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Differential Expression Of Wnt5a Long And Short Isoforms In Non-Muscle-Invasive Bladder Urothelial Carcinoma., Amy M Strope, Cody Phillips, Sabin Khadgi, Scott A Jenkinson, Karen T Coschigano, Ramiro Malgor

Oncology Articles

Wnt ligands belong to a family of secreted glycoproteins in which binding to a range of receptors/co-receptors activates several intracellular pathways. WNT5A, a member of the Wnt family, is classified as a non-canonical Wnt whose activation triggers planar cell polarity (PCP) and Ca+2 downstream pathways. Aberrant expression of WNT5A has been shown to play both protective and harmful roles in an array of conditions, such as inflammatory disease and cancer. In the present study, using histological, immunohistochemical, and molecular methods, we investigated the expression of two isoforms of WNT5A, WNT5A-Short (WNT5A-S) and WNT5A-Long (WNT5A-L) in bladder urothelial carcinoma (UC). Three …

Whamm Functions In Kidney Reabsorption And Polymerizes Actin To Promote Autophagosomal Membrane Closure And Cargo Sequestration., Alyssa M Coulter, Valerie Cortés, Corey J Theodore, Rachel E Cianciolo, Ron Korstanje, Kenneth G Campellone

Faculty Research 2024

The actin cytoskeleton is essential for many functions of eukaryotic cells, but the factors that nucleate actin assembly are not well understood at the organismal level or in the context of disease. To explore the function of the actin nucleation factor WHAMM in mice, we examined how Whamm inactivation impacts kidney physiology and cellular proteostasis. We show that male WHAMM knockout mice excrete elevated levels of albumin, glucose, phosphate, and amino acids, and display structural abnormalities of the kidney proximal tu- bule, suggesting that WHAMM activity is important for nutrient reabsorption. In kidney tis- sue, the loss of WHAMM results …

Metabolomics Profiling Reveals Distinct, Sex-Specific Signatures In Serum And Brain Metabolomes In Mouse Models Of Alzheimer's Disease., Ravi S Pandey, Mattias Arnold, Richa Batra, Jan Krumsiek, Kevin P Kotredes, Dylan Garceau, Harriet M. Jackson, Michael Sasner, Gareth R Howell, Rima Kaddurah-Daouk, Gregory W. Carter

Faculty Research 2024

INTRODUCTION: Increasing evidence suggests that metabolic impairments contribute to early Alzheimer's disease (AD) mechanisms and subsequent dementia. Signals in metabolic pathways conserved across species can facilitate translation.

METHODS: We investigated differences in serum and brain metabolites between the early-onset 5XFAD and late-onset LOAD1 (APOE4.Trem2*R47H) mouse models of AD to C57BL/6J controls at 6 months of age.

RESULTS: We identified sex differences for several classes of metabolites, such as glycerophospholipids, sphingolipids, and amino acids. Metabolic signatures were notably different between brain and serum in both mouse models. The 5XFAD mice exhibited stronger differences in brain metabolites, whereas LOAD1 mice showed more …

Characterizing Molecular And Synaptic Signatures In Mouse Models Of Late-Onset Alzheimer's Disease Independent Of Amyloid And Tau Pathology., Kevin P Kotredes, Ravi S Pandey, Scott Persohn, Kierra Elderidge, Charles P Burton, Ethan W Miner, Kathryn A Haynes, Diogo Francisco S Santos, Sean-Paul Williams, Nicholas Heaton, Cynthia M Ingraham, Christopher Lloyd, Dylan Garceau, Rita O'Rourke, Sarah Herrick, Claudia Rangel-Barajas, Surendra Maharjan, Nian Wang, Michael Sasner, Bruce T Lamb, Paul R Territo, Stacey J Sukoff Rizzo, Gregory W. Carter, Gareth R Howell, Adrian L Oblak

Faculty Research 2024

INTRODUCTION: MODEL-AD (Model Organism Development and Evaluation for Late-Onset Alzheimer's Disease) is creating and distributing novel mouse models with humanized, clinically relevant genetic risk factors to capture the trajectory and progression of late-onset Alzheimer's disease (LOAD) more accurately.

METHODS: We created the LOAD2 model by combining apolipoprotein E4 (APOE4), Trem2*R47H, and humanized amyloid-beta (Aβ). Mice were subjected to a control diet or a high-fat/high-sugar diet (LOAD2+HFD). We assessed disease-relevant outcome measures in plasma and brain including neuroinflammation, Aβ, neurodegeneration, neuroimaging, and multi-omics.

