and genetic ablation of IKK components increases TFEB stability, upregulates lysosomal genes, and enhances lysosomal biogenesis and degradative capacity. Mechanistically, we show that IKK phosphorylates TFEB on a cluster of serine residues …

Beyond The Brain: How Does Alzheimer’S Disease Affect The Body?, Ye-Jin Park, Hongjie Li

Center on Aging Staff Publications

No abstract provided.

Bacteriophage-Mediated Reduction Of Uropathogenic E Coli From The Urogenital Epithelium, Bishnu Joshi, Jacob J Zulk, Camille Serchejian, Zainab A Hameed, Addison B Larson, Austen L Terwilliger, Deepak Kumar, Indira U Mysorekar, Robert A Britton, Anthony W Maresso, Kathryn A Patras

Center on Aging Staff Publications

Urinary tract infections (UTIs), primarily caused by uropathogenic Escherichia coli (UPEC), affect millions annually. UPEC gains access to the urinary tract through mucosal reservoirs, including the vaginal tract. With rising antibiotic resistance and frequent recurrence, alternative non-antibiotic strategies like bacteriophage (phage) therapy are gaining attention. We explored the potential of a lytic phage, ΦHP3, as well as a phage cocktail to decolonize UPEC from the urogenital tract using in vitro and in vivo models. Phage demonstrated replication and lytic activity in both bacteriologic medium and simulated vaginal fluid. Pretreatment of human vaginal epithelial cells (VK2/E6E7) and bladder carcinoma cells (HTB-9) …

Association Of Area Deprivation Index With Perinatal And Covid-19 Outcomes During The Early Pandemic: A Secondary Analysis Of A Prospective Cohort Study, Abigail Bell, Megan Foeller, Candice Woolfolk, Emily Diveley, Fan Zhang, Amy Scheffer, Ruizhi Huang, Daniel Jackson, Nandini Raghuraman, Ebony Carter, Indira U Mysorekar, Jeannie C Kelly

Center on Aging Staff Publications

Objective: We sought to evaluate the relationship between neighborhood-level deprivation and perinatal outcomes, particularly preterm birth, as well as COVID-19 outcomes among pregnant patients during the early pandemic.

Methods: We performed a secondary analysis of a prospective longitudinal cohort study that investigated the impact of prenatal COVID-19 exposure on perinatal outcomes. Pregnant patients were recruited 12/23/20-7/18/22 and serially assessed for COVID-19 exposure during pregnancy, with serum antibody testing, electronic medical record review, and patient report. For this secondary analysis, address at the time of delivery was used to categorize patients into low ADI (≤50th percentile Area Deprivation Index, indicating low …

Surgical Removal Of Implanted Microchips To Correct Mri Susceptibility Artifacts In Mice, Elizabeth Hipskind, Nicole Hernandez, Sydney Fox, Tina Manirambona, Rita Schack, Brian Gibson, Robia G Pautler

Center on Aging Staff Publications

Purpose: Implanted microchips are becoming increasingly common in research for animal identification and have been adopted by commercial vendors for some mouse strains. However, they often contain metal components, which generate magnetic susceptibility artifacts on MR images. Despite this, some microchips are marketed as MR-compatible, even though they are likely to affect image quality.

Methods: We assessed the impact of a radiofrequency identification microchip on MR images of the mouse brain and present a method for precise surgical removal. A handheld magnet was used to locate and stabilize the microchips during removal. Mice were imaged before and after microchip removal. …

Peritoneal Immunosurgery: Immunotherapy Augmented Surgery For The Treatment Of Peritoneal Cancers, Ada I Ozcan, Arianexys Aquino López, Mary K Mckenna, Malcolm K Brenner, Alastair M Thompson

Faculty, Staff and Students Publications

Peritoneal malignancy often indicates disruptions in multiple physiological systems resulting from widespread cancer. The heterogenous origin and dynamic nature of peritoneal cancer make it difficult to treat with standard approaches that fit into guidelines. We describe how successful treatment should address the underlying pathology, the systemic response to surgical treatments and target the immune perturbations that facilitate the establishment and propagation of this multifaceted disease.

