Digital Commons Network^™

Cortical Structure In Nodes Of The Default Mode Network Estimates General Intelligence, Abhinav Yadav, Archana Purushotham

Faculty, Staff and Students Publications

Introduction: A growing number of studies implicate functional brain networks in intelligence, but it is unclear if network nodal structure relates to intelligence.

Methods: Using MRI, we studied the relationship of the general intelligence factor (g) with cortical thickness (CT), local gyrification index (LGI), and voxel-based morphometry in the nodes of the default mode network (DMN) and task-positive network (TPN) in a cohort of 44 young, healthy adults. Employing a novel strategy, we performed repeated analyses with multiple sets of g estimates to remove false positives.

Results: CT and LGI in medial and temporal nodes of the DMN were reliably …

Gdf15 Links Adipose Tissue Lipolysis With Anxiety, Logan K Townsend, Léa J Becker, Jordan G Mccall, Et Al.

2020-Current year OA Pubs

Psychological stress changes both behaviour and metabolism to protect organisms. Adrenaline is an important driver of this response. Anxiety correlates with circulating free fatty acid levels and can be alleviated by a peripherally restricted β-blocker, suggesting a peripheral signal linking metabolism with behaviour. Here we show that adrenaline, the β3 agonist CL316,243 and acute restraint stress induce growth differentiation factor 15 (GDF15) secretion in white adipose tissue of mice. Genetic inhibition of adipose triglyceride lipase or genetic deletion of β-adrenergic receptors blocks β-adrenergic-induced increases in GDF15. Increases in circulating GDF15 require lipolysis-induced free fatty acid stimulation of M2-like macrophages within …

Multi-Omic And Spatial Analysis Of Mouse Kidneys Highlights Sex-Specific Differences In Gene Regulation Across The Lifespan, Siqi Chen, Ruiyang Liu, Chia-Kuei Mo, Michael C Wendl, Andrew Houston, Preet Lal, Yanyan Zhao, Wagma Caravan, Andrew T Shinkle, Atieh Abedin-Do, Nataly Naser Al Deen, Kazuhito Sato, Xiang Li, André Luiz N Targino Da Costa, Yize Li, Alla Karpova, John M Herndon, Maxim N Artyomov, Joshua B Rubin, Sanjay Jain, Sheila A Stewart, Li Ding, Feng Chen, Et Al.

2020-Current year OA Pubs

There is a sex bias in the incidence and progression of many kidney diseases. To better understand such sexual dimorphism, we integrated data from six platforms, characterizing 76 kidney samples from 68 mice at six developmental and adult time points, creating a molecular atlas of the mouse kidney across the lifespan for both sexes. We show that proximal tubules have the most sex-biased differentially expressed genes emerging after 3 weeks of age and are associated with hormonal regulations. We reveal potential mechanisms involving both direct and indirect regulation by androgens and estrogens. Spatial profiling identifies distinct sex-biased spatial patterns in …

Wb5, A Novel Biomarker For Monitoring Efficacy And Success Of Mass Drug Administration Programs For Wuchereria Bancrofti Elimination, Rachel E. Pietrow, Catherine Bjerum, Benjamin G. Koudou, Taniawati Supali, Philip J Budge, Peter U. Fischer, Thomas B. Nutman, Sasisekhar Bennuru

2020-Current year OA Pubs

The success of mass drug administration at reducing the prevalence of lymphatic filariasis in endemic areas has led to an increased need for highly sensitive and specific diagnostic assays. To be useful in post-elimination surveillance in areas with low to zero prevalence, high test performance characteristics are required to enable the early detection of infection recrudescence. As current testing suffers from either sensitivity or specificity levels that fail to meet adopted target product profiles, additional targets that could be used as confirmatory tests or in multiplexed assays could overcome these issues. To this end, bioinformatic analyses coupled with stage-specific expression …

