Digital Commons Network^™

Open-Sourced Civic Annotation Pipeline To Identify And Annotate Clinically Relevant Variants Using Single-Molecule Molecular Inversion Probes, Erica K Barnell, Adam Waalkes, Matt C Mosior, Kelsi Penewit, Kelsy C Cotto, Arpad M Danos, Lana M Sheta, Katie M Campbell, Kilannin Krysiak, Damian Rieke, Nicholas C Spies, Zachary L Skidmore, Colin C Pritchard, Todd A Fehniger, Ravindra Uppaluri, Ramaswamy Govindan, Malachi Griffith, Stephen J Salipante, Obi L Griffith

Open Access Publications

PURPOSE: Clinical targeted sequencing panels are important for identifying actionable variants for patients with cancer; however, existing approaches do not provide transparent and rationally designed clinical panels to accommodate the rapidly growing knowledge within oncology.

MATERIALS AND METHODS: We used the Clinical Interpretations of Variants in Cancer (CIViC) database to develop an Open-Sourced CIViC Annotation Pipeline (OpenCAP). OpenCAP provides methods to identify variants within the CIViC database, build probes for variant capture, use probes on prospective samples, and link somatic variants to CIViC clinical relevance statements. OpenCAP was tested using a single-molecule molecular inversion probe (smMIP) capture design on 27 …

Optimizing Postprandial Glucose Management In Adults With Insulin-Requiring Diabetes: Report And Recommendations, John (Jack) L. Leahy, Grazia Aleppo, Vivian A. Fonseca, Satish K. Garg, Irl B. Hirsch, Anthony L. Mccall, Janet B. Mcgill, William H. Polonsky

Open Access Publications

Faster-acting insulins, new noninsulin drug classes, more flexible insulin-delivery systems, and improved continuous glucose monitoring devices offer unprecedented opportunities to improve postprandial glucose (PPG) management and overall care for adults with insulin-treated diabetes. These developments led the Endocrine Society to convene a working panel of diabetes experts in December 2018 to assess the current state of PPG management, identify innovative ways to improve self-management and quality of life, and align best practices to current and emerging treatment and monitoring options. Drawing on current research and collective clinical experience, we considered the following issues for the ∼200 million adults worldwide with …

Tic Suppression In Children With Recent-Onset Tics Predicts 1-Year Tic Outcome, Soyoung Kim, Deanna J Greene, Amy Robichaux-Viehoever, Emily C Bihun, Jonathan M Koller, Haley Acevedo, Bradley L Schlaggar, Kevin J Black

Open Access Publications

Successful voluntary tic suppression is a key component of the behavioral interventions that are used to treat tic disorders. This study aimed to examine tic suppression in children with recent-onset tics and determine whether the capacity to suppress tics predicts future tic severity. We tested 45 children (30 male, mean age 7.74 years) with recent-onset tics (mean 3.47 months prior to the first study visit; baseline) and re-examined each child at the 12-month anniversary of the first recognized tic (follow-up). At the baseline visit, children performed a tic suppression task with several conditions: tic freely, inhibit tics given a verbal …

The Diagnostic Yield Of Malignancy Comparing Cytology, Fish, And Molecular Analysis Of Cell Free Cytology Brush Supernatant In Patients With Biliary Strictures Undergoing Endoscopic Retrograde Cholangiography (Erc): A Prospective Study, Vladimir M Kushnir, Daniel K Mullady, Koushik Das, Gabriel Lang, Thomas G Hollander, Faris M Murad, Sara A Jackson, Nicole A Toney, Sydney D Finkelstein, Steven A Edmundowicz

Open Access Publications

BACKGROUND: Routine cytology of biliary stricture brushings obtained during endoscopic retrograde cholangiopancreatography (ERCP) has suboptimal sensitivity for malignancy. We compared the individual and combined ability of cytology, fluorescence in situ hybridization (FISH) analysis and PCR-based mutation profiling (MP) to detect malignancy in standard biliary brushings.