Social Disparities, Delirium Occurrence, And Related Outcomes Among Hospitalized Older Adults, Alan P Pan, Kathryn Agarwal, Thomas Potter, Karim Borei, Sara Nowakowski, Courtenay R Bruce, George E Taffet, Farhaan S Vahidy

Faculty, Staff and Students Publications

Background: Underlying socio-economic and health burden may variably impact delirium presentation among older adults. We characterized differences in patient factors related to social marginalization and studied their effects on delirium occurrence and hospital outcomes.

Methods: We conducted a 7-year retrospective analysis of older adults (aged ≥ 70 years) who systematically underwent screening for delirium at an 8-hospital healthcare system. Our primary exposure included patient characteristics related to demographics and social marginalization. Multivariable logistic regression models were built to identify factors associated with increased odds of delirium occurrence, either (1) present-on-admission (D-POA) or (2) hospital-acquired (HAD). Secondary outcomes included hospital length …

The Causal Pivot: A Structural Approach To Genetic Heterogeneity And Variant Discovery In Complex Diseases, Chad A Shaw, C J Williams, Taotao Tan, Daniel Illera, Nicholas Di, Joshua M Shulman, John W Belmont

Center on Aging Staff Publications

We present the Causal Pivot (CP) as a structural causal model (SCM) for analyzing genetic heterogeneity in complex diseases. The CP leverages an established causal factor or factors to detect the contribution of additional suspected causes. Specifically, polygenic risk scores (PRSs) serve as known causes, while rare variants (RVs) or RV ensembles are evaluated as candidate causes. The CP incorporates outcome-induced association by conditioning on disease status. We derive a conditional maximum-likelihood procedure for binary and quantitative traits and develop the Causal Pivot likelihood ratio test (CP-LRT) to detect causal signals. Through simulations, we demonstrate the CP-LRT’s robust power and …

Deepmvp: Deep Learning Models Trained On High-Quality Data Accurately Predict Ptm Sites And Variant-Induced Alterations, Bo Wen, Chenwei Wang, Kai Li, Ping Han, Matthew V Holt, Sara R Savage, Jonathan T Lei, Yongchao Dou, Zhiao Shi, Yi Li, Bing Zhang

Center on Aging Staff Publications

Post-translational modifications (PTMs) are critical regulators of protein function, and their disruption is a key mechanism by which missense variants contribute to disease. Accurate PTM site prediction using deep learning can help identify PTM-altering variants, but progress has been limited by the lack of large, high-quality training datasets. Here, we introduce PTMAtlas, a curated compendium of 397,524 PTM sites generated through systematic reprocessing of 241 public mass-spectrometry datasets, and DeepMVP, a deep learning framework trained on PTMAtlas to predict PTM sites for phosphorylation, acetylation, methylation, sumoylation, ubiquitination and N-glycosylation. DeepMVP substantially outperforms existing tools across all six PTM types. Its …

Lessons In Longevity From Blood Stem Cells Under Protein Stress, André Catic

Center on Aging Staff Publications

Blood stem cells are among the body's longest-living cells despite being highly vulnerable to proteotoxic damage, which accelerates their aging. To maintain protein homeostasis (proteostasis), hematopoietic stem cells (HSCs) employ mechanisms such as reduced translation rates, high chaperone activity, autophagy, and selective protein degradation. These strategies mitigate protein misfolding, maintain quiescence, and preserve regenerative potential. Disruptions in proteostasis can lead to the elimination of impaired HSCs through differentiation or apoptosis, ensuring the integrity of the stem cell pool. Due to the systemic impact of the blood on aging and its experimental and clinical accessibility, investigating HSC proteostasis provides insights into …

Smartboot: Real-Time Monitoring Of Patient Activity Via Remote Edge Computing Technologies, Gozde Cay, Myeounggon Lee, David G Armstrong, Bijan Najafi

