Medicine and Health Sciences Commons^™

A Distinct Human Cell Type Expressing Mhcii And Rorγt With Dual Characteristics Of Dendritic Cells And Type 3 Innate Lymphoid Cells, Alina Ulezko Antonova, Changxu Fan, Natalia Jaeger, Patrick Fernandes Rodrigues, Simone Brioschi, Tihana Trsan, José L Fachi, Khai M Nguyen, Ryan M Nunley, Ting Wang, Marina Cella, William Vermi, Marco Colonna, Et Al.

2020-Current year OA Pubs

Recent studies have characterized various mouse antigen-presenting cells (APCs) expressing the lymphoid-lineage transcription factor RORγt (Retinoid-related orphan receptor gamma t), which exhibit distinct phenotypic features and are implicated in the induction of peripheral regulatory T cells (Tregs) and immune tolerance to microbiota and self-antigens. These APCs encompass Janus cells and Thetis cell subsets, some of which express the AutoImmune REgulator (AIRE). RORγt

A Broadly Reactive Antibody Targeting The N-Terminal Domain Of Sars-Cov-2 Spike Confers Fc-Mediated Protection, Lucas J Adams, Laura A Vanblargan, Zhuoming Liu, Pavlo Gilchuk, Haiyan Zhao, Rita E Chen, Saravanan Raju, Zhenlu Chong, Bradley M Whitener, Swathi Shrihari, Prashant N Jethva, Michael L Gross, James E Crowe Jr., Sean P J Whelan, Michael S Diamond, Daved H Fremont

2020-Current year OA Pubs

Most neutralizing anti-SARS-CoV-2 monoclonal antibodies (mAbs) target the receptor binding domain (RBD) of the spike (S) protein. Here, we characterize a panel of mAbs targeting the N-terminal domain (NTD) or other non-RBD epitopes of S. A subset of NTD mAbs inhibits SARS-CoV-2 entry at a post-attachment step and avidly binds the surface of infected cells. One neutralizing NTD mAb, SARS2-57, protects K18-hACE2 mice against SARS-CoV-2 infection in an Fc-dependent manner. Structural analysis demonstrates that SARS2-57 engages an antigenic supersite that is remodeled by deletions common to emerging variants. In neutralization escape studies with SARS2-57, this NTD site accumulates mutations, including …

Apobec-1 Deletion Enhances Cisplatin-Induced Acute Kidney Injury, Xiaojia Guo, Valerie Blanc, Nicholas O Davidson, Heino Velazquez, Tian-Min Chen, Dennis G Moledina, Gilbert W Moeckel, Robert L Safirstein, Gary V Desir

2020-Current year OA Pubs

Cisplatin (CP) induces acute kidney injury (AKI) whereby proximal tubules undergo regulated necrosis. Repair is almost complete after a single dose. We now demonstrate a role for Apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (Apobec-1) that is prominently expressed at the interface between acute and chronic kidney injury (CKD), in the recovery from AKI. Apobec-1 knockout (KO) mice exhibited greater mortality than in wild type (WT) and more severe AKI in both CP- and unilateral ischemia reperfusion (IR) with nephrectomy. Specifically, plasma creatinine (pCr) 2.6 ± 0.70 mg/dL for KO, n = 10 and 0.16 ± 0.02 for WT, …

A Drosophila Heart Optical Coherence Microscopy Dataset For Automatic Video Segmentation, Matthew Fishman, Abigail Matt, Fei Wang, Elena Gracheva, Jiantao Zhu, Xiangping Ouyang, Andrey Komarov, Yuxuan Wang, Hongwu Liang, Chao Zhou

2020-Current year OA Pubs

The heart of the fruit fly, Drosophila melanogaster, is a particularly suitable model for cardiac studies. Optical coherence microscopy (OCM) captures in vivo cross-sectional videos of the beating Drosophila heart for cardiac function quantification. To analyze those large-size multi-frame OCM recordings, human labelling has been employed, leading to low efficiency and poor reproducibility. Here, we introduce a robust and accurate automated Drosophila heart segmentation algorithm, called FlyNet 2.0+, which utilizes a long short-term memory (LSTM) convolutional neural network to leverage time series information in the videos, ensuring consistent, high-quality segmentation. We present a dataset of 213 Drosophila heart videos, equivalent …