METHODS: We performed a prospective study of patients undergoing ERCP using histology or 1 year follow-up to determine patient outcomes. MP was performed on free-DNA from biliary brushing specimens using normally discarded supernatant fluid. MP examined KRAS point mutations and tumor suppressor gene associated loss of heterozygosity mutations at 10 genomic loci. FISH examined chromosome …

Casein Kinase 1 Family Proteins Promote Slimb-Dependent Expanded Degradation, Alexander D. Fulford, Maxine V. Holder, David Frith, Ambrosius P. Snijders, Nicolas Tapon, Paulo S. Ribeiro

Open Access Publications

Hippo signalling integrates diverse stimuli related to epithelial architecture to regulate tissue growth and cell fate decisions. The Hippo kinase cascade represses the growth-promoting transcription co-activator Yorkie. The FERM protein Expanded is one of the main upstream Hippo signalling regulators in

Inhibition Of 4-Aminobutyrate Aminotransferase Protects Against Injury-Induced Osteoarthritis In Mice, Jie Shen, Cuicui Wang, Jun Ying, Taotao Xu, Audrey Mcalinden, Regis J. O'Keefe

Open Access Publications

Recently we demonstrated that ablation of the DNA methyltransferase enzyme, Dnmt3b, resulted in catabolism and progression of osteoarthritis (OA) in murine articular cartilage through a mechanism involving increased mitochondrial respiration. In this study, we identify 4-aminobutyrate aminotransferase (Abat) as a downstream target of Dnmt3b. Abat is an enzyme that metabolizes γ-aminobutyric acid to succinate, a key intermediate in the tricarboxylic acid cycle. We show that Dnmt3b binds to the Abat promoter, increases methylation of a conserved CpG sequence just upstream of the transcriptional start site, and inhibits Abat expression. Dnmt3b deletion in articular chondrocytes results in reduced methylation of the …

Noninvasive Mapping Of The Electrophysiological Substrate In Cardiac Amyloidosis And Its Relationship To Structural Abnormalities, Michele Orini, Adam J Graham, Ana Martinez-Naharro, Christopher M Andrews, Antonio De Marvao, Ben Statton, Stuart A Cook, Declan P O'Regan, Philip N Hawkins, Yoram Rudy, Marianna Fontana, Pier D Lambiase

Open Access Publications

Background The relationship between structural pathology and electrophysiological substrate in cardiac amyloidosis is unclear. Differences between light-chain (AL) and transthyretin (ATTR) cardiac amyloidosis may have prognostic implications. Methods and Results ECG imaging and cardiac magnetic resonance studies were conducted in 21 cardiac amyloidosis patients (11 AL and 10 ATTR). Healthy volunteers were included as controls. With respect to ATTR, AL patients had lower amyloid volume (51.0/37.7 versus 73.7/16.4 mL, P=0.04), lower myocardial cell volume (42.6/19.1 versus 58.5/17.2 mL, P=0.021), and higher T1 (1172/64 versus 1109/80 ms, P=0.022) and T2 (53.4/2.9 versus 50.0/3.1 ms, P=0.003). ECG imaging revealed differences between cardiac …

Race And Risk Of Subsequent Aggressive Breast Cancer Following Ductal Carcinoma In Situ, Ying Liu, Robert West, Jason D Weber, Graham A Colditz

Open Access Publications

BACKGROUND: General populations of black women have a higher risk of developing breast cancer negative for both estrogen receptor (ER) and progesterone receptor (PR) in comparison with white counterparts. Racial differences remain unknown in the risk of developing aggressive invasive breast cancer (IBC) that is characterized by negativity for both ER and PR (ER-PR-) or higher 21-gene recurrence scores after ductal carcinoma in situ (DCIS).

METHODS: This study identified 163,892 women (10.5% black, 9.8% Asian, and 8.6% Hispanic) with incident DCIS between 1990 and 2015 from the Surveillance, Epidemiology, and End Results data sets. Cox proportional hazards regression was used …

Identification Of 4-Amino-Thieno[2,3-D]Pyrimidines As Qcrb Inhibitors In Mycobacterium Tuberculosis, Gregory A Harrison, Anne E Mayer Bridwell, Megh Singh, Keshav Jayaraman, Leslie A Weiss, Rachel L Kinsella, Janessa S Aneke, Kelly Flentie, Miranda E Schene, Margaret Gaggioli, Samantha D Solomon, Scott A Wildman, Marvin J Meyers, Christina L Stallings

Open Access Publications

Antibiotic resistance is a global crisis that threatens our ability to treat bacterial infections, such as tuberculosis, caused by

Vincristine And Bortezomib Use Distinct Upstream Mechanisms To Activate A Common Sarm1-Dependent Axon Degeneration Program, Stefanie Geisler, Ryan A Doan, Galen C Cheng, Aysel Cetinkaya-Fisgin, Shay X Huang, Ahmet Höke, Jeffrey Milbrandt, Aaron Diantonio