Center on Aging Staff Publications

Diabetic foot ulcers (DFUs) are a serious complication of diabetes, associated with high recurrence and amputation rates. Adherence to offloading devices is critical for wound healing but remains inadequately monitored in real-world settings. This study evaluates the SmartBoot edge-computing system-a wearable, real-time remote monitoring solution integrating an inertial measurement unit (Sensoria Core) and smartwatch-for its validity in quantifying cadence and step count as digital biomarkers of frailty, and for detecting adherence. Twelve healthy adults wore two types of removable offloading boots (Össur and Foot Defender) during walking tasks at varied speeds; system outputs were validated against a gold-standard wearable and …

Integrative Spatial Omics Reveals Distinct Tumor-Promoting Multicellular Niches And Immunosuppressive Mechanisms In Black American And White American Patients With Tnbc, Qian Zhu, Akhila Balasubramanian, Jaya Ruth Asirvatham, Megha Chatterjee, Badrajee Piyarathna, Jaspreet Kaur, Nada Mohamed, Ling Wu, Stacy Wang, Niloufar Pourfarrokh, Paula Danika Binsol, Mahak Bhargava, Uttam Rasaily, Yitian Xu, Junjun Zheng, Deborah Jebakumar, Arundhati Rao, Carolina Gutierrez, Angela R Omilian, Carl Morrison, Gokul M Das, Christine Ambrosone, Erin H Seeley, Shu-Hsia Chen, Yi Li, Eric Chang, Xiaoxian Li, Elizabeth Baker, Ritu Aneja, Xiang H-F Zhang, Arun Sreekumar

Center on Aging Staff Publications

Racial disparities in the clinical outcomes of triple-negative breast cancer (TNBC) have been well-documented, but the underlying biological mechanisms remain poorly understood. To investigate these disparities, we employed a multi-omic approach integrating imaging mass cytometry and spatial transcriptomics to characterize the tumor microenvironment (TME) in self-identified Black American (BA) and White American (WA) TNBC patients. Our analysis revealed that the TME in BA patients is marked by a network of endothelial cells, macrophages, and mesenchymal-like cells, which correlates with reduced patient survival. In contrast, the WA TNBC microenvironment is enriched in T-cells and neutrophils, indicative of T-cell exhaustion and suppressed …

The Landscape Of Malignant Transition: Unraveling Cancer Cell-Of-Origin And Heterogeneous Tissue Microenvironment, Ruihan Luo, Jiajia Liu, Tiangang Wang, Weiling Zhao, Yanfei Wang, Jianguo Wen, Hongyu Wang, Shanli Ding, Xiaobo Zhou

Faculty, Staff and Student Publications

Understanding disease progression and sophisticated tumor ecosystems is imperative for investigating tumorigenesis mechanisms and developing novel prevention strategies. Here, we dissected heterogeneous microenvironments during malignant transitions by leveraging data from 1396 samples spanning 13 major tissues. Within transitional stem-like subpopulations highly enriched in precancers and cancers, we identified 30 recurring cellular states strongly linked to malignancy, including hypoxia and epithelial senescence, revealing a high degree of plasticity in epithelial stem cells. By characterizing dynamics in stem-cell crosstalk with the microenvironment along the pseudotime axis, we found differential roles of ANXA1 at different stages of tumor development. In precancerous stages, reduced …

Muscle Rev-Erb Controls Time-Dependent Adaptations To Chronic Exercise In Mice, Jidong Liu, Fang Xiao, Abhinav Choubey, Udhaya Kumar S, Yanxiang Wang, Sungguan Hong, Tingting Yang, Husniye Gul Otlu, Ege Sanem Oturmaz, Emanuele Loro, Yuxiang Sun, Pradip Saha, Tejvir S Khurana, Li Chen, Xinguo Hou, Zheng Sun

