Digital Commons Network^™

Task And Stimulus Coding In The Multiple-Demand Network, Sneha Shashidhara, Moataz Assem, Matthew F Glasser, John Duncan

2020-Current year OA Pubs

In the human brain, a multiple-demand (MD) network plays a key role in cognitive control, with core components in lateral frontal, dorsomedial frontal and lateral parietal cortex, and multivariate activity patterns that discriminate the contents of many cognitive activities. In prefrontal cortex of the behaving monkey, different cognitive operations are associated with very different patterns of neural activity, while details of a particular stimulus are encoded as small variations on these basic patterns (Sigala et al, 2008). Here, using the advanced fMRI methods of the Human Connectome Project and their 360-region cortical parcellation, we searched for a similar result in …

Pathogenic Variants In Autism Gene Katnal2 Cause Hydrocephalus And Disrupt Neuronal Connectivity By Impairing Ciliary Microtubule Dynamics, Tyrone Despenza, Shujuan Zhao, Sheng Chih Jin, Et Al.

2020-Current year OA Pubs

Enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles (cerebral ventriculomegaly), the cardinal feature of congenital hydrocephalus (CH), is increasingly recognized among patients with autism spectrum disorders (ASD).

In Vivo Validation Of Late-Onset Alzheimer's Disease Genetic Risk Factors., Michael Sasner, Christoph Preuss, Ravi S Pandey, Asli Uyar, Dylan Garceau, Kevin P Kotredes, Harriet M. Jackson, Adrian L Oblak, Peter Bor-Chian Lin, Bridget Perkins, Disha Soni, Cindy Ingraham, Audrey Lee-Gosselin, Bruce T Lamb, Gareth R Howell, Gregory W. Carter

Faculty Research 2024

INTRODUCTION: Genome-wide association studies have identified over 70 genetic loci associated with late-onset Alzheimer's disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action.

METHODS: Candidate genetic risk variants were informatically prioritized and individually engineered into a LOAD-sensitized mouse model that carries the AD risk variants APOE ε4/ε4 and Trem2*R47H. The potential disease relevance of each model was assessed by comparing brain transcriptomes measured with the Nanostring Mouse AD Panel at 4 and 12 months of age with human study cohorts.

RESULTS: We created new models for 11 coding and loss-of-function risk variants. …

Assessment Of Neurovascular Uncoupling: Apoe Status Is A Key Driver Of Early Metabolic And Vascular Dysfunction., Kristen D. Onos, Peter B Lin, Ravi S Pandey, Scott A Persohn, Charles P Burton, Ethan W Miner, Kierra Eldridge, Jonathan Nyandu Kanyinda, Kate E Foley, Gregory W. Carter, Gareth R Howell, Paul R Territo

Faculty Research 2024

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein Eε4 (APOEε4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection.

METHODS: PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology.

RESULTS: All hAPOE strains showed AD phenotype progression by 8 months, with females exhibiting the regional changes, which correlated with GO-term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (↓ …

Preeclampsia, Fetal Growth Restriction, And 24-Month Neurodevelopment In Very Preterm Infants., Jennifer Check, Coral Shuster, Julie Hofheimer, Marie Camerota, Lynne M. Dansereau, Lynne M. Smith, Brian S. Carter, Sheri A. Dellagrotta, Jennifer Helderman, Howard Kilbride, Cynthia M. Loncar, Elisabeth Mcgowan, Charles R. Neal, T Michael O'Shea, Steven L. Pastyrnak, Stephen J. Sheinkopf, Barry M. Lester

Manuscripts, Articles, Book Chapters and Other Papers

IMPORTANCE: Preeclampsia has direct influences on a developing fetus and may impact postnatal health, and fetal growth restriction (FGR) is often seen co-occurring with preeclampsia. The development of children born very preterm after preeclampsia diagnosis with and without FGR is not well characterized.

OBJECTIVE: To examine the associations of preeclampsia and FGR with developmental and/or behavioral outcomes in a cohort of very preterm infants.

DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, infants in the prospective Neonatal Neurobehavior and Outcomes in Very Preterm Infants study were enrolled between April 2014 and June 2016 from 9 US university-affiliated neonatal intensive care …

Pharmacokinetic Modeling Of The Effect Of Tariquidar On Ondansetron Disposition Into The Central Nervous System, Manting Chiang, Hyunmoon Back, Jong Bong Lee, Sarah Oh, Tiffany Guo, Simone Girgis, Celine Park, Simon Haroutounian, Leonid Kagan

2020-Current year OA Pubs

PURPOSE: Serotonin (5-HT

METHODS: Ondansetron (10 mg/kg) and tariquidar (7.5 mg/kg) were administered intravenously, plasma and tissue samples were collected and analyzed by HPLC. A mathematical model with brain, spinal cord, cerebrospinal fluid and two systemic disposition compartments was developed to describe the data.

RESULTS: The results demonstrate that tariquidar at 7.5 mg/kg resulted in a complete inhibition of Pgp efflux of ondansetron in the brain and spinal cord. The compartmental model successfully captured pharmacokinetics of ondansetron in wild type and Pgp knockout (KO) animals receiving the drug alone or in wild type animals receiving the ondansetron and tariquidar combination. …

Epigenetic Developmental Mechanisms Underlying Sex Differences In Cancer, Joshua B. Rubin, Tamara Abou-Antoun, Joseph E. Ippolito, Lorida Llaci, Camryn T. Marquez, Jason P. Wong, Lihua Yang

2020-Current year OA Pubs

Cancer risk is modulated by hereditary and somatic mutations, exposures, age, sex, and gender. The mechanisms by which sex and gender work alone and in combination with other cancer risk factors remain underexplored. In general, cancers that occur in both the male and female sexes occur more commonly in XY compared with XX individuals, regardless of genetic ancestry, geographic location, and age. Moreover, XY individuals are less frequently cured of their cancers, highlighting the need for a greater understanding of sex and gender effects in oncology. This will be necessary for optimal laboratory and clinical cancer investigations. To that end, …

Homozygous Missense Variants In Ykt6 Result In Loss Of Function And Are Associated With Developmental Delay, With Or Without Severe Infantile Liver Disease And Risk For Hepatocellular Carcinoma, Mengqi Ma, Mythily Ganapathi, Yiming Zheng, Kai-Li Tan, Oguz Kanca, Kevin E Bove, Norma Quintanilla, Sebnem O Sag, Sehime G Temel, Charles A Leduc, Amanda J Mcpartland, Elaine M Pereira, Yufeng Shen, Jacob Hagen, Christie P Thomas, Nhu Thao Nguyen Galván, Xueyang Pan, Shenzhao Lu, Jill A Rosenfeld, Daniel G Calame, Michael F Wangler, James R Lupski, Davut Pehlivan, Paula M Hertel, Wendy K Chung, Hugo J Bellen

Faculty, Staff and Students Publications

PURPOSE: YKT6 plays important roles in multiple intracellular vesicle trafficking events but has not been associated with Mendelian diseases.

METHODS: We report 3 unrelated individuals with rare homozygous missense variants in YKT6 who exhibited neurological disease with or without a progressive infantile liver disease. We modeled the variants in Drosophila. We generated wild-type and variant genomic rescue constructs of the fly ortholog dYkt6 and compared their ability in rescuing the loss-of-function phenotypes in mutant flies. We also generated a dYkt6

RESULTS: Two individuals are homozygous for YKT6 [NM_006555.3:c.554A>G p.(Tyr185Cys)] and exhibited normal prenatal course followed by failure to thrive, …

[18f]F-Arag Imaging Reveals Association Between Neuroinflammation And Brown- And Bone Marrow Adipose Tissue, Jelena Levi, Caroline Guglielmetti, Et Al.

2020-Current year OA Pubs

Brown and brown-like adipose tissues have attracted significant attention for their role in metabolism and therapeutic potential in diabetes and obesity. Despite compelling evidence of an interplay between adipocytes and lymphocytes, the involvement of these tissues in immune responses remains largely unexplored. This study explicates a newfound connection between neuroinflammation and brown- and bone marrow adipose tissue. Leveraging the use of [

Plasmacytoid Dendritic Cells Control Homeostasis Of Megakaryopoiesis, Florian Gaertner, Marco Colonna, Et Al.