Open Access Publications

Chemotherapy-induced peripheral neuropathy is one of the most prevalent dose-limiting toxicities of anticancer therapy. Development of effective therapies to prevent chemotherapy-induced neuropathies could be enabled by a mechanistic understanding of axonal breakdown following exposure to neuropathy-causing agents. Here, we reveal the molecular mechanisms underlying axon degeneration induced by 2 widely used chemotherapeutic agents with distinct mechanisms of action: vincristine and bortezomib. We showed previously that genetic deletion of SARM1 blocks vincristine-induced neuropathy and demonstrate here that it also prevents axon destruction following administration of bortezomib in vitro and in vivo. Using cultured neurons, we found that vincristine and bortezomib converge …

Association Of Timing Of Adverse Childhood Experiences And Caregiver Support With Regionally Specific Brain Development In Adolescents, Joan L. Luby, Rebecca Tillman, Deanna M. Barch

Open Access Publications

Importance: Few data are available to inform the associations and timing of the associations between adversity, caregiver support, and brain outcomes. Consideration of timing has important public health implications to inform more precise prevention strategies.

Objective: To evaluate the timing and regional specificity of the association between adverse childhood experiences (ACEs) and caregiver support to structural development of limbic and striatal brain regions in middle childhood and adolescence.

Design, Setting, and Participants: This 15-year developmental, neuroimaging cohort study included 211 children and their caregivers screened from day care centers and preschools in the St Louis, Missouri, metropolitan area during the …

Mining Biosynthetic Gene Clusters In Virgibacillus Genomes, Ghofran Othoum, Salim Bougouffa, Ameerah Bokhari, Feras F Lafi, Takashi Gojobori, Heribert Hirt, Ivan Mijakovic, Vladimir B Bajic, Magbubah Essack

Open Access Publications

BACKGROUND: Biosynthetic gene clusters produce a wide range of metabolites with activities that are of interest to the pharmaceutical industry. Specific interest is shown towards those metabolites that exhibit antimicrobial activities against multidrug-resistant bacteria that have become a global health threat. Genera of the phylum Firmicutes are frequently identified as sources of such metabolites, but the biosynthetic potential of its Virgibacillus genus is not known. Here, we used comparative genomic analysis to determine whether Virgibacillus strains isolated from the Red Sea mangrove mud in Rabigh Harbor Lagoon, Saudi Arabia, may be an attractive source of such novel antimicrobial agents.

RESULTS: …

A Gorilla Adenovirus-Based Vaccine Against Zika Virus Induces Durable Immunity And Confers Protection In Pregnancy, Ahmed O Hassan, Igor P Dmitriev, Elena A Kashentseva, Haiyan Zhao, Douglas E Brough, Daved H Fremont, David T Curiel, Michael S Diamond

Open Access Publications

The teratogenic potential of Zika virus (ZIKV) has made the development of an effective vaccine a global health priority. Here, we generate two gorilla adenovirus-based ZIKV vaccines that encode for pre-membrane (prM) and envelope (E) proteins (GAd-Zvp) or prM and the ectodomain of E protein (GAd-Eecto). Both vaccines induce humoral and cell-mediated immune responses and prevent lethality after ZIKV challenge in mice. Protection is antibody dependent, CD8

Exome Sequencing Of Abcb5 Identifies Recurrent Melanoma Mutations That Result In Increased Proliferative And Invasive Capacities, Géraldine Sana, James P Madigan, Jared J Gartner, Marie Fourrez, Jimmy Lin, Nouar Qutob, Jitendra Narayan, Suneet Shukla, Suresh V Ambudkar, Di Xia, Steven A Rosenberg, Michael M Gottesman, Yardena Samuels, Jean-Pierre Gillet

Open Access Publications

ABCB5 is an ABC transporter that was shown to confer low-level multidrug resistance in cancer. In this study, we show that ABCB5 was mutated in 13.75% of the 640 melanoma samples analyzed. Besides nonsense mutations, two mutation hotspots were found in the ABCB5 protein, in the drug-binding pocket and the nucleotide-binding domains. Four mutations, which are representative of the mutation pattern, were selected. ATPase assays showed that these mutations resulted in a decrease in basal ATP hydrolysis by ABCB5. To select informative melanoma cell lines, mutational profiles of the clinical samples were further analyzed. This study showed mutations in the …

Assessing Organizational Supports For Evidence-Based Decision Making In Local Public Health Departments In The United States: Development And Psychometric Properties Of A New Measure, Stephanie Mazzucca, Renee G Parks, Rachel G Tabak, Peg Allen, Maureen Dobbins, Katherine A Stamatakis, Ross C Brownson

Open Access Publications

CONTEXT: Fostering evidence-based decision making (EBDM) within local public health departments and among local health department (LHD) practitioners is crucial for the successful translation of research into public health practice to prevent and control chronic disease.