RESULTS: By 18 months, LOAD2+HFD mice exhibited sex-specific neuron loss, elevated insoluble brain Aβ42, increased plasma neurofilament light …

The Complete Sequence And Comparative Analysis Of Ape Sex Chromosomes., Kateryna D Makova, Brandon D Pickett, Robert S Harris, Gabrielle A Hartley, Monika Cechova, Karol Pal, Sergey Nurk, Dongahn Yoo, Qiuhui Li, Prajna Hebbar, Barbara C Mcgrath, Francesca Antonacci, Margaux Aubel, Arjun Biddanda, Matthew Borchers, Erich Bornberg-Bauer, Gerard G Bouffard, Shelise Y Brooks, Lucia Carbone, Laura Carrel, Andrew Carroll, Pi-Chuan Chang, Chen-Shan Chin, Daniel E Cook, Sarah J C Craig, Luciana De Gennaro, Mark Diekhans, Amalia Dutra, Gage H Garcia, Patrick G S Grady, Richard E Green, Diana Haddad, Pille Hallast, William T Harvey, Glenn Hickey, David A Hillis, Savannah J Hoyt, Hyeonsoo Jeong, Kaivan Kamali, Sergei L Kosakovsky Pond, Troy M Lapolice, Charles Lee, Alexandra P Lewis, Yong-Hwee E Loh, Patrick Masterson, Kelly M Mcgarvey, Rajiv C Mccoy, Paul Medvedev, Karen H Miga, Katherine M Munson, Evgenia Pak, Benedict Paten, Brendan J Pinto, Tamara Potapova, Arang Rhie, Joana L Rocha, Fedor Ryabov, Oliver A Ryder, Samuel Sacco, Kishwar Shafin, Valery A Shepelev, Viviane Slon, Steven J Solar, Jessica M Storer, Peter H Sudmant, Sweetalana, Alex Sweeten, Michael G Tassia, Françoise Thibaud-Nissen, Mario Ventura, Melissa A Wilson, Alice C Young, Huiqing Zeng, Xinru Zhang, Zachary A Szpiech, Christian D Huber, Jennifer L Gerton, Soojin V Yi, Michael C Schatz, Ivan A Alexandrov, Sergey Koren, Rachel J O'Neill, Evan E Eichler, Adam M Phillippy

Faculty Research 2024

Apes possess two sex chromosomes-the male-specific Y chromosome and the X chromosome, which is present in both males and females. The Y chromosome is crucial for male reproduction, with deletions being linked to infertility

Reversal Of Propofol-Induced Depression Of The Hypoxic Ventilatory Response By Bk-Channel Blocker Ena-001: A Randomized Controlled Trial, Simone Jansen, Maarten Van Lemmen, Erik Olofsen, Laurence Moss, Joseph Pergolizzi, Thomas Miller, Robert Colucci, Monique Van Velzen, Philip Kremer, Albert Dahan, Rutger Van Der Schrier, Marieke Niesters

Department of Medicine Faculty Papers

BACKGROUND: The use of anesthetics may result in depression of the hypoxic ventilatory response. Since there are no receptor-specific antagonists for most anesthetics, there is the need for agnostic respiratory stimulants that increase respiratory drive irrespective of its cause. The authors tested whether ENA-001, an agnostic respiratory stimulant that blocks carotid body BK-channels, could restore the hypoxic ventilatory response during propofol infusion. They hypothesize that ENA-001 is able to fully restore the hypoxic ventilatory response.

METHODS: In this randomized, double-blind crossover trial, 14 male and female healthy volunteers were randomized to receive placebo and low- and high-dose ENA-001 on three …

A Delphi Panel To Build Consensus On Assessing Disease Severity And Disease Progression In Adult Patients With Hypophosphatasia In The United States., K M Dahir, Eric T. Rush, S Diaz-Mendoza, P S Kishnani

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Hypophosphatasia (HPP) is an inborn error of metabolism with a variable presentation. We conducted a modified Delphi panel to obtain expert consensus on knowledge gaps regarding disease severity and progression in adult patients with HPP.