2020-Current year OA Pubs

Platelet homeostasis is essential for vascular integrity and immune defence

Ccr2+ Monocytes Promote White Matter Injury And Cognitive Dysfunction After Myocardial Infarction, Edward B Thorp, Mallory Filipp, Maria Dima, Chunfeng Tan, Matthew Feinstein, Brian Popko, Matthew Deberge

Faculty, Staff and Student Publications

Survivors of myocardial infarction are at increased risk for vascular dementia. Neuroinflammation has been implicated in the pathogenesis of vascular dementia, yet little is known about the cellular and molecular mediators of neuroinflammation after myocardial infarction. Using a mouse model of myocardial infarction coupled with flow cytometric analyses and immunohistochemistry, we discovered increased monocyte abundance in the brain after myocardial infarction, which was associated with increases in brain-resident perivascular macrophages and microglia. Myeloid cell recruitment and activation was also observed in post-mortem brains of humans that died after myocardial infarction. Spatial and single cell transcriptomic profiling of brain-resident myeloid cells …

Impact Of Lifetime Stressor Exposure On Neuroenergetics In Schizophrenia Spectrum Disorders, Joshua Chiappelli, Anya Savransky, Yizhou Ma, Si Gao, Mark D Kvarta, Peter Kochunov, George M Slavich, L Elliot Hong

Faculty, Staff and Student Publications

N-acetylasparate and lactate are two prominent brain metabolites closely related to mitochondrial functioning. Prior research revealing lower levels of NAA and higher levels of lactate in the cerebral cortex of patients with schizophrenia suggest possible abnormalities in the energy supply pathway necessary for brain function. Given that stress and adversity are a strong risk factor for a variety of mental health problems, including psychotic disorders, we investigated the hypothesis that stress contributes to abnormal neuroenergetics in patients with schizophrenia. To test this hypothesis, we used the Stress and Adversity Inventory (STRAIN) to comprehensively assess the lifetime stressor exposure profiles of …

Cancer Incidence After Diagnosis Of Abdominal Aortic Aneurysm-Brief Report, Lingfeng Luo, Allen M Haas, Caitlin F Bell, Richard A Baylis, Shaunak S Adkar, Changhao Fu, Ivan Angelov, Sharon H Giordano, Derek Klarin, Nicholas J Leeper, Kevin T Nead

Faculty, Staff and Student Publications

Background: Epidemiological and mechanistic data support a potential causal link between cardiovascular disease (CVD) and cancer. Abdominal aortic aneurysms (AAAs) represent a common form of CVD with at least partially distinct genetic and biologic pathogenesis from other forms of CVD. The risk of cancer and how this risk differs compared with other forms of CVD, is unknown among AAA patients. We conducted a retrospective cohort study using the IBM MarketScan Research Database to test whether individuals with AAA have a higher cancer risk independent of traditional shared risk factors.

Methods: All individuals ≥18 years of age with ≥36 months of …

Plasmacytoid Dendritic Cells Control Homeostasis Of Megakaryopoiesis, Florian Gaertner, Hellen Ishikawa-Ankerhold, Susanne Stutte, Wenwen Fu, Jutta Weitz, Anne Dueck, Bhavishya Nelakuditi, Valeria Fumagalli, Dominic Van Den Heuvel, Larissa Belz, Gulnoza Sobirova, Zhe Zhang, Anna Titova, Alejandro Martinez Navarro, Kami Pekayvaz, Michael Lorenz, Louisa Von Baumgarten, Jan Kranich, Tobias Straub, Bastian Popper, Vanessa Zheden, Walter Anton Kaufmann, Chenglong Guo, Guido Piontek, Saskia Von Stillfried, Peter Boor, Marco Colonna, Sebastian Clauß, Christian Schulz, Thomas Brocker, Barbara Walzog, Christoph Scheiermann, William C Aird, Claus Nerlov, Konstantin Stark, Tobias Petzold, Stefan Engelhardt, Michael Sixt, Robert Hauschild, Martina Rudelius, Robert A J Oostendorp, Matteo Iannacone, Matthias Heinig, Steffen Massberg