Proteogenomic Analysis Reveals Cytoplasmic Sequestration Of Runx1 By The Acute Myeloid Leukemia-Initiating Cbfb::Myh11 Oncofusion Protein, Ryan B. Day, Julia A. Hickman, Ziheng Xu, Casey Ds Katerndahl, Francesca Ferraro, Sai Makund Ramakrishnan, Petra Erdmann-Gilmore, Robert W. Sprung, Yiling Mi, R. Reid Townsend, Christopher A. Miller, Timothy J. Ley

2020-Current year OA Pubs

Several canonical translocations produce oncofusion genes that can initiate acute myeloid leukemia (AML). Although each translocation is associated with unique features, the mechanisms responsible remain unclear. While proteins interacting with each oncofusion are known to be relevant for how they act, these interactions have not yet been systematically defined. To address this issue in an unbiased fashion, we fused a promiscuous biotin ligase (TurboID) in-frame with 3 favorable-risk AML oncofusion cDNAs (PML::RARA, RUNX1::RUNX1T1, and CBFB::MYH11) and identified their interacting proteins in primary murine hematopoietic cells. The PML::RARA- and RUNX1::RUNX1T1-TurboID fusion proteins labeled common and unique nuclear repressor complexes, implying their …

Docking For Ep4r Antagonists Active Against Inflammatory Pain, Stefan Gahbauer, Tao Che, Et Al.

2020-Current year OA Pubs

The lipid prostaglandin E

Design And Structural Validation Of Peptide-Drug Conjugate Ligands Of The Kappa-Opioid Receptor, Edin Muratspahić, Jianming Han, Balazs R Varga, Kevin Appourchaux, Susruta Majumdar, Tao Che, Et Al.

2020-Current year OA Pubs

Despite the increasing number of GPCR structures and recent advances in peptide design, the development of efficient technologies allowing rational design of high-affinity peptide ligands for single GPCRs remains an unmet challenge. Here, we develop a computational approach for designing conjugates of lariat-shaped macrocyclized peptides and a small molecule opioid ligand. We demonstrate its feasibility by discovering chemical scaffolds for the kappa-opioid receptor (KOR) with desired pharmacological activities. The designed De Novo Cyclic Peptide (DNCP)-β-naloxamine (NalA) exhibit in vitro potent mixed KOR agonism/mu-opioid receptor (MOR) antagonism, nanomolar binding affinity, selectivity, and efficacy bias at KOR. Proof-of-concept in vivo efficacy studies …

Dna Methylation-Mediated Rbpjk Suppression Protects Against Fracture Nonunion Caused By Systemic Inflammation, Ding Xiao, Liang Fang, Zhongting Liu, Yonghua He, Jun Ying, Haocheng Qin, Aiwu Lu, Meng Shi, Tiandao Li, Bo Zhang, Jianjun Guan, Cuicui Wang, Yousef Abu-Amer, Jie Shen

2020-Current year OA Pubs

Challenging skeletal repairs are frequently seen in patients experiencing systemic inflammation. To tackle the complexity and heterogeneity of the skeletal repair process, we performed single-cell RNA sequencing and revealed that progenitor cells were one of the major lineages responsive to elevated inflammation and this response adversely affected progenitor differentiation by upregulation of Rbpjk in fracture nonunion. We then validated the interplay between inflammation (via constitutive activation of Ikk2, Ikk2ca) and Rbpjk specifically in progenitors by using genetic animal models. Focusing on epigenetic regulation, we identified Rbpjk as a direct target of Dnmt3b. Mechanistically, inflammation decreased Dnmt3b expression in progenitor cells, …

Maternal Diet During Early Gestation Influences Postnatal Taste Activity-Dependent Pruning By Microglia, Chengsan Sun, Shuqiu Zheng, Justin S A Perry, Geoffrey T Norris, Mei Cheng, Fanzhen Kong, Rolf Skyberg, Jianhua Cang, Alev Erisir, Jonathan Kipnis, David L Hill

2020-Current year OA Pubs

A key process in central sensory circuit development involves activity-dependent pruning of exuberant terminals. Here, we studied gustatory terminal field maturation in the postnatal mouse nucleus of the solitary tract (NST) during normal development and in mice where their mothers were fed a low NaCl diet for a limited period soon after conception. Pruning of terminal fields of gustatory nerves in controls involved the complement system and is likely driven by NaCl-elicited taste activity. In contrast, offspring of mothers with an early dietary manipulation failed to prune gustatory terminal fields even though peripheral taste activity developed normally. The ability to …