METHODS: Healthcare professionals (HCPs) with experience managing adult patients with HPP were recruited to participate in a 3-round Delphi panel (round 1: paper survey and 1:1 interview; rounds 2-3: email survey). Panelists rated the extent of their agreement with statements about disease severity and progression in adult patients with HPP. Consensus was defined as ≥ 80% agreement.

RESULTS: Ten HCPs completed round 1; nine …

Naturalistic Assessment Of Reaction Time Variability In Older Adults At Risk For Alzheimer's Disease, Matthew S Welhaf, Hannah Wilks, Andrew J Aschenbrenner, David A Balota, Suzanne E Schindler, Tammie L S Benzinger, Brian A Gordon, Carlos Cruchaga, Chengjie Xiong, John C Morris, Jason Hassenstab

2020-Current year OA Pubs

OBJECTIVE: Maintaining attention underlies many aspects of cognition and becomes compromised early in neurodegenerative diseases like Alzheimer's disease (AD). The consistency of maintaining attention can be measured with reaction time (RT) variability. Previous work has focused on measuring such fluctuations during in-clinic testing, but recent developments in remote, smartphone-based cognitive assessments can allow one to test if these fluctuations in attention are evident in naturalistic settings and if they are sensitive to traditional clinical and cognitive markers of AD.

METHOD: Three hundred and seventy older adults (aged 75.8 +/- 5.8 years) completed a week of remote daily testing on the …

Efemp1 Haploinsufficiency Causes A Marfan-Like Hereditary Connective Tissue Disorder, Irman Forghani, Steven H Lang, Matthew J Rodier, Stephanie A Bivona, Alejo A Morales, Stephan Zuchner, Guney Bademci, Mustafa Tekin

Faculty, Staff and Students Publications

Phenotypic features of a hereditary connective tissue disorder, including craniofacial characteristics, hyperextensible skin, joint laxity, kyphoscoliosis, arachnodactyly, inguinal hernia, and diverticulosis associated with biallelic pathogenic variants in EFEMP1 have been previously described in four patients. Genome sequencing on a proband and her mother with comparable phenotypic features revealed that both patients were heterozygous for a stop-gain variant c.1084C>T (p.Arg362*). Complementary RNA-seq on fibroblasts revealed significantly reduced levels of mutant EFEMP1 transcript. Considering the absence of other molecular explanations, we extrapolated that EFEMP1 could be the cause of the patient's phenotypes. Furthermore, nonsense-mediated decay was demonstrated for the mutant allele …

Cadherin-11 Targeted Cell-Specific Liposomes Enabled Skin Fibrosis Treatment By Inducing Apoptosis, Himanshu N Bhatt, Rimpy Diwan, Igor L Estevao, Rui Dong, Jennifer Smith, Chuan Xiao, Sandeep K Agarwal, Md Nurunnabi

Faculty, Staff and Students Publications

Continuous and aberrant activation of myofibroblasts is the hallmark of pathological fibrosis (e.g., abnormal wound healing). The deposition of excessive extracellular matrix (ECM) components alters or increases the stiffness of tissue and primarily accounts for multiple organ dysfunctions. Among various proteins, Cadherin-11 (CDH11) has been reported to be overexpressed on myofibroblasts in fibrotic tissues. Anti-apoptotic proteins such as (B cell lymphoma-2) (BCL-2) are also upregulated on myofibroblasts. Therefore, we hypothesize that CDH11 could be a targeted domain for cell-specific drug delivery and targeted inhibition of BCL-2 to ameliorate the development of fibrosis in the skin. To prove our hypothesis, we …

Hyperkinetic Movement Disorder Caused By The Recurrent C892c>T Nacc1 Variant, Jonna Komulainen-Ebrahim, Salla M Kangas, Estrella López-Martín, Timothy Feyma, Fernando Scaglia, Beatriz Martínez-Delgado, Outi Kuismin, Maria Suo-Palosaari, Lucinda Carr, Reetta Hinttala, Manju A Kurian, Johanna Uusimaa

Faculty, Staff and Students Publications

BACKGROUND: Genetic syndromes of hyperkinetic movement disorders associated with epileptic encephalopathy and intellectual disability are becoming increasingly recognized. Recently, a de novo heterozygous NACC1 (nucleus accumbens-associated 1) missense variant was described in a patient cohort including one patient with a combined mitochondrial oxidative phosphorylation (OXPHOS) deficiency.

OBJECTIVES: The objective is to characterize the movement disorder in affected patients with the recurrent c.892C>T NACC1 variant and study the NACC1 protein and mitochondrial function at the cellular level.