Center on Aging Staff Publications

The best time of the day for chronic exercise training and the mechanism underlying the timing effects is unclear. Here, we show that low-intensity, low-volume treadmill training in mice before sleep yields greater benefits than after waking for muscle contractile performance and systemic glucose tolerance. Baseline muscle performance also exhibits diurnal variations, with higher strength but lower endurance before sleep than after waking. Muscle-specific knockout of circadian clock genes Rev-erbα/β (Rev-MKO) in male mice eradicates the diurnal variations in both training and baseline conditions without affecting muscle mass, mitochondrial content, food intake, or spontaneous activities. Multi-omics and metabolic measurements reveal …

Enzyme-Independent Functions Of Hdac3 In The Adult Hear, Sichong Qian, Chen Zhang, Wenbo Li, Shiyang Song, Guanqiao Lin, Zixiu Cheng, Wenjun Zhou, Huiqi Yin, Yueli Wang, Haiyang Li, Ying H Shen, Zheng Sun

Center on Aging Staff Publications

The cardioprotective effects of histone deacetylase (HDAC) inhibitors (HDIs) are at odds with the deleterious effects of HDAC depletion. Here, we use HDAC3 as a prototype HDAC to address this contradiction. We show that adult-onset cardiac-specific depletion of HDAC3 in mice causes cardiac hypertrophy and contractile dysfunction on a high-fat diet (HFD), excluding developmental disruption as a major reason for the contradiction. Genetically abolishing HDAC3 enzymatic activity without affecting its protein level does not cause cardiac dysfunction on HFD. HDAC3 depletion causes robust downregulation of lipid oxidation/bioenergetic genes and upregulation of antioxidant/anti-apoptotic genes. In contrast, HDAC3 enzyme activity abolishment causes …

Reduction Of Neuronal Activity Mediated By Blood-Vessel Regression In The Adult Brain, Xiaofei Gao, Xing-Jun Chen, Meng Ye, Jun-Liszt Li, Nannan Lu, Di Yao, Bo Ci, Fei Chen, Lijun Zheng, Yating Yi, Shiwen Zhang, Zhanying Bi, Xinwei Gao, Yuanlei Yue, Tingbo Li, Jiafu Lin, Ying-Chao Shi, Kaibin Shi, Nicholas E Propson, Yubin Huang, Katherine Poinsatte, Zhaohuan Zhang, Dale B Bosco, Shi-Bing Yang, Ralf H Adams, Volkhard Lindner, Fen Huang, Long-Jun Wu, Hui Zheng, Simon Hippenmeyer, Ann M Stowe, Bo Peng, Marta Margeta, Qingchun Guo, Xiaoqun Wang, Qiang Liu, Jakob Körbelin, Martin Trepel, Hui Lu, Guoen Cai, Bo O Zhou, Bo Shen, Ying-Mei Lu, Wenzhi Sun, Jie-Min Jia, Feng Han, Hu Zhao, Robert M Bachoo, Woo-Ping Ge

Center on Aging Staff Publications

The brain vasculature supplies neurons with glucose and oxygen, but little is known about how vascular plasticity contributes to brain function. Using longitudinal in vivo imaging, we report that a substantial proportion of blood vessels in the adult mouse brain sporadically occlude and regress. Their regression proceeds through sequential stages of blood-flow occlusion, endothelial cell collapse, relocation or loss of pericytes, and retraction of glial endfeet. Regressing vessels are found to be widespread in mouse, monkey and human brains. We further reveal that blood vessel regression cause a reduction of neuronal activity due to a dysfunction in mitochondrial metabolism and …