Increasing Energetic Demands On Photoreceptors In Diabetes Corrects Retinal Lipid Dysmetabolism And Reduces Subsequent Microvascular Damage, Sheng Zhang, Xiaochao Wei, Megan Bowers, Sebastian Jessberger, Marcin Golczak, Clay F Semenkovich, Rithwick Rajagopal

2020-Current year OA Pubs

Mechanisms responsible for the pathogenesis of diabetic retinal disease remain incompletely understood, but they likely involve multiple cellular targets, including photoreceptors. Evidence suggests that dysregulated de novo lipogenesis in photoreceptors is a critical early target of diabetes. Following on this observation, the present study aimed to determine whether two interventions shown to improve diabetic retinopathy in mice-pharmacologic visual cycle inhibition and prolonged dark adaptation-reduce photoreceptor anabolic lipid metabolism. Elevated retinal lipid biosynthetic signaling was observed in two mouse models of diabetes, with both models showing reduced retinal AMP-activated kinase (AMPK) signaling, elevated acetyl CoA carboxylase (ACC) signaling, and increased activity …

Optimized Strategy For Real-Time Qpcr Detection Of Onchocerca Volvulus Dna In Pooled Simulium Sp. Blackfly Vectors, Mary Doherty, Peter U. Fischer, Et Al.

2020-Current year OA Pubs

BACKGROUND: Onchocerca volvulus is a filarial parasite that is a major cause of dermatitis and blindness in endemic regions primarily in sub-Saharan Africa. Widespread efforts to control the disease caused by O. volvulus infection (onchocerciasis) began in 1974 and in recent years, following successful elimination of transmission in much of the Americas, the focus of efforts in Africa has moved from control to the more challenging goal of elimination of transmission in all endemic countries. Mass drug administration (MDA) with ivermectin has reached more than 150 million people and elimination of transmission has been confirmed in four South American countries, …

Purification Of Modified Mammalian Actin Isoforms For In Vitro Reconstitution Assays, David J Kast, Silvia Jansen

2020-Current year OA Pubs

In vitro reconstitution assays using purified actin have greatly improved our understanding of cytoskeletal dynamics and their regulation by actin-binding proteins. However, early purification methods consisted of harsh conditions to obtain pure actin and often did not include correct maturation and obligate modification of the isolated actin monomers. Novel insights into the folding requirements and N-terminal processing of actin as well as a better understanding of the interaction of actin with monomer sequestering proteins such as DNaseI, profilin and gelsolin, led to the development of more gentle approaches to obtain pure recombinant actin isoforms with known obligate modifications. This review …

Neurofibromin 1 Mutations Impair The Function Of Human Induced Pluripotent Stem Cell-Derived Microglia, Leonard D Kuhrt, Edyta Motta, Nirmeen Elmadany, Hannah Weidling, Raphaela Fritsche-Guenther, Ibrahim E Efe, Olivia Cobb, Jit Chatterjee, Lucy G Boggs, Marina Schnauß, Sebastian Diecke, Marcus Semtner, Corina Anastasaki, David H Gutmann, Helmut Kettenmann

2020-Current year OA Pubs

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by germline mutations in the neurofibromin 1 (NF1) gene. Children with NF1 are prone to the development of multiple nervous system abnormalities, including autism and brain tumors, which could reflect the effect of NF1 mutation on microglia function. Using heterozygous Nf1-mutant mice, we previously demonstrated that impaired purinergic signaling underlies deficits in microglia process extension and phagocytosis in situ. To determine whether these abnormalities are also observed in human microglia in the setting of NF1, we leveraged an engineered isogenic series of human induced pluripotent stem cells to generate human …

An "Off-The-Shelf" Cd2 Universal Car-T Therapy For T-Cell Malignancies, Jingyu Xiang, Jessica M Devenport, Alun J Carter, Karl W Staser, Miriam Y Kim, Julie O' Neal, Julie K Ritchey, Michael P Rettig, Feng Gao, Garrett Rettig, Rolf Turk, Byung Ha Lee, Matthew L Cooper, John F Dipersio

2020-Current year OA Pubs

T-cell malignancies are associated with frequent relapse and high morbidity, which is partly due to the lack of effective or targeted treatment options. To broaden the use of CAR-T cells in pan T-cell malignancies, we developed an allogeneic "universal" CD2-targeting CAR-T cell (UCART2), in which the CD2 antigen is deleted to prevent fratricide, and the T-cell receptor is removed to prevent GvHD. UCART2 demonstrated efficacy against T-ALL and CTCL and prolonged the survival of tumor-engrafted NSG mice in vivo. To evaluate the impact of CD2 on CAR-T function, we generated CD19 CAR-T cells (UCART19) with or without CD2 deletion, single-cell …

Single-Cell Analysis Of Chromatin Accessibility In The Adult Mouse Brain, Songpeng Zu, Yang Eric Li, Et Al.