METHODS: The movement disorder was analyzed on four patients with the NACC1 c.892C>T (p.Arg298Trp) variant. Studies on NACC1 protein and mitochondrial function …

Inherited C-Terminal Trex1 Variants Disrupt Homology-Directed Repair To Cause Senescence And Dna Damage Phenotypes In Drosophila, Mice, And Humans, Samuel D Chauvin, Fang R Zhao, W Alexander Stinson, Wei Qian, Prabhakar S Andhey, Maxim N Artyomov, Elisha D O Roberson, Jonathan J Miner, Et Al.

2020-Current year OA Pubs

Age-related microangiopathy, also known as small vessel disease (SVD), causes damage to the brain, retina, liver, and kidney. Based on the DNA damage theory of aging, we reasoned that genomic instability may underlie an SVD caused by dominant C-terminal variants in TREX1, the most abundant 3'-5' DNA exonuclease in mammals. C-terminal TREX1 variants cause an adult-onset SVD known as retinal vasculopathy with cerebral leukoencephalopathy (RVCL or RVCL-S). In RVCL, an aberrant, C-terminally truncated TREX1 mislocalizes to the nucleus due to deletion of its ER-anchoring domain. Since RVCL pathology mimics that of radiation injury, we reasoned that nuclear TREX1 would cause …

Co-Aggregation With Apolipoprotein E Modulates The Function Of Amyloid-Β In Alzheimer's Disease, Zengjie Xia, Michael R Strickland, Hong Jiang, David M Holtzman, Et Al.

2020-Current year OA Pubs

Which isoforms of apolipoprotein E (apoE) we inherit determine our risk of developing late-onset Alzheimer's Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between apoE and amyloid-β (Aβ) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with Aβ in the early stages of aggregation and then fall away as fibrillation happens. ApoE-Aβ co-aggregates account for ~50% of the mass of diffusible Aβ aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. We show how dynamic interactions between apoE and Aβ tune disease-related …

Unveiling Myeloid Transformation: T-Lgll With Eosinophilia Masking Myeloid-Associated Stat5b Mutation Culminating In Aml, Qianze Dong, Yang Wang, Yan Xiu, Xiaogang Wu, Stacey O'Neill, Howard Meyerson, Tobias Suske, Richard Moriggl, Shimin Hu, Wei Wang, Chen Zhao

Faculty, Staff and Student Publications

No abstract provided.

A Novel Missense Variant Located Within The Zinc Finger Domain Of The Gli3 Gene Was Identified In A Vietnamese Pedigree With Index Finger Polydactyly, Thy Ngoc Nguyen, Giang Son Tran, Hai Duc Hoang, Long Giang Nguyen

Faculty, Staff and Student Publications

BACKGROUND: Polydactyly, particularly of the index finger, remains an intriguing anomaly for which no specific gene or locus has been definitively linked to this phenotype. In this study, we conducted an investigation of a three-generation family displaying index finger polydactyly.

METHODS: Exome sequencing was conducted on the patient, with a filtration to identify potential causal variation. Validation of the obtained variant was conducted by Sanger sequencing, encompassing all family members.

RESULTS: Exome analysis uncovered a novel heterozygous missense variant (c.1482A>T; p.Gln494His) at the zinc finger DNA-binding domain of the GLI3 protein within the proband and all affected family members. …

Endothelial Knockdown Of The Tumor Suppressor, Wwox, Increases Inflammation In Ventilator-Induced Lung Injury, Zhenguo Zeng, Eltyeb Abdelwahid, Weiguo Chen, Christian Ascoli, Trinh Pham, Jeffrey R Jacobson, Steven M Dudek, Viswanathan Natarajan, C Marcelo Aldaz, Roberto F Machado, Sunit Singla

Faculty, Staff and Student Publications

Chronic cigarette smoke exposure decreases lung expression of WWOX which is known to protect the endothelial barrier during infectious models of acute respiratory distress syndrome (ARDS). Proteomic analysis of WWOX-silenced endothelial cells (ECs) was done using tandem mass tag mass spectrometry (TMT-MS). WWOX-silenced ECs as well as those isolated from endothelial cell Wwox knockout (EC Wwox KO) mice were subjected to cyclic stretch (18% elongation, 0.5 Hz, 4 h). Cellular lysates and media supernatant were harvested for assays of cellular signaling, protein expression, and cytokine release. These were repeated with dual silencing of WWOX and zyxin. Control and …