OBJECTIVE: The purpose of this study was to identify organizational supports for EBDM within LHDs and determine psychometric properties of a measure of organizational supports for EBDM in LHDs.

DESIGN: Cross-sectional, observation study.

SETTING: Local public health departments in the United States.

PARTICIPANTS: Local health department practitioners (N = 376) across the United States participated in the study.

MAIN OUTCOME MEASURES: Local health department …

Videofluoroscopic Swallow Study Features Of Lower Esophageal Sphincter Achalasia-Like Syndrome In Dogs, Megan E Grobman, James Schachtel, C Prakash Gyawali, Teresa E Lever, Carol R Reinero

Open Access Publications

BACKGROUND: Megaesophagus (ME) carries a poor long-term prognosis in dogs. In people, lower esophageal sphincter (LES) disorders causing functional obstruction are rare causes of ME that may respond to targeted treatment. Functional LES disorders are reported rarely in dogs because of challenges in diagnostic methodologies.

HYPOTHESIS/OBJECTIVES: To identify dogs with videofluoroscopic swallow study (VFSS) features of LES achalasia-like syndrome (LES-AS). We hypothesized that dogs with LES-AS could be distinguished from normal dogs using standardized VFSS criteria.

ANIMALS: Dogs with LES-AS by VFSS (n = 19), healthy normal dogs (n = 20).

METHODS: Retrospective study. One-hundred thirty dogs presented to the …

An Open-Source, Automated Home-Cage Sipper Device For Monitoring Liquid Ingestive Behavior In Rodents, Elizabeth Godynyuk, Maya N Bluitt, Jessica R Tooley, Alexxai V Kravitz, Meaghan C Creed

Open Access Publications

Measuring ingestive behavior of liquids in rodents is commonly used in studies of reward, metabolism, and circadian biology. Common approaches for measuring liquid intake in real time include computer-tethered lickometers or video-based systems. Additionally, liquids can be measured or weighed to determine the amount consumed without real-time sensing. Here, we built a photobeam-based sipper device that has the following advantages over traditional methods: (1) it is battery powered and fits in vivarium caging to allow home-cage measurements; (2) it quantifies the intake of two different liquids simultaneously for preference studies; (3) it is low cost and easily constructed, enabling high-throughput …

Tyk2 Promotes Malignant Peripheral Nerve Sheath Tumor Progression Through Inhibition Of Cell Death, Wenjing Qin, Abigail Godec, Xiaochun Zhang, Cuige Zhu, Jieya Shao, Yu Tao, Xianzhang Bu, Angela C Hirbe

Open Access Publications

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that arise most commonly in the setting of the Neurofibromatosis Type 1 (NF1) cancer predisposition syndrome. Despite aggressive multimodality therapy, outcomes are dismal and most patients die within 5 years of diagnosis. Prior genomic studies in our laboratory identified tyrosine kinase 2 (TYK2) as a frequently mutated gene in MPNST. Herein, we explored the function of TYK2 in MPNST pathogenesis.

METHODS: Immunohistochemistry was utilized to examine expression of TYK2 in MPNSTs and other sarcomas. To establish a role for TYK2 in MPNST pathogenesis, murine and human TYK2 knockdown and knockout …

Steady-State Activation And Modulation Of The Synaptic-Type Α1Β2Γ2l Gabaa Receptor By Combinations Of Physiological And Clinical Ligands, Allison L Germann, Spencer R Pierce, Thomas C Senneff, Ariel B Burbridge, Joe Henry Steinbach, Gustav Akk

Open Access Publications

The synaptic α1β2γ2 GABA

Dhx33 Interacts With Ap-2Β To Regulate Bcl-2 Gene Expression And Promote Cancer Cell Survival, Jiuling Wang, Weimin Feng, Zhen Yuan, Jason D. Weber, Yandong Zhang

Open Access Publications

The RNA helicase DHX33 has been found to be overexpressed in human cancers, where it promotes cancer development. Previous reports have shown that DHX33 deficiency caused cancer cell apoptosis, but the underlying mechanism remains unknown. In this study, we discovered that DHX33 regulates Bcl-2 family protein expression. In multiple human cancer cell lines, DHX33 was found to stimulate the transcription of