2020-Current year OA Pubs

Recent advances in single-cell technologies have led to the discovery of thousands of brain cell types; however, our understanding of the gene regulatory programs in these cell types is far from complete

Conserved And Divergent Gene Regulatory Programs Of The Mammalian Neocortex, Nathan R Zemke, Daofeng Li, Xiaoyu Zhuo, Vincent Xu, Ting Wang, Et Al.

2020-Current year OA Pubs

Divergence of cis-regulatory elements drives species-specific traits

Recombinant Human Perlecan Dv And Its Lg3 Subdomain Are Neuroprotective And Acutely Functionally Restorative In Severe Experimental Ischemic Stroke, Ifechukwude Joachim Biose, Ibolya Rutkai, Bryan Clossen, Gary Gage, Kenneth Schechtman, H Davis Adkisson 4th, Gregory J Bix

2020-Current year OA Pubs

Despite recent therapeutic advancements, ischemic stroke remains a major cause of death and disability. It has been previously demonstrated that  ~ 85-kDa recombinant human perlecan domain V (rhPDV) binds to upregulated integrin receptors (α2β1 and α5β1) associated with neuroprotective and functional improvements in various animal models of acute ischemic stroke. Recombinant human perlecan laminin-like globular domain 3 (rhPDV

Gut Microbiota Induces Weight Gain And Inflammation In The Gut And Adipose Tissue Independent Of Manipulations In Diet, Genetics, And Immune Development, Devesha H Kulkarni, Brigida Rusconi, Alexandria N Floyd, Elisabeth L Joyce, Khushi B Talati, Hrishi Kousik, Dereck Alleyne, Dalia L Harris, Lorena Garnica, Ryan Mcdonough, Shay S Bidani, Hrishikesh S Kulkarni, Elizabeth P Newberry, Keely G Mcdonald, Rodney D Newberry

2020-Current year OA Pubs

Obesity and the metabolic syndrome are complex disorders resulting from multiple factors including genetics, diet, activity, inflammation, and gut microbes. Animal studies have identified roles for each of these, however the contribution(s) specifically attributed to the gut microbiota remain unclear, as studies have used combinations of genetically altered mice, high fat diet, and/or colonization of germ-free mice, which have an underdeveloped immune system. We investigated the role(s) of the gut microbiota driving obesity and inflammation independent of manipulations in diet and genetics in mice with fully developed immune systems. We demonstrate that the human obese gut microbiota alone was sufficient …

Increasing Energetic Demands On Photoreceptors In Diabetes Corrects Retinal Lipid Dysmetabolism And Reduces Subsequent Microvascular Damage, Sheng Zhang, Xiaochao Wei, Megan Bowers, Sebastian Jessberger, Marcin Golczak, Clay F Semenkovich, Rithwick Rajagopal

2020-Current year OA Pubs

Mechanisms responsible for the pathogenesis of diabetic retinal disease remain incompletely understood, but they likely involve multiple cellular targets, including photoreceptors. Evidence suggests that dysregulated de novo lipogenesis in photoreceptors is a critical early target of diabetes. Following on this observation, the present study aimed to determine whether two interventions shown to improve diabetic retinopathy in mice-pharmacologic visual cycle inhibition and prolonged dark adaptation-reduce photoreceptor anabolic lipid metabolism. Elevated retinal lipid biosynthetic signaling was observed in two mouse models of diabetes, with both models showing reduced retinal AMP-activated kinase (AMPK) signaling, elevated acetyl CoA carboxylase (ACC) signaling, and increased activity …

Endothelial Adam10 Utilization Defines A Molecular Pathway Of Vascular Injury In Mice With Bacterial Sepsis, Danielle N. Alfano, Mark J. Miller, Juliane Bubeck-Wardenburg

2020-Current year OA Pubs

The endothelium plays a critical role in the host response to infection and has been a focus of investigation in sepsis. While it is appreciated that intravascular thrombus formation, severe inflammation, and loss of endothelial integrity impair tissue oxygenation during sepsis, the precise molecular mechanisms that lead to endothelial injury remain poorly understood. We demonstrate here that endothelial ADAM10 was essential for the pathogenesis of Staphylococcus aureus sepsis, contributing to α-toxin-mediated (Hla-mediated) microvascular thrombus formation and lethality. As ADAM10 is essential for endothelial development and homeostasis, we examined whether other major human sepsis pathogens also rely on ADAM10-dependent pathways in …

Genetic Separation Of Brca1 Functions Reveal Mutation-Dependent Polθ Vulnerabilities, John J Krais, Et Al.