Serendipitous Supernormality, Behzad B. Pavri, Eitan Frankel

Division of Cardiology Faculty Papers

We describe a patient who underwent AV node modification to create complete heart block in the setting of incessant, ablation-and-drug-refractory, symptomatic atypical atrial flutter. His dual chamber defibrillator (previously implanted for resuscitated cardiac arrest) was programmed to the VVIR mode at a faster pacing rate of 85 bpm. Serendipitously, this rate was an almost exact factorial of his flutter rate of 250-260 bpm. This resulted in every 6th flutter wave falling in the supernormal period, resulting in fixed-coupled supraventricular bigeminy and trigeminy in the setting of complete heart block. Reprogramming the pacing rate to 75 bpm abolished bigeminy and trigeminy.

Bmal1-Hif2a Heterodimer Modulates Circadian Variations Of Myocardial Injury, Wei Ruan, Tao Li, In Hyuk Bang, Jaewoong Lee, Wankun Deng, Xinxin Ma, Cong Luo, Fang Du, Seung-Hee Yoo, Boyun Kim, Jiwen Li, Xiaoyi Yuan, Katherine Figarella, Yu A An, Yin-Ying Wang, Yafen Liang, Matthew Deberge, Dongze Zhang, Zhen Zhou, Yanyu Wang, Joshua M Gorham, Jonathan G Seidman, Christine E Seidman, Sary F Aranki, Ragini Nair, Lei Li, Jagat Narula, Zhongming Zhao, Alemayehu A Gorfe, Jochen D Muehlschlegel, Kuang-Lei Tsai, Holger K Eltzschig

Faculty, Staff and Student Publications

Acute myocardial infarction is a leading cause of morbidity and mortality worldwide1. Clinical studies have shown that the severity of cardiac injury after myocardial infarction exhibits a circadian pattern, with larger infarcts and poorer outcomes in patients experiencing morning-onset events2–7. However, the molecular mechanisms underlying these diurnal variations remain unclear. Here we show that the core circadian transcription factor BMAL17–11 regulates circadian-dependent myocardial injury by forming a transcriptionally active heterodimer with a non-canonical partner—hypoxia-inducible factor 2 alpha (HIF2A)12–16—in a diurnal manner. To substantiate this finding, we determined …

Longevity Humans Have Youthful Erythrocyte Function And Metabolic Signatures, Fang Yu, Changhan Chen, Wuping Liu, Zhixiang Zhao, Yuhua Fan, Zhenjiang Li, Weilun Huang, Tingting Xie, Cheng Luo, Zhouzhou Yao, Qi Guo, Zhiyu Yang, Juan Liu, Yujin Zhang, Rodney E Kellems, Jian Xia, Ji Li, Yang Xia

Faculty, Staff and Student Publications

Longevity individuals have lower susceptibility to chronic hypoxia, inflammation, oxidative stress, and aging-related diseases. It has long been speculated that "rejuvenation molecules" exist in their blood to promote extended lifespan. We unexpectedly discovered that longevity individuals exhibit erythrocyte oxygen release function similar to young individuals, whereas most elderly show reduced oxygen release capacity. Untargeted erythrocyte metabolomics profiling revealed that longevity individuals are characterized by youth-like metabolic reprogramming and these metabolites effectively differentiate the longevity from the elderly. Quantification analyses led us to identify multiple novel longevity-related metabolites within erythrocytes including adenosine, sphingosine-1-phosphate (S1P), and glutathione (GSH) related amino acids. Mechanistically, …

Chd1 Loss Reprograms Srebp2-Driven Cholesterol Synthesis To Fuel Androgen-Responsive Growth And Castration Resistance In Spop-Mutated Prostate Tumors, Feiyu Chen, Haoyan Li, Yin Wang, Ximing Tang, Kevin Lin, Qidong Li, Chenling Meng, Wei Shi, Javier Leo, Xin Liang, Jie Zhang, Vivien Van, Iqbal Mahmud, Bo Wei, Philip L Lorenzi, Maria G Raso, Ana Aparicio, Yue Lu, Daniel E Frigo, Boyi Gan, Di Zhao