The Somatic Mosaicism Across Human Tissues Network, Tim H H Coorens, Ji Won Oh, Yujin Angelina Choi, Nam Seop Lim, Boxun Zhao, Adam Voshall, Alexej Abyzov, Lucinda Antonacci-Fulton, Samuel Aparicio, Kristin G Ardlie, Thomas J Bell, James T Bennett, Bradley E Bernstein, Thomas G Blanchard, Alan P Boyle, Jason D Buenrostro, Kathleen H Burns, Fei Chen, Rui Chen, Sangita Choudhury, Harsha V Doddapaneni, Evan E Eichler, Gilad D Evrony, Melissa A Faith, Thomas G Fazzio, Robert S Fulton, Manuel Garber, Nils Gehlenborg, Soren Germer, Gad Getz, Richard A Gibbs, Raquel G Hernandez, Fulai Jin, Jan O Korbel, Dan A Landau, Heather A Lawson, Niall J Lennon, Heng Li, Yan Li, Po-Ru Loh, Gabor Marth, Michael J Mcconnell, Ryan E Mills, Stephen B Montgomery, Pradeep Natarajan, Peter J Park, Rahul Satija, Fritz J Sedlazeck, Diane D Shao, Hui Shen, Andrew B Stergachis, Hunter R Underhill, Alexander E Urban, Melissa W Vondran, Christopher A Walsh, Ting Wang, Tao P Wu, Chenghang Zong, Eunjung Alice Lee, Flora M Vaccarino

Center on Aging Staff Publications

From fertilization onwards, the cells of the human body acquire variations in their DNA sequence, known as somatic mutations. These postzygotic mutations arise from intrinsic errors in DNA replication and repair, as well as from exposure to mutagens. Somatic mutations have been implicated in some diseases, but a fundamental understanding of the frequency, type and patterns of mutations across healthy human tissues has been limited. This is primarily due to the small proportion of cells harbouring specific somatic variants within an individual, making them more challenging to detect than inherited variants. Here we describe the Somatic Mosaicism across Human Tissues …

Managing Hypercholesterolemia In Adults Older Than 75 Years Without A History Of Atherosclerotic Cardiovascular Disease: An Expert Clinical Consensus From The National Lipid Association And The American Geriatrics Society, Vera Bittner, Sunny A Linnebur, Dave L Dixon, Daniel E Forman, Ariel R Green, Terry A Jacobson, Ariela R Orkaby, Joseph J Saseen, Salim S Virani

Faculty, Staff and Students Publications

The risk of atherosclerotic cardiovascular disease increases with advancing age. Elevated LDL-cholesterol and non-HDL-cholesterol levels remain predictive of incident atherosclerotic cardiovascular events among individuals older than 75 years. Risk prediction among older individuals is less certain because most current risk calculators lack specificity in those older than 75 years and do not adjust for co-morbidities, functional status, frailty, and cognition which significantly impact prognosis in this age group. Data on the benefits and risks of lowering LDL-cholesterol with statins in older patients without atherosclerotic cardiovascular disease are also limited since most primary prevention trials have included mostly younger patients. Available …

Dnmt3a Regulates Murine Megakaryocyte-Biased Hematopoietic Stem Cell Fate Decisions, Sarah M Waldvogel, Virginia Camacho, Dandan Fan, Anna G Guzman, Alejandra Garcia-Martell, Elmira Khabusheva, Jacey Rodriguez Pridgen, Josephine De La Fuente, Rachel Rau, Ashlyn G Laidman, Maria N Barrachina, Estelle Carminita, Justin A Courson, Michael R Williamson, Joanne I Hsu, Chun-Wei Chen, Jaime Reyes, Subhashree Pradhan, Rolando E Rumbaut, Alan R Burns, Benjamin Deneen, Jianzhong Su, Kellie R Machlus, Margaret A Goodell

Center on Aging Staff Publications

Hematopoietic stem cells (HSCs) are defined by their capacity to regenerate all main components of peripheral blood, but individual HSCs exhibit a range of preferences for generating downstream cell types. Their propensities are thought to be epigenetically encoded, but few differential regulatory mechanisms have been identified. In this work, we explored the role of DNA methyltransferase 3A (DNMT3A) in the megakaryocyte-biased HSC population, which is thought to reside at the top of the hematopoietic hierarchy. We demonstrate that heterozygous loss of DNMT3A (Dnmt3a+/-) in these megakaryocyte-biased HSCs has distinct consequences compared with the rest of the HSC pool. These megakaryocyte-biased …