Faculty, Staff and Student Publications

Platelet homeostasis is essential for vascular integrity and immune defence1,2. Although the process of platelet formation by fragmenting megakaryocytes (MKs; thrombopoiesis) has been extensively studied, the cellular and molecular mechanisms required to constantly replenish the pool of MKs by their progenitor cells (megakaryopoiesis) remains unclear3,4. Here we use intravital imaging to track the cellular dynamics of megakaryopoiesis over days. We identify plasmacytoid dendritic cells (pDCs) as homeostatic sensors that monitor the bone marrow for apoptotic MKs and deliver IFNα to the MK niche triggering local on-demand proliferation and maturation of MK progenitors. This pDC-dependent feedback loop is crucial for MK …

Randomized Placebo-Controlled, Biomarker-Stratified Phase Ib Microbiome Modulation In Melanoma: Impact Of Antibiotic Preconditioning On Microbiome And Immunity, Isabella C Glitza, Yongwoo David Seo, Christine N Spencer, Jennifer R Wortman, Elizabeth M Burton, Farah A Alayli, Christopher P Loo, Shikha Gautam, Ashish Damania, Julie Densmore, Justin Fairchild, Christopher R Cabanski, Matthew C Wong, Christine B Peterson, Brian Weiner, Nathan Hicks, John Aunins, Christopher Mcchalicher, Emily Walsh, Michael T Tetzlaff, Omid Hamid, Patrick A Ott, Genevieve M Boland, Ryan J Sullivan, Kenneth F Grossmann, Nadim J Ajami, Theresa Lavallee, Matthew R Henn, Hussein A Tawbi, Jennifer A Wargo

Faculty, Staff and Student Publications

Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate …

Genome-Wide Association Study Identifies High-Impact Susceptibility Loci For Hcc In North America, Manal M Hassan, Donghui Li, Younghun Han, Jinyoung Byun, Rikita I Hatia, Erping Long, Jiyeon Choi, Robin Kate Kelley, Sean P Cleary, Anna S Lok, Paige Bracci, Jennifer B Permuth, Roxana Bucur, Jian-Min Yuan, Amit G Singal, Prasun K Jalal, R Mark Ghobrial, Regina M Santella, Yuko Kono, Dimpy P Shah, Mindie H Nguyen, Geoffrey Liu, Neehar D Parikh, Richard Kim, Hui-Chen Wu, Hashem El-Serag, Ping Chang, Yanan Li, Yun Shin Chun, Sunyoung S Lee, Jian Gu, Ernest Hawk, Ryan Sun, Chad Huff, Asif Rashid, Hesham M Amin, Laura Beretta, Robert A Wolff, Samuel O Antwi, Yehuda Patt, Lu-Yu Hwang, Alison P Klein, Karen Zhang, Mikayla A Schmidt, Donna L White, John A Goss, Saira A Khaderi, Jorge A Marrero, Francisco G Cigarroa, Pankil K Shah, Ahmed O Kaseb, Lewis R Roberts, Christopher I Amos

Faculty, Staff and Student Publications

BACKGROUND AND AIMS: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP).

APPROACH AND RESULTS: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a …

Nfatc1 Is Required For Vitamin D- And Phosphate-Mediated Regulation Of Osteocyte Lacuno-Canalicular Remodeling, Supriya Jagga, Ashleigh Hughes, Niusha Manoochehri Arash, Melissa Sorsby, Daniel J Brooks, Paola Divieti Pajevic, Eva S Liu

Staff and Researcher Publications

Osteocytes are embedded in lacunae and connected by canaliculi (lacuno-canalicular network, LCN). Bones from mice with X-linked hypophosphatemia (Hyp), which have impaired production of 1,25 dihydroxyvitamin D (1,25D) and hypophosphatemia, have abnormal LCN structure that is improved by treatment with 1,25D or an anti-FGF23 targeting antibody, supporting roles for 1,25D and phosphate in regulating LCN remodeling. Bones from mice lacking the vitamin D receptor (VDR) in osteocytes (Vdrf/f;Dmp1Cre+) and mice lacking the sodium phosphate transporter 2a (Npt2aKO), which have low serum phosphate with high serum 1,25D, have impaired LCN organization, demonstrating that osteocyte-specific actions of 1,25D and hypophosphatemia regulate LCN …

Distinguishing Recrudescence From Reinfection In Lymphatic Filariasis, Young-Jun Choi, Kerstin Fischer, Aboulaye Méité, Benjamin G Koudou, Peter U Fischer, Makedonka Mitreva

2020-Current year OA Pubs

BACKGROUND: The Global Program to Eliminate Lymphatic Filariasis (GPELF) is the largest public health program based on mass drug administration (MDA). Despite decades of MDA, ongoing transmission in some countries remains a challenge. To optimise interventions, it is critical to differentiate between recrudescence and new infections. Since adult filariae are inaccessible in humans, deriving a method that relies on the offspring microfilariae (mf) is necessary.