Faculty, Staff and Student Publications

Despite undergoing castration, most individuals with prostate cancer (PCa) experience progression to castration-resistant PCa (CRPC), in which the androgen receptor (AR) remains an important driver. Concurrent genetic alterations in SPOP and CHD1 define a unique subtype of PCa, but their interactions in tumor progression and therapy response remain unclear. Here, we provide genetic evidence supporting that CHD1 loss accelerates disease progression and confers resistance to castration in males with SPOP-mutated PCa. By leveraging genetic engineering and multiomics, we uncovered a noncanonical function of CHD1 in lipid metabolism reprogramming via repressing the SREBP2 transcriptome. Loss of CHD1 induces cholesterol production, supplies …

Diroximel Fumarate Acts Through Nrf2 To Attenuate Methylglyoxal-Induced Nociception In Mice And Decrease Isr Activation In Drg Neurons, Muhammad Saad Yousuf, Marisol Mancilla Moreno, Brodie J Woodall, Vikram Thakur, Jiahe Li, Lucy He, Rohita Arjarapu, Danielle Royer, Jennifer Zhang, Munmun Chattopadhyay, Peter M Grace, Theodore J Price

Faculty, Staff and Student Publications

Diabetic neuropathic pain is associated with elevated plasma levels of methylglyoxal (MGO). MGO is a metabolite of glycolysis that causes pain hypersensitivity in mice by stimulating the phosphorylation of eukaryotic initiation factor 2α (p-eIF2α) and subsequently activating the integrated stress response (ISR). We first established that Zucker diabetic fatty rats have enhanced MGO signaling, engage ISR, and develop pain hypersensitivity. Since nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of antioxidant proteins that neutralize MGO, we hypothesized that fumarates, like diroximel fumarate (DRF), will stimulate Nrf2 signaling, and prevent MGO-induced ISR and pain hypersensitivity. DRF (100 mg/kg) treated …

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 …

Maternal Dysbiosis Produces Long-Lasting Behavioral Changes In Offspring, Jacob Hudobenko, Claudia M Di Gesù, Patrick R Mooz, Joseph Petrosino, Nagireddy Putluri, Bhanu P Ganesh, Kristen Rebeles, Frank W Blixt, Venugopal R Venna, Louise D Mccullough

Faculty, Staff and Student Publications

Advanced maternal age (AMA) is defined as a pregnancy in a woman older than 35 years of age. AMA increases the risk for both maternal and neonatal complications, including miscarriage and stillbirth. AMA has also been linked to neurodevelopmental and neuropsychiatric disorders in the offspring. Recent studies have found that age-associated compositional shifts in the gut microbiota contribute to altered microbial metabolism and enhanced inflammation in the host. We investigated the specific contribution of the maternal microbiome on pregnancy outcomes and offspring behavior by recolonizing young female mice with aged female microbiome prior to pregnancy. We discovered that pre-pregnancy colonization …

The Small Gtpase Rap1 In Pomc Neurons Regulates Leptin Actions And Glucose Metabolism, Kentaro Kaneko, Weisheng Lu, Yong Xu, Alexei Morozov, Makoto Fukuda

Faculty, Staff and Students Publications

The hypothalamic leptin-proopiomelanocortin (POMC) pathway is critical for regulating metabolism. POMC neurons in the arcuate nucleus respond to leptin and play a pivotal role in mediating energy and glucose balance. However, during diet-induced obesity (DIO), these neurons often develop resistance to exogenous leptin. Recently, the small GTPase Rap1 has been implicated as an inhibitor of neuronal leptin signaling; however, its specific role within POMC neurons remains unexplored. We generated tamoxifen-inducible, POMC neuron-specific Rap1 knockout mice to selectively delete both Rap1a and Rap1b isoforms in POMC neurons. By analyzing these mice through metabolic phenotyping, immunohistochemistry, and biochemical assays, we show that …