Distribution Of Cardiovascular Health By Individual- And Neighborhood-Level Socioeconomic Status: Findings From The Jackson Heart Study, Randi E Foraker, Christopher Bush, Melissa A Greiner, Mario Sims, Kamal Henderson, Sakima Smith, Aurelian Bidulescu, Abigail B Shoben, N Chantelle Hardy, Emily O'Brien

Open Access Publications

BACKGROUND: Data demonstrate a positive relationship between socioeconomic status (SES) and cardiovascular health (CVH).

OBJECTIVE: To assess the association between individual- and neighborhood-level SES and CVH among participants of the JHS (Jackson Heart Study), a community-based cohort of African Americans in Jackson, Mississippi.

METHODS: We included all JHS participants with complete SES and CVH information at the baseline study visit (n = 3,667). We characterized individual- and neighborhood-level SES according to income (primary analysis) and education (secondary analysis), respectively. The outcome of interest for these analyses was a CVH score, based on 7 modifiable behaviors and factors, summed to a …

Hiv And Tuberculosis Co-Infection In East Asia And The Pacific From 1990 To 2017: Results From The Global Burden Of Disease Study 2017, Jianrong Zhang, Stephanie Kern-Allely, Tiange Yu, Rumi Kato Price

Open Access Publications

Background: Periodic surveillance is crucial to provide information for resource allocation to control HIV/AIDS, tuberculosis (TB), and their co-infection, especially in areas with high morbidity and mortality like East Asia and the Pacific. Therefore, we examined the morbidity and mortality of HIV/AIDS and TB co-infection in this region from 1990 to 2017.

Methods: Utilizing the Global Burden of Disease (GBD) Study 2017, we obtained incidence, prevalence, and mortality numbers and rates of HIV/AIDS and TB co-infection, including HIV and drug-susceptible TB (DS-TB), multidrug-resistant TB without extensive drug resistance (MDR-TB without XDR), and extensive drug-resistant TB (XDR-TB). The trends in incidence, …

The Role Of The Immune System In Lung Transplantation: Towards Improved Long-Term Results, Ramsey R. Hachem

Open Access Publications

Over the past 35 years, lung transplantation has evolved from an experimental treatment to the treatment of choice for patients with end-stage lung disease. Beyond the immediate period after lung transplantation, rejection and infection are the leading causes of death. The risk of rejection after lung transplantation is generally higher than after other solid organ transplants, and this necessitates more intensive immunosuppression. However, this more intensive treatment does not reduce the risk of rejection sufficiently, and rejection is one of the most common complications after transplantation. There are multiple forms of rejection including acute cellular rejection, antibody-mediated rejection, and chronic …

Omnipresence Of Inflammasome Activities In Inflammatory Bone Diseases, Yael Alippe, Gabriel Mbalaviele

Open Access Publications

The inflammasomes are intracellular protein complexes that are assembled in response to a variety of perturbations including infections and injuries. Failure of the inflammasomes to rapidly clear the insults or restore tissue homeostasis can result in chronic inflammation. Recurring inflammation is also provoked by mutations that cause the constitutive assembly of the components of these protein platforms. Evidence suggests that chronic inflammation is a shared mechanism in bone loss associated with aging, dysregulated metabolism, autoinflammatory, and autoimmune diseases. Mechanistically, inflammatory mediators promote bone resorption while suppressing bone formation, an imbalance which over time leads to bone loss and increased fracture …

Four-Jointed Knock-Out Delays Renal Failure In An Adpkd Model With Kidney Injury, Chiara Formica, Hester Happé, Kimberley Am Veraar, Andrea Vortkamp, Marion Scharpfenecker, Helen Mcneill, Dorien Jm Peters

Open Access Publications

Autosomal Dominant Polycystic Kidney Disease is characterised by the development of fluid-filled cysts in the kidneys which lead to end-stage renal disease (ESRD). In the majority of cases, the disease is caused by a mutation in the Pkd1 gene. In a previous study, we demonstrated that renal injury can accelerate cyst formation in Pkd1 knock-out (KO) mice. In that study, we found that after injury four-jointed (Fjx1), an upstream regulator of planar cell polarity and the Hippo pathway, was aberrantly expressed in Pkd1 KO mice compared to WT. Therefore, we hypothesised a role for Fjx1 in injury/repair and cyst formation. …