Association Of Tea And Coffee Consumption And Biliary Tract Cancer Risk: The Biliary Tract Cancers Pooling Project, Yu-Han Huang, Erikka Loftfield, Ilona Argirion, Hans-Olov Adami, Demetrius Albanes, Andrew T Chan, Veronika Fedirko, Gary E Fraser, Neal D Freedman, Graham G Giles, Patricia Hartge, Verena Katzke, Synnove F Knutsen, James Lacey, Linda M Liao, Juhua Luo, Roger L Milne, Katie M O'Brien, Ulrike Peters, Jenny N Poynter, Mark P Purdue, Kim Robien, Sven Sandin, Dale P Sandler, Veronica W Setiawan, Jae H Kang, Tracey G Simon, Rashmi Sinha, Trang Vopham, Stephanie J Weinstein, Emily White, Xuehong Zhang, Bin Zhu, Katherine A Mcglynn, Peter T Campbell, Mei-Hsuan Lee, Jill Koshiol

Faculty, Staff and Student Publications

Background and aims: Tea and coffee are widely consumed beverages worldwide. We evaluated their association with biliary tract cancer (BTC) incidence.

Approach and results: We pooled data from 15 studies in the Biliary Tract Cancers Pooling Project to evaluate associations between tea and coffee consumption and biliary tract cancer development. We categorized participants as nondrinkers (0 cup/day), moderate drinkers (>0 and < 3 cups/day), and heavy drinkers (≥3 cups/day). We estimated multivariable HRs and 95% CIs using Cox models. During 29,911,744 person-years of follow-up, 851 gallbladder, 588 intrahepatic bile duct, 753 extrahepatic bile duct, and 458 ampulla of Vater cancer cases were diagnosed. Individuals who drank tea showed a statistically significantly lower incidence rate of gallbladder cancer (GBC) relative to tea nondrinkers (HR=0.77; 95% CI, 0.64-0.91), and intrahepatic bile duct cancer (IHBDC) had an inverse association (HR=0.81; 95% CI, 0.66-1.00). However, no associations were observed for extrahepatic bile duct cancer (EHBDC) or ampulla of Vater cancer (AVC). In contrast, coffee consumption was positively associated with GBC, with a higher incidence rate for individuals consuming more coffee (HR< 3 cups/day =1.29; 95% CI, 1.01-1.66; HR≥3 cups/day =1.49; 95% CI, 1.11-1.99, Ptrend=0.01) relative to coffee nondrinkers. However, there was no association between coffee consumption and GBC when restricted to coffee drinkers. There was little evidence of associations between coffee consumption and other biliary tract cancers.

Conclusions: Tea consumption was associated with a lower incidence of GBC and possibly IHBDC. Further research is warranted to replicate the observed positive association between coffee and GBC.

Mesenchymal-Specific Alms1 Knockout In Mice Recapitulates Metabolic Features Of Alström Syndrome, Eleanor J Mckay, Ineke Luijten, Xiong Weng, Pablo B Martinez De Morentin, Elvira De Frutos González, Zhanguo Gao, Mikhail G Kolonin, Lora K Heisler, Robert K Semple

Faculty, Staff and Student Publications

OBJECTIVE: Alström Syndrome (AS), caused by biallelic ALMS1 mutations, includes obesity with disproportionately severe insulin resistant diabetes, dyslipidemia, and fatty liver. Prior studies suggest that hyperphagia is accounted for by loss of ALMS1 function in hypothalamic neurones, whereas disproportionate metabolic complications may be due to impaired adipose tissue expandability. We tested this by comparing the metabolic effects of global and mesenchymal stem cell (MSC)-specific Alms1 knockout.