METHODS: We developed a genome amplification and kinship analysis-based approach using Brugia malayi samples from gerbils, and applied it to analyse Wuchereria bancrofti mf from humans in Côte d'Ivoire. We examined the pre-treatment genetic diversity …

Clinicopathologic Dissociation: Robust Lafora Body Accumulation In Malin Ko Mice Without Observable Changes In Home-Cage Behavior, Vaishnav Krishnan, Jun Wu, Arindam Ghosh Mazumder, Jessica L Kamen, Catharina Schirmer, Nandani Adhyapak, John Samuel Bass, Samuel C Lee, Atul Maheshwari, Gemma Molinaro, Jay R Gibson, Kimberly M Huber, Berge A Minassian

Faculty, Staff and Students Publications

Lafora disease (LD) is a syndrome of progressive myoclonic epilepsy and cumulative neurocognitive deterioration caused by recessively inherited genetic lesions of EPM2A (laforin) or NHLRC1 (malin). Neuropsychiatric symptomatology in LD is thought to be directly downstream of neuronal and astrocytic polyglucosan aggregates, termed Lafora bodies (LBs), which faithfully accumulate in an age-dependent manner in all mouse models of LD. In this study, we applied home-cage monitoring to examine the extent of neurobehavioral deterioration in a model of malin-deficient LD as a means to identify robust preclinical endpoints that may guide the selection of novel genetic treatments. At 6 weeks, ∼6-7 …

Exome Sequencing Identifies Novel Genes Underlying Primary Congenital Glaucoma In The National Birth Defects Prevention Study, Elizabeth E Blue, Kristin J Moore, Kari E North, Tania A Desrosiers, Suzan L Carmichael, Janson J White, Jessica X Chong, Michael J Bamshad, Mary M Jenkins, Lynn M Almli, Lawrence C Brody, Sharon F Freedman, Jennita Reefhuis, Paul A Romitti, Gary M Shaw, Martha Werler, Denise M Kay, Marilyn L Browne, Marcia L Feldkamp, Richard H Finnell, Wendy N Nembhard, Faith Pangilinan, Andrew F Olshan, National Institutes Of Health Intramural Sequencing Center, University Of Washington Center For Mendelian Genomics, National Birth Defects Prevention Study

Faculty, Staff and Students Publications

Background: Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, CYP1B1, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants.

Methods: We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention …

A Klf2-Bmper-Smad1/5 Checkpoint Regulates High Fluid Shear Stress-Mediated Artery Remodeling, Hanqiang Deng, Jiasheng Zhang, Yewei Wang, Divyesh Joshi, Xinchun Pi, Sarah De Val, Martin A Schwartz

Faculty, Staff and Students Publications

Vascular remodeling to match arterial diameter to tissue requirements commonly fails in ischemic disease. Endothelial cells sense fluid shear stress (FSS) from blood flow to maintain FSS within a narrow range in healthy vessels. Thus, high FSS induces vessel outward remodeling, but mechanisms are poorly understood. We previously reported that Smad1/5 is maximally activated at physiological FSS. Smad1/5 limits Akt activation, suggesting that inhibiting Smad1/5 may facilitate outward remodeling. Here we report that high FSS suppresses Smad1/5 by elevating KLF2, which induces the bone morphogenetic protein (BMP) pathway inhibitor, BMP-binding endothelial regulator (BMPER), thereby de-inhibiting Akt. In mice, surgically induced …

Mhealth-Based Just-In-Time Adaptive Intervention To Improve The Physical Activity Levels Of Individuals With Spinal Cord Injury: Protocol For A Randomized Controlled Trial, Rachel Carey, Ha Le, Donna Coffman, Inbal Nahum-Shani, Mohanraj Thirumalai, Cole Hagen, Laura Baehr, M. Schmidt-Read, Marlyn Lamboy, Stephanie A Kolakowsky-Hayner, Ralph Marino, Stephen Intille, Shivayogi Hiremath