Macrophage-Mediated Il-6 Signaling Drives Ryanodine Receptor-2 Calcium Leak In Postoperative Atrial Fibrillation, Joshua A Keefe, Yuriana Aguilar-Sanchez, J Alberto Navarro-Garcia, Isabelle Ong, Luge Li, Amelie Paasche, Issam Abu-Taha, Marcel A Tekook, Florian Bruns, Shuai Zhao, Markus Kamler, Ying H Shen, Mihail G Chelu, Na Li, Dobromir Dobrev, Xander Ht Wehrens

Faculty, Staff and Students Publications

Postoperative atrial fibrillation (poAF) is AF occurring days after surgery, with a prevalence of 33% among patients undergoing open-heart surgery. The degree of postoperative inflammation correlates with poAF risk, but less is known about the cellular and molecular mechanisms driving postoperative atrial arrhythmogenesis. We performed single-cell RNA-seq comparing atrial nonmyocytes from mice with and without poAF, which revealed infiltrating CCR2+ macrophages to be the most altered cell type. Pseudotime trajectory analyses identified Il-6 as a gene of interest driving in macrophages, which we confirmed in pericardial fluid collected from human patients after cardiac surgery. Indeed, macrophage depletion and macrophage-specific Il6ra …

Repeat Ascaris Challenge Reduces Worm Intensity Through Gastric Cellular Reprograming, Yifan Wu, Charlie Suarez-Reyes, Nina L Tang, Alexander R Kneubehl, Jill E Weatherhead

Faculty, Staff and Students Publications

Ascariasis (roundworm) is the most prevalent parasitic nematode infection worldwide, impacting approximately 500 million people predominantly in low- and middle-income countries (LMICs). While people of all ages are infected with Ascaris, infection intensity (defined by worm burden) paradoxically peaks in pre-school and school-aged children but then declines with age. The cause of age-dependent Ascaris worm intensity is not well understood but may be dependent on cellular changes in mucosal barrier sites. We have previously found that the gastric mucosa is a critical barrier site for Ascaris infection as ingested Ascaris larvae use acidic mammalian chitinase (AMCase) secreted by gastric chief …

Mapping The Developmental Profile Of Ventricular Zone-Derived Neurons In The Human Cerebellum, Anders W Erickson, Henry Tan, Liam D Hendrikse, Jake Millman, Zachary Thomson, Joseph Golser, Omar Khan, Guanyi He, Kathleen Bach, Arpit Suresh Mishra, Janja Kopic, Zeljka Krsnik, Ferechte Encha-Razavi, Giulia Petrilli, Fabien Guimiot, Evelina Silvestri, Kimberly A Aldinger, Michael D Taylor, Kathleen J Millen, Parthiv Haldipur

Faculty, Staff and Students Publications

The cerebellar ventricular zone (VZ) is the primary source of progenitors that generate cerebellar GABAergic neurons, including Purkinje cells (PCs) and interneurons (INs). This study provides detailed characterization of human cerebellar GABAergic neurogenesis using transcriptomic and histopathological analyses and reveals conserved and unique features compared to rodents. We show that the sequential progression of neurogenesis is conserved and occurs before 8 postconception weeks. Notably, PC differentiation occurs in the outer subventricular zone (SVZ), a region absent in the mouse cerebellum. Human PCs are generated during a compact two-week period before the onset of cerebral cortex histogenesis. A subset of human …

Distinct Oxytocin Signaling Pathways Synergistically Mediate Rescue-Like Behavior In Mice, Feng-Rui Zhang, Juan Liu, Jieqi Wen, Zi-Yan Zhang, Yijia Li, Eric Song, Li Hu, Zhou-Feng Chen