Comparative Genomics Of Antibiotic-Resistant Uropathogens Implicates Three Routes For Recurrence Of Urinary Tract Infections, Robert Thänert, Kimberly A Reske, Tiffany Hink, Meghan A Wallace, Bin Wang, Drew J Schwartz, Sondra Seiler, Candice Cass, Carey-Ann D. Burnham, Erik R Dubberke, Jennie H Kwon, Gautam Dantas

Open Access Publications

The rise of antimicrobial resistance in uropathogens has complicated the management of urinary tract infections (UTIs), particularly in patients who are afflicted by recurrent episodes of UTIs. Antimicrobial-resistant (AR) uropathogens persistently colonizing individuals at asymptomatic time points have been implicated in the pathophysiology of UTIs. The dynamics of uropathogen persistence following the resolution of symptomatic disease are, however, mostly unclear. To further our understanding, we determined longitudinal AR uropathogen carriage and clonal persistence of uropathogenic

Obstructive Sleep Apnoea, Positive Airway Pressure Treatment And Postoperative Delirium: Protocol For A Retrospective Observational Study, Christopher R King, Krisztina E Escallier, Yo-El S Ju, Nan Lin, Ben Julian Palanca, Sherry Lynn Mckinnon, Michael Simon Avidan

Open Access Publications

INTRODUCTION: Obstructive sleep apnoea (OSA) is common among older surgical patients, and delirium is a frequent and serious postoperative complication. Emerging evidence suggests that OSA increases the risk for postoperative delirium. We hypothesise that OSA is an independent risk factor for postoperative delirium, and that in patients with OSA, perioperative adherence to positive airway pressure (PAP) therapy decreases the incidence of postoperative delirium and its sequelae. The proposed retrospective cohort analysis study will use existing datasets to: (i) describe and compare the incidence of postoperative delirium in surgical patients based on OSA diagnosis and treatment with PAP; (ii) assess whether …

Sensorimotor Coding Of Vermal Granule Neurons In The Developing Mammalian Cerebellum, Kelly H. Markwalter, Yue Yang, Timothy E. Holy, Azad Bonni

Open Access Publications

The vermal cerebellum is a hub of sensorimotor integration critical for postural control and locomotion, but the nature and developmental organization of afferent information to this region have remained poorly understood

Mucosal Infection Rewires Tnfɑ Signaling Dynamics To Skew Susceptibility To Recurrence, Lu Yu, Valerie P. O'Brien, Jonathan Livny, Denise Dorsey, Nirmalya Bandyopadhyay, Marco Colonna, Michael G. Caparon, Elisha D.O. Roberson, Scott J. Hultgren, Thomas Hannan

Open Access Publications

A mucosal infectious disease episode can render the host either more or less susceptible to recurrent infection, but the specific mechanisms that tip the balance remain unclear. We investigated this question in a mouse model of recurrent urinary tract infection and found that a prior bladder infection resulted in an earlier onset of tumor necrosis factor-alpha (TNFɑ)-mediated bladder inflammation upon subsequent bacterial challenge, relative to age-matched naive mice. However, the duration of TNFɑ signaling activation differed according to whether the first infection was chronic (Sensitized) or self-limiting (Resolved). TNFɑ depletion studies revealed that transient early-phase TNFɑ signaling in Resolved mice …

A Single-Nuclei Rna Sequencing Study Of Mendelian And Sporadic Ad In The Human Brain, Jorge L Del-Aguila, Zeran Li, Umber Dube, Kathie A Mihindukulasuriya, John P Budde, Maria Victoria Fernandez, Laura Ibanez, Joseph Bradley, Fengxian Wang, Kristy Bergmann, Richard Davenport, John C Morris, David M Holtzman, Richard J Perrin, Bruno A Benitez, Joseph Dougherty, Carlos Cruchaga, Oscar Harari

Open Access Publications

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. This neurodegenerative disorder is associated with neuronal death and gliosis heavily impacting the cerebral cortex. AD has a substantial but heterogeneous genetic component, presenting both Mendelian and complex genetic architectures. Using bulk RNA-seq from the parietal lobes and deconvolution methods, we previously reported that brains exhibiting different AD genetic architecture exhibit different cellular proportions. Here, we sought to directly investigate AD brain changes in cell proportion and gene expression using single-cell resolution.

METHODS: We generated unsorted single-nuclei RNA sequencing data from brain tissue. We leveraged the tissue donated from …