Moss-Magee Rehabilitation Papers

BACKGROUND: The lack of regular physical activity (PA) in individuals with spinal cord injury (SCI) in the United States is an ongoing health crisis. Regular PA and exercise-based interventions have been linked with improved outcomes and healthier lifestyles among those with SCI. Providing people with an accurate estimate of their everyday PA level can promote PA. Furthermore, PA tracking can be combined with mobile health technology such as smartphones and smartwatches to provide a just-in-time adaptive intervention (JITAI) for individuals with SCI as they go about everyday life. A JITAI can prompt an individual to set a PA goal or …

Aging- And Alcohol-Associated Spatial Transcriptomic Signature In Mouse Acute Pancreatitis Reveals Heterogeneity Of Inflammation And Potential Pathogenic Factors, Rachel R Tindall, Yuntao Yang, Isabella Hernandez, Amy Qin, Jiajing Li, Yinjie Zhang, Thomas H Gomez, Mamoun Younes, Qiang Shen, Jennifer M Bailey-Lundberg, Zhongming Zhao, Daniel Kraushaar, Patricia Castro, Yanna Cao, W Jim Zheng, Tien C Ko

Faculty, Staff and Student Publications

The rapidly aging population is consuming more alcohol, leading to increased alcohol-associated acute pancreatitis (AAP) with high mortality. However, the mechanisms remain undefined, and currently there are no effective therapies available. This study aims to elucidate aging- and alcohol-associated spatial transcriptomic signature by establishing an aging AAP mouse model and applying Visium spatial transcriptomics for understanding of the mechanisms in the context of the pancreatic tissue. Upon alcohol diet feeding and caerulein treatment, aging mice (18 months) developed significantly more severe AAP with 5.0-fold increase of injury score and 2.4-fold increase of amylase compared to young mice (3 months). Via …

Detection Of Early-Stage Nash Using Non-Invasive Hyperpolarized 13c Metabolic Imaging, Cornelius Von Morze, Tyler Blazey, Ashley Shaw, William M Spees, Kooresh I Shoghi, Michael A Ohliger

2020-Current year OA Pubs

Non-alcoholic steatohepatitis (NASH) is characterized from its early stages by a profound remodeling of the liver microenvironment, encompassing changes in the composition and activities of multiple cell types and associated gene expression patterns. Hyperpolarized (HP)

Examining Associations Between Smartphone Use And Clinical Severity In Frontotemporal Dementia: Proof-Of-Concept Study, Emily W Paolillo, Nupur Ghoshal, Et Al.

2020-Current year OA Pubs

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged <65 years. Several challenges to conducting in-person evaluations in FTLD illustrate an urgent need to develop remote, accessible, and low-burden assessment techniques. Studies of unobtrusive monitoring of at-home computer use in older adults with mild cognitive impairment show that declining function is reflected in reduced computer use; however, associations with smartphone use are unknown.

OBJECTIVE: This study aims to characterize daily trajectories in smartphone battery use, a proxy for smartphone use, and examine relationships with clinical indicators of severity in FTLD.

METHODS: Participants were 231 adults (mean age 52.5, SD 14.9 years; n=94, 40.7% men; n=223, 96.5% non-Hispanic White) enrolled in the Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL study) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS study) Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Mobile App study, including 49 (21.2%) with mild neurobehavioral changes and no functional …

Role Of The Afferent Lymph As An Immunological Conduit To Analyze Tissue Antigenic And Inflammatory Load, Padma P Nanaware, Cheryl F Lichti, Xiaoxiao Wan, Emil R Unanue, Et Al.