2020-Current year OA Pubs

Homologous recombination (HR)-deficiency induces a dependency on DNA polymerase theta (Polθ/Polq)-mediated end joining, and Polθ inhibitors (Polθi) are in development for cancer therapy. BRCA1 and BRCA2 deficient cells are thought to be synthetic lethal with Polθ, but whether distinct HR gene mutations give rise to equivalent Polθ-dependence, and the events that drive lethality, are unclear. In this study, we utilized mouse models with separate Brca1 functional defects to mechanistically define Brca1-Polθ synthetic lethality. Surprisingly, homozygous Brca1 mutant, Polq

Heterogeneous Cardiac Sympathetic Innervation Gradients Promote Arrhythmogenesis In Murine Dilated Cardiomyopathy, Al-Hassan J Dajani, Carla Valenzuela-Ripoll, Ali Javaheri, Et Al.

2020-Current year OA Pubs

Ventricular arrhythmias (VAs) in heart failure are enhanced by sympathoexcitation. However, radiotracer studies of catecholamine uptake in failing human hearts demonstrate a proclivity for VAs in patients with reduced cardiac sympathetic innervation. We hypothesized that this counterintuitive finding is explained by heterogeneous loss of sympathetic nerves in the failing heart. In a murine model of dilated cardiomyopathy (DCM), delayed PET imaging of sympathetic nerve density using the catecholamine analog [11C]meta-Hydroxyephedrine demonstrated global hypoinnervation in ventricular myocardium. Although reduced, sympathetic innervation in 2 distinct DCM models invariably exhibited transmural (epicardial to endocardial) gradients, with the endocardium being devoid of sympathetic nerve …

Simulation Study Of A Novel Small Animal Flash Irradiator (Safi) With Integrated Inverse-Geometry Ct Based On Circularly Distributed Kv X-Ray Sources, Yuewen Tan, Shuang Zhou, Jonathan Haefner, Qinghao Chen, Thomas R Mazur, Arash Darafsheh, Tiezhi Zhang

2020-Current year OA Pubs

Ultra-high dose rate (UHDR) radiotherapy (RT) or FLASH-RT can potentially reduce normal tissue toxicity. A small animal irradiator that can deliver FLASH-RT treatments similar to clinical RT treatments is needed for pre-clinical studies of FLASH-RT. We designed and simulated a novel small animal FLASH irradiator (SAFI) based on distributed x-ray source technology. The SAFI system comprises a distributed x-ray source with 51 focal spots equally distributed on a 20 cm diameter ring, which are used for both FLASH-RT and onboard micro-CT imaging. Monte Carlo simulation was performed to estimate the dosimetric characteristics of the SAFI treatment beams. The maximum dose …

Mutation Of Key Signaling Regulators Of Cerebrovascular Development In Vein Of Galen Malformations, Shujuan Zhao, Po-Ying Fu, Yung-Chun Wang, Sheng Chih Jin, Et Al.

2020-Current year OA Pubs

To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and most severe of congenital brain arteriovenous malformations, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (2042.5-fold, p = 4.79 x 10

Contribution Of Macrophages To Neural Survival And Intracochlear Tissue Remodeling Responses Following Cochlear Implantation, Muhammad Taifur Rahman, Brian J Mostaert, Bryce Hunger, Utsow Saha, Alexander D Claussen, Ibrahim Razu, Farjana Nasrin, Nashwaan Ali Khan, Peter Eckard, Sarah Coleman, Jacob Oleson, Jonathon R Kirk, Keiko Hirose, Marlan R Hansen

2020-Current year OA Pubs

BACKGROUND: Cochlear implants (CIs) restore hearing to deafened patients. The foreign body response (FBR) following cochlear implantation (post-CI) comprises an infiltration of macrophages, other immune and non-immune cells, and fibrosis into the scala tympani, a space that is normally devoid of cells. This FBR is associated with negative effects on CI outcomes including increased electrode impedances and loss of residual acoustic hearing. This study investigates the extent to which macrophage depletion by an orally administered CSF-1R specific kinase (c-FMS) inhibitor, PLX-5622, modulates the tissue response to CI and neural health.