2020-Current year OA Pubs

Spontaneous rescue behavior enhances the well-being and survival of social animals, yet the neural mechanisms underlying the recognition and response to conspecifics in need remain unclear. Here, we report that observer mice experience distress when encountering anesthetized conspecifics, prompting spontaneous rescue-like behavior toward the unconscious mice. This behavior facilitates the earlier awakening of anesthetized mice while simultaneously alleviating stress in the helper mice. Our findings reveal that endogenous oxytocin (OXT) release from the hypothalamic paraventricular nucleus (PVN) to the oxytocin receptor (OXTR) in the central nucleus of the amygdala (CeA) regulates the emotional component of rescue-like behavior. In contrast, OXT …

A Secretome Atlas Of Cardiac Fibroblasts From Healthy And Infarcted Mouse Hearts, Jasmin Bahr, Junedh M Amrute, Kory J Lavine, Et Al.

2020-Current year OA Pubs

Cardiac fibroblasts (CF) are key players after myocardial infarction (MI), but their signaling is only incompletely understood. Here we report a first secretome atlas of CF in control (cCF) and post-MI mouse hearts (miCF), combining a rapid cell isolation technique with SILAC and click chemistry. In CF, numerous paracrine factors involved in immune homeostasis are identified. Comparing secretome, transcriptome (SLAMseq), and cellular proteome disclose protein turnover. In miCF at day 5 post-MI, significantly upregulated proteins include SLIT2, FN1, and CRLF1 in mouse and human samples. Comparing the miCF secretome at days 3 and 5 post-MI reveals the dynamic nature of …

Building A Pre-Surgical Multiparametric-Mri-Based Morphologic, Qualitative, Semiquantitative, First And High-Order Radiomic Predictive Treatment Response Model For Undifferentiated Pleomorphic Sarcoma To Replace Recist, Raul F Valenzuela, Elvis Duran-Sierra, Mathew Antony, Behrang Amini, Sam Lo, Keila E Torres, Robert S Benjamin, Jingfei Ma, Ken-Pin Hwang, R Jason Stafford, Dejka Araujo, Andrew J Bishop, Ravin Ratan, Wei-Lien Wang, Jossue Espinoza, Pia V Valenzuela, Chengyue Wu, John E Madewell, William A Murphy, Colleen M Costelloe

Faculty, Staff and Student Publications

Background: Undifferentiated pleomorphic sarcoma (UPS) is the largest subgroup of soft-tissue sarcomas. It demonstrates post-therapeutic hemosiderin deposition, granulation tissue formation, fibrosis, and calcification. Our research aims to establish the multiparametric MRI (mp-MRI) value for predicting UPS treatment response.

Methods: An IRB-approved retrospective study included 33 extremity UPS patients with pre-operative mp-MRI, including diffusion-weighted imaging (DWI), contrast-enhanced susceptibility-weighted imaging (CE-SWI), and perfusion-weighted imaging with dynamic contrast-enhancement (PWI/DCE), and surgical resection between February 2021 and May 2023. Lesions were visually classified on CE-SWI into one of 6 morphology patterns. On PWI/DCE, lesions were classified into one of 6 patterns, and time-intensity curves …

Acute Brcaness Induction And Ar Pathway Blockage Through Cdk12/7/9 Degradation Enhances Parp Inhibitor Sensitivity In Prostate Cancer, Fu Gui, Baishan Jiang, Jie Jiang, Zhixiang He, Takuya Tsujino, Tomoaki Takai, Seiji Arai, Celine Pana, Jens Köllermann, Gary Andrew Bradshaw, Robyn Eisert, Marian Kalocsay, Anne Fassl, Steven P Balk, Adam S Kibel, Li Jia

Faculty, Staff and Student Publications

Current treatments for advanced prostate cancer (PCa) primarily target the androgen receptor (AR) pathway. However, the emergence of castration-resistant prostate cancer (CRPC) and resistance to AR pathway inhibitors (APPIs) remains ongoing challenges. Here, we present BSJ-5-63, a proteolysis-targeting chimera (PROTAC) targeting cyclin-dependent kinases (CDKs) CDK12, CDK7, and CDK9, offering a multipronged approach to CRPC therapy. BSJ-5-63 degrades CDK12, diminishing BRCA1 and BRCA2 expression and inducing a sustained "BRCAness" state. This sensitizes cancer cells to PARP inhibitors (PARPis) regardless of their homologous recombination repair (HRR) status. Furthermore, CDK7 and CDK9 degradation attenuates AR signaling, enhancing its therapeutic efficacy. Preclinical studies, including …