2020-Current year OA Pubs

The lymphatic fluid is the conduit by which part of the tissue "omics" is transported to the draining lymph node for immunosurveillance. Following cannulation of the pre-nodal cervical and mesenteric afferent lymphatics, herein we investigate the lymph proteomic composition, uncovering that its composition varies according to the tissue of origin. Tissue specificity is also reflected in the dendritic cell-major histocompatibility complex class II-eluted immunopeptidome harvested from the cervical and mesenteric nodes. Following inflammatory disruption of the gut barrier, the lymph antigenic and inflammatory loads are analyzed in both mice and subjects with inflammatory bowel diseases. Gastrointestinal tissue damage reflects the …

Injury-Induced Foxm1 Expression In The Mouse Kidney Drives Epithelial Proliferation By A Cyclin F-Dependent Mechanism, Megan L. Noonan, Yoshiharu Muto, Yasuhiro Yoshimura, Aidan Leckie-Harre, Haojia Wu, Vladimir V. Kalinichenko, Benjamin D. Humphreys, Monica Chang-Panesso

2020-Current year OA Pubs

Acute kidney injury (AKI) strongly upregulates the transcription factor Foxm1 in the proximal tubule in vivo, and Foxm1 drives epithelial proliferation in vitro. Here, we report that deletion of Foxm1 either with a nephron-specific Cre driver or by inducible global deletion reduced proximal tubule proliferation after ischemic injury in vivo. Foxm1 deletion led to increased AKI to chronic kidney disease transition, with enhanced fibrosis and ongoing tubule injury 6 weeks after injury. We report ERK mediated FOXM1 induction downstream of the EGFR in primary proximal tubule cells. We defined FOXM1 genomic binding sites by cleavage under targets and release using …

Hypoxia Inducible Factor 2Α Promotes Tolerogenic Macrophage Development During Cardiac Transplantation Through Transcriptional Regulation Of Colony Stimulating Factor 1 Receptor, Matthew Deberge, Samantha Schroth, Fanfan Du, Xin Yi Yeap, Jiao-Jing Wang, Zheng Jenny Zhang, Mohammed Javeed Ansari, Evan A Scott, Edward B Thorp

Faculty, Staff and Student Publications

Solid organ transplantation mobilizes myeloid cells, including monocytes and macrophages, which are central protagonists of allograft rejection. However, myeloid cells can also be functionally reprogrammed by perioperative costimulatory blockade to promote a state of transplantation tolerance. Transplantation tolerance holds promise to reduce complications from chronic immunosuppression and promote long-term survival in transplant recipients. We sought to identify different mediators of transplantation tolerance by performing single-cell RNA sequencing of acute rejecting or tolerized cardiac allografts. This led to the unbiased identification of the transcription factor, hypoxia inducible factor (HIF)-2α, in a subset of tolerogenic monocytes. Using flow cytometric analyses and mice …

Dorsal Raphe Neurons Integrate The Values Of Reward Amount, Delay, And Uncertainty In Multi-Attribute Decision-Making, Yang-Yang Feng, Ethan S Bromberg-Martin, Ilya E Monosov

2020-Current year OA Pubs

The dorsal raphe nucleus (DRN) is implicated in psychiatric disorders that feature impaired sensitivity to reward amount, impulsivity when facing reward delays, and risk-seeking when confronting reward uncertainty. However, it has been unclear whether and how DRN neurons signal reward amount, reward delay, and reward uncertainty during multi-attribute value-based decision-making, where subjects consider these attributes to make a choice. We recorded DRN neurons as monkeys chose between offers whose attributes, namely expected reward amount, reward delay, and reward uncertainty, varied independently. Many DRN neurons signaled offer attributes, and this population tended to integrate the attributes in a manner that reflected …

Age, Sex And Alzheimer's Disease: A Longitudinal Study Of 3xtg-Ad Mice Reveals Sex-Specific Disease Trajectories And Inflammatory Responses Mirrored In Postmortem Brains From Alzheimer's Patients., Alicia J Barber, Carmen L Del Genio, Anna Beth Swain, Elizabeth M Pizzi, Sarah C Watson, Vedant N Tapiavala, George J Zanazzi, Arti B Gaur

Faculty Research 2024

BACKGROUND: Aging and sex are major risk factors for developing late-onset Alzheimer's disease. Compared to men, women experience worse neuropathological burden and cognitive decline despite living longer with the disease. Similarly, male 3xTg-AD mice, developed to model Alzheimer's disease, no longer consistently exhibit standard Alzheimer's neuropathology yet experience higher rates of mortality - providing a unique opportunity to further elucidate this dichotomy. We hypothesized that sex differences in the biological aging process yield distinct pathological and molecular Alzheimer's disease signatures in males and females, which could be harnessed for therapeutic and biomarker development.

METHODS: We aged male and female, 3xTg-AD …