METHODS: Global Alms1 knockout (KO) mice were generated by crossing floxed Alms1 and CAG-Cre mice. A Pdgfrα-Cre driver was used to abrogate Alms1 function selectively in MSCs and their descendants, including preadipocytes. We combined …

Individual Disruption Of 12 Testis-Enriched Genes Via The Crispr/Cas9 System Does Not Affect The Fertility Of Male Mice, Akira Suzuki, Norikazu Yabuta, Keisuke Shimada, Daisuke Mashiko, Keizo Tokuhiro, Yuki Oyama, Haruhiko Miyata, Thomas X Garcia, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

More than 1200 genes have been shown in the database to be expressed predominantly in the mouse testes. Advances in genome editing technologies such as the CRISPR/Cas9 system have made it possible to create genetically engineered mice more rapidly and efficiently than with conventional methods, which can be utilized to screen genes essential for male fertility by knocking out testis-enriched genes. Finding such genes related to male fertility would not only help us understand the etiology of human infertility but also lead to the development of male contraceptives. In this study, we generated knockout mice for 12 genes (Acrv1, Adgrf3, …

Purkinje Cell Dysfunction Causes Disrupted Sleep In Ataxic Mice, Luis E Salazar Leon, Amanda M Brown, Heet Kaku, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

Purkinje cell dysfunction disrupts movement and causes disorders such as ataxia. Recent evidence suggests that Purkinje cell dysfunction may also alter sleep regulation. Here, we used an ataxic mouse model generated by silencing Purkinje cell neurotransmission (L7Cre;Vgatfx/fx) to better understand how cerebellar dysfunction impacts sleep physiology. We focused our analysis on sleep architecture and electrocorticography (ECoG) patterns based on their relevance to extracting physiological measurements during sleep. We found that circadian activity was unaltered in the mutant mice, although their sleep parameters and ECoG patterns were modified. The L7Cre;Vgatfx/fx mutant mice had decreased wakefulness and rapid eye movement (REM) sleep, …

Persistent ∆Fosb Expression Limits Recurrent Seizure Activity And Provides Neuroprotection In The Dentate Gyrus Of App Mice, Gabriel S Stephens, Jin Park, Andrew Eagle, Jason You, Manuel Silva-Pérez, Chia-Hsuan Fu, Sumin Choi, Corey P St Romain, Chiho Sugimoto, Shelly A Buffington, Yi Zheng, Mauro Costa-Mattioli, Yin Liu, A J Robison, Jeannie Chin

Faculty, Staff and Student Publications

Recurrent seizures lead to accumulation of the activity-dependent transcription factor ∆FosB in hippocampal dentate granule cells in both mouse models of epilepsy and mouse models of Alzheimer's disease (AD), which is also associated with increased incidence of seizures. In patients with AD and related mouse models, the degree of ∆FosB accumulation corresponds with increasing severity of cognitive deficits. We previously found that ∆FosB impairs spatial memory in mice by epigenetically regulating expression of target genes such as calbindin that are involved in synaptic plasticity. However, the suppression of calbindin in conditions of neuronal hyperexcitability has been demonstrated to provide neuroprotection …

Serum Extracellular Vesicle Protein Profiling For Prediction Of Corneal Transplant Rejection, Hyun Ju Lee, Eun-Hye Bae, Jong Min Choi, Hyemee Kim, Hyeon Ji Kim, Heather Barreda, Sung Yun Jung, Joo Youn Oh, Ryang Hwa Lee

Faculty, Staff and Students Publications

Background: Corneal transplantation is the most common transplant procedure worldwide. Despite immune and angiogenic privilege of the cornea, 50% to 70% of corneal transplants fail in high-risk recipients, primarily because of immune rejection. Therefore, it is crucial to identify predictive biomarkers of rejection to improve transplant survival.

Methods: In search for predictive biomarkers, we performed proteomics analysis of serum extracellular vesicles (EVs) in a fully major histocompatibility complex-mismatched (C57BL/6-to-BALB/c) murine corneal transplantation model, wherein 50% of transplants undergo rejection by day 28 following transplantation.

Results: Our time course study revealed a decrease in the number of serum EVs on day …

Variant-Specific Pathophysiological Mechanisms Of Aff3 Differently Influence Transcriptome Profiles, Sissy Bassani, Jacqueline Chrast, Giovanna Ambrosini, Norine Voisin, Frédéric Schütz, Alfredo Brusco, Fabio Sirchia, Lydia Turban, Susanna Schubert, Rami Abou Jamra, Jan-Ulrich Schlump, Desiree Demille, Pinar Bayrak-Toydemir, Gary Rex Nelson, Kristen Nicole Wong, Laura Duncan, Mackenzie Mosera, Christian Gilissen, Lisenka E L M Vissers, Rolph Pfundt, Rogier Kersseboom, Hilde Yttervik, Geir Åsmund Myge Hansen, Marie Falkenberg Smeland, Kameryn M Butler, Michael J Lyons, Claudia M B Carvalho, Chaofan Zhang, James R Lupski, Lorraine Potocki, Leticia Flores-Gallegos, Rodrigo Morales-Toquero, Florence Petit, Binnaz Yalcin, Annabelle Tuttle, Houda Zghal Elloumi, Lane Mccormick, Mary Kukolich, Oliver Klaas, Judit Horvath, Marcello Scala, Michele Iacomino, Francesca Operto, Federico Zara, Karin Writzl, Aleš Maver, Maria K Haanpää, Pia Pohjola, Harri Arikka, Anneke J A Kievit, Camilla Calandrini, Christian Iseli, Nicolas Guex, Alexandre Reymond