Adipose-Derived Leptin And Complement Factor D Mediate Osteoarthritis Severity And Pain, Kelsey H Collins, Kristin L Lenz, Hope D Welhaven, Erica Ely, Luke E Springer, Sophie Paradi, Ruhang Tang, Lauryn Braxton, Antonina Akk, Huimin Yan, Bo Zhang, Xiaobo Wu, John P Atkinson, Arin K Oestreich, Ron K June, Christine T N Pham, Farshid Guilak

2020-Current year OA Pubs

Obesity is a risk factor for osteoarthritis (OA), and leptin is among the adipokines implicated in obesity-induced OA. However, the specific role of leptin in OA severity and pain is not known. Using lipodystrophic (LD) mice, we show that fat-secreted factors are required for knee OA development, implicating a fat-cartilage cross-talk. Fat pad implantation or systemic leptin restoration in LD mice reintroduced structural OA and pain, whereas implantation of leptin-deficient fat pad did not change OA susceptibility. Isochronic parabiosis and spatial transcriptomics confirmed that a fat-joint cross-talk likely occurred via soluble mediators. Global unsupervised multiomics of conditioned media from fat …

Distinct Adipose Progenitor Cells Emerging With Age Drive Active Adipogenesis, Guan Wang, Gaoyan Li, Anying Song, Yutian Zhao, Jiayu Yu, Yifan Wang, Wenting Dai, Martha Salas, Hanjun Qin, Leonard Medrano, Joan Dow, Aimin Li, Brian Armstrong, Patrick T Fueger, Hua Yu, Yi Zhu, Mengle Shao, Xiwei Wu, Lei Jiang, Judith Campisi, Xia Yang, Qiong A Wang

Children’s Nutrition Research Center Staff Publications

Starting at middle age, adults often suffer from visceral adiposity and associated adverse metabolic disorders. Lineage tracing in mice revealed that adipose progenitor cells (APCs) in visceral fat undergo extensive adipogenesis during middle age. Thus, despite the low turnover rate of adipocytes in young adults, adipogenesis is unlocked during middle age. Transplantations quantitatively showed that APCs in middle-aged mice exhibited high adipogenic capacity cell-autonomously. Single-cell RNA sequencing identified a distinct APC population, the committed preadipocyte, age-enriched (CP-A), emerging at this age. CP-As demonstrated elevated proliferation and adipogenesis activity. Pharmacological and genetic manipulations indicated that leukemia inhibitory factor receptor signaling was …

Induction Of Cardiac Fibulin-4 Protects Against Pressure Overload-Induced Cardiac Hypertrophy And Heart Failure, E D Van Deel, C M Halabi, Et Al.

2020-Current year OA Pubs

The prevailing view of fibulin-4 deficient mice is that the cardiac phenotype is the result of aortic and/or valvular disease. In the present study, we have tested whether the cardiac phenotype is, at least in part, the consequence of primary cardiac effects of fibulin-4. We have found fibulin-4 expression to be activated throughout the myocardium in wildtype (fibulin-4

Difference In Clinical Presentation And Surgical Outcomes In Pediatric And Adult Patients With Chiari Malformation Type 1: A Single Center Retrospective Study, Erik Öhlén, Victor Gabriel El-Hajj, Victor E. Staartjes, Pascal Jabbour, Erik Edström, Adrian Elmi-Terander

Department of Neurosurgery Faculty Papers

INTRODUCTION: Chiari malformation type 1 (CM1) is a common congenital disorder affecting both children and adults. Although pediatric and adult CM1 patients share many characteristics, the differences between the groups are not fully described.