The Infected Diabetic Foot: Bacteraemia And Endocarditis Complicating Moderate And Severe Foot Infections, Mario C Reyes, Arthur N Tarricone, Mathew J Sideman, Michael C Siah, Bijan Najafi, Edgar J G Peters, Lawrence A Lavery

Center on Aging Staff Publications

To identify the incidence of blood stream infections (BSIs) and endocarditis in patients with diabetic foot infections (DFIs), risk factors and clinical outcomes. A post hoc analysis of 280 patients using pooled patient level data from three RTCs. Blood cultures were drawn at time of admission for DFI. Deep intraoperative cultures were obtained from infected foot wounds. Data from the 12-month follow-up were used to determine clinical outcomes. 77.1% (N = 216) had blood cultures of which 15.7% (n = 34) had BSI. One patient (3.3%) had endocarditis. Risk factors for BSI included Charcot Neuroarthropathy history (20.6% vs. 7.1%, p …

Clonal Dynamics And Somatic Evolution Of Haematopoiesis In Mouse, Chiraag D Kapadia, Nicholas Williams, Kevin J Dawson, Caroline Watson, Matthew J Yousefzadeh, Duy Le, Kudzai Nyamondo, Sreeya Kodavali, Alex Cagan, Sarah Waldvogel, Xiaoyan Zhang, Josephine De La Fuente, Daniel Leongamornlert, Emily Mitchell, Marcus A Florez, Krzysztof Sosnowski, Rogelio Aguilar, Alejandra Martell, Anna Guzman, David Harrison, Laura J Niedernhofer, Katherine Y King, Peter J Campbell, Jamie Blundell, Margaret A Goodell, Jyoti Nangalia

Center on Aging Staff Publications

Haematopoietic stem cells maintain blood production throughout life1. Although extensively characterized using the laboratory mouse, little is known about clonal selection and population dynamics of the haematopoietic stem cell pool during murine ageing. We isolated stem cells and progenitors from young and old mice, identifying 221,890 somatic mutations genome-wide in 1,845 single-cell-derived colonies. Mouse stem cells and progenitors accrue approximately 45 somatic mutations per year, a rate only approximately threefold greater than human progenitors despite the vastly different organismal sizes and lifespans. Phylogenetic patterns show that stem and multipotent progenitor cell pools are established during embryogenesis, after which …

The Dialysis Foot- The Impact Of Presenting Estimated Glomerular Filtration Rate On Clinical Outcomes In Patients Hospitalized With Diabetic Foot Infections, Arthur Tarricone, Tyler L Coye, Allen Gee, Bijan Najafi, Michael C Siah, Lawrence A Lavery

Center on Aging Staff Publications

To evaluate the association between presenting estimated glomerular filtration rate (eGFR) and clinical outcomes in patients hospitalized with diabetic foot infections. This retrospective cohort study included 344 patients with moderate to severe diabetic foot infections. Patients were categorized into three groups based on presenting estimated eGFR: eGFR ≥60 (eGFR >60 mL/min), eGFR 30-60 (eGFR 30-60 mL/min) and eGFR < 30 (eGFR < 30 mL/min). Outcomes assessed included wound healing, time to heal, re-infection, amputation, mortality and re-hospitalization for infection. Compared with patients with eGFR < 30, patients with eGFR ≥60 had significantly lower rates of retinopathy, peripheral arterial disease and use of beta blockers or calcium channel blockers. Glycated haemoglobin levels were inversely related to eGFR, decreasing as eGFR severity increased. Haemoglobin levels were significantly lower, and inflammatory markers (ESR and CRP) were significantly higher in patients with eGFR < 30. There were no significant differences among eGFR groups in rates of wound healing, time to heal, re-infection or amputation. However, mortality increased with decreasing eGFR (1.9% in eGFR ≥60 vs. 3.2% in eGFR 30-60 vs. 8.1% in eGFR < 30; p = 0.04). Similarly, re-hospitalization for infection at a different site also increased with decreasing eGFR (20.5% in eGFR ≥60 vs. 28.1% in eGFR 30-60 vs. 48.4% in eGFR < 30; p <  0.01). In diabetic foot infections, presenting eGFR severity did not affect rates of wound healing, time to heal, re-infection or amputation. However, decreasing eGFR was associated with increased mortality and re-hospitalization for infection at a different site. In this study, presenting eGFR was not a predictive value for wound healing or time until healing, however was associated with rehospitalization and overall mortality this diabetic foot population.