MAIN TEXT: 10- to 12-week-old CX3CR1 + /GFP Thy1 + …

A Paracrine Circuit Of Il-1Β/Il-1r1 Between Myeloid And Tumor Cells Drives Genotype-Dependent Glioblastoma Progression, Zhihong Chen, David H. Gutmann, Et Al.

2020-Current year OA Pubs

Monocytes and monocyte-derived macrophages (MDMs) from blood circulation infiltrate glioblastoma (GBM) and promote growth. Here, we show that PDGFB-driven GBM cells induce the expression of the potent proinflammatory cytokine IL-1β in MDM, which engages IL-1R1 in tumor cells, activates the NF-κB pathway, and subsequently leads to induction of monocyte chemoattractant proteins (MCPs). Thus, a feedforward paracrine circuit of IL-1β/IL-1R1 between tumors and MDM creates an interdependence driving PDGFB-driven GBM progression. Genetic loss or locally antagonizing IL-1β/IL-1R1 leads to reduced MDM infiltration, diminished tumor growth, and reduced exhausted CD8+ T cells and thereby extends the survival of tumor-bearing mice. In contrast …

Mechanical Loading And Hyperosmolarity As A Daily Resetting Cue For Skeletal Circadian Clocks, Michal Dudek, Dharshika R J Pathiranage, Beatriz Bano-Otalora, Anna Paszek, Natalie Rogers, Cátia F Gonçalves, Craig Lawless, Dong Wang, Zhuojing Luo, Liu Yang, Farshid Guilak, Judith A Hoyland, Qing-Jun Meng

2020-Current year OA Pubs

Daily rhythms in mammalian behaviour and physiology are generated by a multi-oscillator circadian system entrained through environmental cues (e.g. light and feeding). The presence of tissue niche-dependent physiological time cues has been proposed, allowing tissues the ability of circadian phase adjustment based on local signals. However, to date, such stimuli have remained elusive. Here we show that daily patterns of mechanical loading and associated osmotic challenge within physiological ranges reset circadian clock phase and amplitude in cartilage and intervertebral disc tissues in vivo and in tissue explant cultures. Hyperosmolarity (but not hypo-osmolarity) resets clocks in young and ageing skeletal tissues …

Missense Mutations In Crx Homeodomain Cause Dominant Retinopathies Through Two Distinct Mechanisms, Yiqiao Zheng, Chi Sun, Xiaodong Zhang, Philip A Ruzycki, Shiming Chen

2020-Current year OA Pubs

Homeodomain transcription factors (HD TFs) are instrumental to vertebrate development. Mutations in HD TFs have been linked to human diseases, but their pathogenic mechanisms remain elusive. Here, we use

A Cre-Dependent Massively Parallel Reporter Assay Allows For Cell-Type Specific Assessment Of The Functional Effects Of Non-Coding Elements In Vivo, Tomas Lagunas Jr, Stephen P Plassmeyer, Anthony D Fischer, Ryan Z Friedman, Michael A Rieger, Din Selmanovic, Simona Sarafinovska, Yvette K Sol, Michael J Kasper, Stuart B Fass, Alessandra F Aguilar Lucero, Joon-Yong An, Stephan J Sanders, Barak A Cohen, Joseph D Dougherty

2020-Current year OA Pubs

The function of regulatory elements is highly dependent on the cellular context, and thus for understanding the function of elements associated with psychiatric diseases these would ideally be studied in neurons in a living brain. Massively Parallel Reporter Assays (MPRAs) are molecular genetic tools that enable functional screening of hundreds of predefined sequences in a single experiment. These assays have not yet been adapted to query specific cell types in vivo in a complex tissue like the mouse brain. Here, using a test-case 3'UTR MPRA library with genomic elements containing variants from autism patients, we developed a method to achieve …

Repeated Multi-Domain Cognitive Training Prevents Cognitive Decline, Anxiety And Amyloid Pathology Found In A Mouse Model Of Alzheimer Disease, Jogender Mehla, Scott H Deibel, Hadil Karem, Nancy S Hong, Shakhawat R Hossain, Sean G Lacoursiere, Robert J Sutherland, Majid H Mohajerani, Robert J Mcdonald

2020-Current year OA Pubs

Education, occupation, and an active lifestyle, comprising enhanced social, physical, and mental components are associated with improved cognitive functions in aged people and may delay the progression of various neurodegenerative diseases including Alzheimer's disease. To investigate this protective effect, 3-month-old APP