METHOD: A comparative analysis was made of two previously defined cohorts of adult and pediatric non-syndromic CM1, surgically treated at the study center. Clinical outcomes were assessed using the Chicago Chiari outcome scale (CCOS) and radiological outcomes were measured as change in cerebellar tonsil and syringomyelia status.

RESULTS: A total of 209 patients (73 pediatric, 136 adults) were included, with median ages of 11 and 33 …

Impact Of Antidiabetic Medication Type On A New Episode Of Depression: A Retrospective Cohort Study In Texas, Usa, Lin-Na Chou, Mukaila A Raji, Holly M Holmes, Yong-Fang Kuo

Faculty, Staff and Student Publications

Objectives: To examine the associations between antidiabetic medication type and a new episode of depression using 100% Texas Medicare database during 2009 and 2018.

Design: A retrospective cohort study.

Setting: A population-based study using the Texas Medicare data.

Interventions: 11 common antihyperglycaemic medication types, alone and in combinations: metformin-only, five non-metformin-containing regimens (dipeptidyl peptidase-4 inhibitor (DPP4i) only, sulfonylureas (SU) only, thiazolidinediones (TZD) only, SU/DPP4i and SU/TZD) and five metformin-containing combination treatments (metformin/DPP4i, metformin/SU, metformin/TZD, metformin/SU/DPP4i and metformin/SU/TZD).

Participants: This study included 59 057 type 2 diabetes (T2D) patients from a cohort of Texas Medicare beneficiaries who were aged ≥66 years, …

The Combined Effect Of High-Intensity Interval Training And Time-Restricted Feeding On The Akt-Igf-1-Mtor Signaling Pathway In The Muscle Tissue Of Type 2 Diabetic Rats, Motahareh Mohebinejad, Fatemeh Kazeminasab, Mahtab Ghanbari Rad, Reza Bagheri, Mazdak Razi, Darryn Willoughby, Fred Dutheil

Faculty, Staff and Students Publications

Background/Objectives: High-intensity interval training (HIIT) and time-restricted feeding (TRF) have shown potential in enhancing glucose metabolism, increasing insulin sensitivity, and promoting muscle health. This study investigates the combined effects of HIIT and TRF on the AKT-IGF-1-mTOR signaling pathway in the muscle tissue of type 2 diabetic (T2D) rats.

Methods: 42 male Wistar rats (4-5 weeks of age) were included in the study. The animals were randomly divided into two groups: 1. Standard diet (SD) non-diabetic (n = 7) and 2. High-fat diet (HFD n = 35) for 4 weeks. T2D was induced by intraperitoneal injection (IP) of streptozotocin (STZ) …

Disuse-Driven Plasticity In The Human Thalamus And Putamen, Roselyne J Chauvin, Dillan J Newbold, Ashley N Nielsen, Ryland L Miller, Samuel R Krimmel, Athanasia Metoki, Anxu Wang, Andrew N Van, David F Montez, Scott Marek, Vahdeta Suljic, Noah J Baden, Nadeshka Ramirez-Perez, Kristen M Scheidter, Julia S Monk, Forrest I Whiting, Babatunde Adeyemo, Jarod L Roland, Abraham Z Snyder, Benjamin P Kay, Marcus E Raichle, Timothy O Laumann, Evan M Gordon, Nico U F Dosenbach

2020-Current year OA Pubs

Subcortical plasticity has mainly been studied using invasive electrophysiology in animals. Here, we leverage precision functional mapping (PFM) to study motor plasticity in the human subcortex during 2 weeks of upper-extremity immobilization with daily resting-state and motor task fMRI. We found previously that, in the cortex, limb disuse drastically impacts disused primary motor cortex functional connectivity (FC) and is associated with spontaneous fMRI pulses. It remains unknown whether disuse-driven plasticity pulses and FC changes are cortex specific or whether they could also affect movement-critical nodes in the thalamus and striatum. Tailored analysis methods now show spontaneous disuse pulses and FC …