Inhibition Of Soluble Epoxide Hydrolase Confers Neuroprotection And Restores Microglial Homeostasis In A Tauopathy Mouse Model, Shuo Wang, Chuangye Qi, Chetan Rajpurohit, Baijayanti Ghosh, Wen Xiong, Baiping Wang, Yanyan Qi, Sung Hee Hwang, Bruce D Hammock, Hongjie Li, Li Gan, Hui Zheng

Center on Aging Staff Publications

Background: The epoxyeicosatrienoic acids (EETs) are derivatives of the arachidonic acid metabolism with anti-inflammatory activities. However, their efficacy is limited due to the rapid hydrolysis by soluble epoxide hydrolase (sEH). Inhibition of sEH has been shown to stabilize the EETs and reduce neuroinflammation in Aβ mouse models of Alzheimer's disease (AD). However, the role of the sEH-EET signaling pathway in other CNS cell types and neurodegenerative conditions are less understood.

Methods: Here we investigated the mechanisms and functional role of the sEH-EET axis in tauopathy by treating PS19 mice with a small molecule sEH inhibitor TPPU and by crossing the …

The Havcr1-Centric Host Factor Network Drives Zika Virus Vertical Transmission, Wenzhe Yu, Jun Tao, Hongmin Cao, Wanshan Zheng, Beiang Zhang, Yue Zhang, Peiqun Xu, Yiwei Zhang, Xuan Liu, Yinan Wang, Han Cai, Gang Liu, Fan Liu, Haibin Wang, Haiyan Zhao, Indira U Mysorekar, Xiaoqian Hu, Bin Cao

Center on Aging Staff Publications

Zika virus (ZIKV) vertical transmission results in devastating congenital malformations and pregnancy complications; however, the specific receptor and host factors facilitating ZIKV maternal-fetal transmission remain elusive. Here, we employ a genome-wide CRISPR screening and identify multiple placenta-intrinsic factors modulating ZIKV infection. Our study unveils that hepatitis A virus cellular receptor 1 (HAVCR1) serves as a primary receptor governing ZIKV entry in placental trophoblasts. The GATA3-HAVCR1 axis regulates heterogeneous cell tropism in the placenta. Notably, placenta-specific Havcr1 deletion in mice significantly impairs ZIKV transplacental transmission and associated adverse pregnancy outcomes. Mechanistically, the immunoglobulin variable-like domain of HAVCR1 binds to ZIKV via …

Incident Hearing Loss And Subsequent Risk Of Dementia: The Health And Retirement Study 2010-2018, Jingkai Wei, Youngran Kim, Yike Li, Donglan Zhang, Casey Crump

Faculty, Staff and Student Publications

Background and Objectives

Research Design and Methods

Histone H3 Cysteine 110 Enhances Iron Metabolism And Modulates Replicative Life Span In Saccharomyces Cerevisiae, Chen Cheng, Brenna S Mccauley, Nedas Matulionis, Maria Vogelauer, Dimitrios Camacho, Heather R Christofk, Weiwei Dang, Nicholas A T Irwin, Siavash K Kurdistani

Center on Aging Staff Publications

The discovery of histone H3 copper reductase activity provides a novel metabolic framework for understanding the functions of core histone residues, which, unlike N-terminal residues, have remained largely unexplored. We previously demonstrated that histone H3 cysteine 110 (H3C110) contributes to cupric (Cu2+) ion binding and its reduction to the cuprous (Cu1+) form. However, this residue is absent in Saccharomyces cerevisiae, raising questions about its evolutionary and functional significance. Here, we report that H3C110 has been lost in many fungal lineages despite near-universal conservation across eukaryotes. Introduction of H3C110 into S. cerevisiae increased intracellular Cu1+ levels and ameliorated the iron …