Faculty, Staff and Students Publications

BACKGROUND: We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects.

METHODS: Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants.

RESULTS: We identified …

Propofol Enhancement Of Slow Wave Sleep To Target The Nexus Of Geriatric Depression And Cognitive Dysfunction: Protocol For A Phase I Open Label Trial, Rachel Lynn Rios, Michael Green, S Kendall Smith, Mohammadmehdi Kafashan, Shinung Ching, Nuri B Farber, Nan Lin, Brendan P Lucey, Charles F Reynolds, Eric J Lenze, Ben Julian Agustin Palanca, Swiped Study Team

2020-Current year OA Pubs

INTRODUCTION: Late-life treatment-resistant depression (LL-TRD) is common and increases risk for accelerated ageing and cognitive decline. Impaired sleep is common in LL-TRD and is a risk factor for cognitive decline. Slow wave sleep (SWS) has been implicated in key processes including synaptic plasticity and memory. A deficiency in SWS may be a core component of depression pathophysiology. The anaesthetic propofol can induce electroencephalographic (EEG) slow waves that resemble SWS. Propofol may enhance SWS and oral antidepressant therapy, but relationships are unclear. We hypothesise that propofol infusions will enhance SWS and improve depression in older adults with LL-TRD. This hypothesis has …

Differential Roles Of Key Brain Regions: Ventral Tegmental Area, Locus Coeruleus, Dorsal Raphe, Nucleus Accumbens, Caudate Nucleus, And Prefrontal Cortex In Regulating Response To Methylphenidate: Insights From Neuronal And Behavioral Studies In Freely Behaving Rats, Nachum Dafny, Catherine Claussen, Emilee Frazier, Yin Liu

Faculty, Staff and Student Publications

A total of 3102 neurons were recorded before and following acute and chronic methylphenidate (MPD) administration. Acute MPD exposure elicits mainly increases in neuronal and behavioral activity in dose–response characteristics. The response to chronic MPD exposure, as compared to acute 0.6, 2.5, or 10.0 mg/kg MPD administration, elicits electrophysiological and behavioral sensitization in some animals and electrophysiological and behavioral tolerance in others when the neuronal recording evaluations were performed based on the animals’ behavioral responses, or amount of locomotor activity, to chronic MPD exposure. The majority of neurons recorded from those expressing behavioral sensitization responded to chronic MPD with further …

Loss Of Lpar6 And Cab39l Dysregulates The Basal-To-Luminal Urothelial Differentiation Program, Contributing To Bladder Carcinogenesis, Sangkyou Lee, Jolanta Bondaruk, Yishan Wang, Huiqin Chen, June Goo Lee, Tadeusz Majewski, Rachel D Mullen, David Cogdell, Jiansong Chen, Ziqiao Wang, Hui Yao, Pawel Kus, Joon Jeong, Ilkyun Lee, Woonyoung Choi, Neema Navai, Charles Guo, Colin Dinney, Keith Baggerly, Cathy Mendelsohn, David Mcconkey, Richard R Behringer, Marek Kimmel, Peng Wei, Bogdan Czerniak

Faculty, Staff and Student Publications

We describe a strategy that combines histologic and molecular mapping that permits interrogation of the chronology of changes associated with cancer development on a whole-organ scale. Using this approach, we present the sequence of alterations around RB1 in the development of bladder cancer. We show that RB1 is not involved in initial expansion of the preneoplastic clone. Instead, we found a set of contiguous genes that we term "forerunner" genes whose silencing is associated with the development of plaque-like field effects initiating carcinogenesis. Specifically, we identified five candidate forerunner genes (ITM2B, LPAR6, MLNR, CAB39L, and ARL11) mapping near RB1. Two …