Tobacco Smoking Functional Networks: A Whole-Brain Connectome Analysis In 24 539 Individuals, Yezhi Pan, Chuan Bi, Zhenyao Ye, Hwiyoung Lee, Jiaao Yu, Luba Yammine, Tianzhou Ma, Peter Kochunov, L Elliot Hong, Shuo Chen

Faculty, Staff and Student Publications

Introduction: Nicotine addiction, a multifaceted neuropsychiatric disorder, profoundly impacts brain functions through interactions with neural pathways. Despite its significance, the impact of tobacco smoking on the whole-brain functional connectome remains largely unexplored.

Aims and methods: We conducted a whole-brain analysis on 24 539 adults aged 40 and above from the United Kingdom Biobank cohort. Subjects were categorized into individuals who use nicotine and those who do not use nicotine based on current and chronic tobacco smoking information. Functional connectivity was assessed using resting-state functional magnetic resonance imaging. We employed a network analysis method to assess the systematic effects of tobacco …

Enhancement Of The Endocannabinoid System Through Monoacylglycerol Lipase Inhibition Relieves Migraine-Associated Pain In Mice, Elizaveta Mangutov, Yaseen Awad-Igbaria, Kendra Siegersma, Francois Gastambide, Ayodeji A Asuni, Amynah A A Pradhan

2020-Current year OA Pubs

BACKGROUND: Migraine affects over 1 billion people worldwide and is a leading cause of disability. Targeting the cannabinoid system offers a promising approach for pain and migraine relief. This study evaluated a novel monoacylglycerol lipase (MAGL) inhibitor to prolong endocannabinoid action in acute and chronic mouse models of migraine. It also examined MAGL and cannabinoid receptor 1 (CB

METHODS: C57BL6/J male and female mice received the human migraine trigger nitroglycerin (NTG) acutely or every other day for 9 days. Allodynia was assessed by von Frey hair stimulation of the periorbital area. A single dose of MAGL inhibitor (ABD-1970) was tested …

Age-Related Meningeal Extracellular Matrix Remodeling Compromises Cns Lymphatic Function, Kate Hitpass Romero, Taylor J Stevenson, Leon C D Smyth, Ben Watkin, Samuel J C Mccullough, Luca Vinnell, Amy M Smith, Patrick Schweder, Jason A Correia, Jonathan Kipnis, Mike Dragunow, Justin Rustenhoven

2020-Current year OA Pubs

Efficient clearance of central nervous system (CNS) waste proteins and appropriate immune surveillance is essential for brain health. These processes are facilitated by lymphatic networks present in the meninges that drain cerebrospinal fluid (CSF). Age-related impairments to meningeal lymphatic drainage contribute to CNS waste accumulation and immune dysfunction, yet the underlying mechanisms remain poorly understood. Here, we identify extracellular matrix (ECM) remodeling in the aged dura as a key driver of CSF clearance deficits, demonstrating that peri-lymphatic collagen accumulation disrupts lymphatic function. Exploring immune-derived factors contributing to this ECM remodeling, we identify transforming growth factor beta 1 (TGFβ1) as a …

Asynchronous Development Of The Mouse Auditory Cortex Is Driven By Hemispheric Identity And Sex, Ashlan P Reid, Demetrios Neophytou, Robert Levy, Cody Pham, Hysell V Oviedo

2020-Current year OA Pubs

Lateralized auditory processing is essential for specialized functions such as speech processing, typically dominated by the Left Auditory Cortex (ACx) in humans. Hemispheric specializations also occur in the adult mouse ACx, but their developmental origins are unclear. Our study finds that the Left and Right ACx in mice reach developmental milestones at different ages. Thalamocortical responses and maturation of synaptic dynamics develop earlier in the Right ACx than the Left. We show that this timing offset predicts hemisphere-dependent differences in sensory-driven plasticity. Juvenile tone exposure at specific times results in imbalanced adult tone frequency representations in the Right and Left …