Quantitative Profiling Ph Heterogeneity Of Acidic Endolysosomal Compartments Using Fluorescence Lifetime Imaging Microscopy, Dinghuan Deng, Youchen Guan, Ayse Sena Mutlu, Baiping Wang, Shihong Max Gao, Hui Zheng, Meng C Wang

Center on Aging Staff Publications

The endolysosomal system plays a crucial role in maintaining cellular homeostasis and promoting organism fitness. The pH of its acidic compartments is a crucial parameter for proper function, and it is dynamically influenced by both intracellular and environmental factors. Here, we present a method based on fluorescence lifetime imaging microscopy (FLIM) for quantitatively analyzing the pH profiles of acidic endolysosomal compartments in diverse types of primary mammalian cells and in live organism Caenorhabditis elegans. This FLIM-based method exhibits high sensitivity in resolving subtle pH differences, thereby revealing heterogeneity within a cell and across cell types. This method enables rapid …

Robotic First Rib Resection With Adjuvant Endovascular Therapy For Chronic Paget-Schroetter Syndrome, Alejandro Zulbaran-Rojas, Miguel Montero-Baker, Nihanth Palivela, Catherine Park, Bijan Najafi, Jayer Chung, Joseph L Mills, Bryan M Burt

Center on Aging Staff Publications

Background: Patients with acute Paget-Schroetter syndrome (PSS) are treated with endovascular therapy and first rib resection (FRR); however the care of patients with chronic PSS is less well understood. This report describes an emerging approach of robotic-FRR, with adjuvant endovascular therapy, for chronic PSS.

Methods: A single-center, retrospective analysis was conducted of patients undergoing robotic-FRR for chronic PSS between 2017 and 2020. Chronic PSS was defined by subclavian vein (SCV) fibrosis identified on duplex ultrasound examination. Patency and clinical outcomes were compared before and after robotic-FRR.

Results: Fifteen robotic-FRRs in 14 patients with chronic PSS were analyzed. Median time between …

Associations Between Deficit Accumulation Frailty And Baseline Markers Of Lifestyle In The Us Pointer Trial, Mark A Espeland, Yitbarek N Demesie, Kayloni Olson, Samuel N Lockhart, Sarah E Tomaszewski Farias, Maryjo L Cleveland, Christy C Tangney, Lucia Crivelli, Heather M Snyder, Michele K York, Laura D Baker, Rachel A Whitmer, Rena R Wing, Katelyn R Garcia, Kathryn E Callahan

Faculty, Staff and Students Publications

BACKGROUND: Multidomain lifestyle interventions may have the potential to slow biological aging as captured by deficit accumulation frailty indices. We describe the distribution and composition of the 49-component frailty index developed by the U.S. POINTER clinical trial team of investigators and assess its cross-sectional associations with sociodemographic factors and markers chosen to be representative of behaviors targeted by the trial's multidomain interventions.

METHODS: We draw baseline data from the 2 111 volunteers enrolled in U.S. POINTER who were ages 60-79 years and at increased risk for cognitive decline. Frailty components were grouped into 9 domains. Associations that frailty index scores …

Dental Care Trajectories Among Formerly Incarcerated Older Adults In The United States, Alexander Testa, Luis Mijares, Mateus Renno Santos, Vahed Maroufy, Dylan B Jackson, Rafael Samper-Ternent, Rahma Mungia, Ana C Neumann

Faculty, Staff and Student Publications

A growing body of research has documented an association between prior incarceration and lower dental care use, yet the longitudinal impact of prior incarceration on dental care patterns over time among older adults remains unexplored. This study aims to investigate whether prior incarceration is associated with differing trajectories of dental care use among older adults in the United States. Data were drawn from the 2012-2020 waves of the Health and Retirement Study (HRS), a nationally representative longitudinal survey of older adults in the United States (n =  5,893). Group-based trajectory modeling was used to estimate dental care use patterns over …