Thbs1 Regulates Skeletal Muscle Mass In A Tgfβ-Smad2/3-Atf4-Dependent Manner, Davy Vanhoutte, Tobias G Schips, Rachel A Minerath, Jiuzhou Huo, Naga Swathi Sree Kavuri, Vikram Prasad, Suh-Chin Lin, Michael J Bround, Michelle A Sargent, Christopher M Adams, Jeffery D Molkentin

Faculty, Staff and Students Publications

Loss of muscle mass is a feature of chronic illness and aging. Here, we report that skeletal muscle-specific thrombospondin-1 transgenic mice (Thbs1 Tg) have profound muscle atrophy with age-dependent decreases in exercise capacity and premature lethality. Mechanistically, Thbs1 activates transforming growth factor β (TGFβ)-Smad2/3 signaling, which also induces activating transcription factor 4 (ATF4) expression that together modulates the autophagy-lysosomal pathway (ALP) and ubiquitin-proteasome system (UPS) to facilitate muscle atrophy. Indeed, myofiber-specific inhibition of TGFβ-receptor signaling represses the induction of ATF4, normalizes ALP and UPS, and partially restores muscle mass in Thbs1 Tg mice. Similarly, myofiber-specific deletion of Smad2 and Smad3 …

Metabolic Regulation Of Single Synaptic Vesicle Exo- And Endocytosis In Hippocampal Synapses, Jongyun Myeong, Marion I Stunault, Vitaly A Klyachko, Ghazaleh Ashrafi

2020-Current year OA Pubs

Glucose has long been considered a primary energy source for synaptic function. However, it remains unclear to what extent alternative fuels, such as lactate/pyruvate, contribute to powering synaptic transmission. By detecting individual release events in hippocampal synapses, we find that mitochondrial ATP production regulates basal vesicle release probability and release location within the active zone (AZ), evoked by single action potentials. Mitochondrial inhibition shifts vesicle release closer to the AZ center and alters the efficiency of vesicle retrieval by increasing the occurrence of ultrafast endocytosis. Furthermore, we uncover that terminals can use oxidative fuels to maintain the vesicle cycle during …

Compensation Between Foxp Transcription Factors Maintains Proper Striatal Function, Newaz I Ahmed, Nitin Khandelwal, Ashley G Anderson, Emily Oh, Rachael M Vollmer, Ashwinikumar Kulkarni, Jay R Gibson, Genevieve Konopka

Faculty, Staff and Students Publications

Spiny projection neurons (SPNs) of the striatum are critical in integrating neurochemical information to coordinate motor and reward-based behavior. Mutations in the regulatory transcription factors expressed in SPNs can result in neurodevelopmental disorders (NDDs). Paralogous transcription factors Foxp1 and Foxp2, which are both expressed in the dopamine receptor 1 (D1) expressing SPNs, are known to have variants implicated in NDDs. Utilizing mice with a D1-SPN-specific loss of Foxp1, Foxp2, or both and a combination of behavior, electrophysiology, and cell-type-specific genomic analysis, loss of both genes results in impaired motor and social behavior as well as increased firing of the D1-SPNs. …

Astrocytic Slc4a4 Regulates Blood-Brain Barrier Integrity In Healthy And Stroke Brains Via A Ccl2-Ccr2 Pathway And No Dysregulation, Qi Ye, Juyeon Jo, Chih-Yen Wang, Heavin Oh, Jiangshan Zhan, Tiffany J Choy, Kyoung In Kim, Angelo D'Alessandro, Yana K Reshetnyak, Sung Yun Jung, Zheng Chen, Sean P Marrelli, Hyun Kyoung Lee

Faculty, Staff and Student Publications

Astrocytes play vital roles in blood-brain barrier (BBB) maintenance, yet how they support BBB integrity under normal or pathological conditions remains poorly defined. Recent evidence suggests that ion homeostasis is a cellular mechanism important for BBB integrity. In the current study, we investigated the function of an astrocyte-specific pH regulator, Slc4a4, in BBB maintenance and repair. We show that astrocytic Slc4a4 is required for normal astrocyte morphological complexity and BBB function. Multi-omics analyses identified increased astrocytic secretion of CCL2 coupled with dysregulated arginine-NO metabolism after Slc4a4 deletion. Using a model of ischemic stroke, we found that loss of Slc4a4 exacerbates …