Digital Commons Network^™

Association Of Common And Rare Variants With Alzheimer’S Disease In More Than 13,000 Diverse Individuals With Whole-Genome Sequencing From The Alzheimer’S Disease Sequencing Project, Wan-Ping Lee, Seung Hoan Choi, Margaret G Shea, Po-Liang Cheng, Beth A Dombroski, Achilleas N Pitsillides, Nancy L Heard-Costa, Hui Wang, Katia Bulekova, Amanda B Kuzma, Yuk Yee Leung, John J Farrell, Honghuang Lin, Brian W Kunkle, Adam Naj, Elizabeth E Blue, Frederick Nusetor, Dongyu Wang, Eric Boerwinkle, William S Bush, Xiaoling Zhang, Philip L De Jager, Josée Dupuis, Lindsay A Farrer, Myriam Fornage, Eden Martin, Margaret Pericak-Vance, Sudha Seshadri, Ellen M Wijsman, Li-San Wang, Alzheimer's Disease Sequencing Project, Gerard D Schellenberg, Anita L Destefano, Jonathan L Haines, Gina M Peloso

Center for Medical Ethics and Health Policy Staff Publications

Introduction: Alzheimer's disease (AD) is a common disorder of the elderly that is both highly heritable and genetically heterogeneous.

Methods: We investigated the association of AD with both common variants and aggregates of rare coding and non-coding variants in 13,371 individuals of diverse ancestry with whole genome sequencing (WGS) data.

Results: Pooled-population analyses of all individuals identified genetic variants at apolipoprotein E (APOE) and BIN1 associated with AD (p < 5 × 10-8). Subgroup-specific analyses identified a haplotype on chromosome 14 including PSEN1 associated with AD in Hispanics, further supported by aggregate testing of rare coding and non-coding variants in the region. Common variants in LINC00320 were observed associated with AD in Black individuals (p = 1.9 × 10-9). Finally, we observed rare non-coding variants in the promoter of TOMM40 distinct of APOE in pooled-population analyses (p = 7.2 × 10-8).

Discussion: We observed that complementary pooled-population and subgroup-specific analyses offered unique insights into the genetic architecture of AD.

Highlights: We determine the association of genetic variants with Alzheimer's disease (AD) using …

A Transgenic Mouse Model Of Down Syndrome Acute Lymphoblastic Leukemia Identifies Targetable Vulnerabilities, Jacob J Junco, Max Rochette, Michelle Alozie, Raushan Rashid, Maci Terrell, Barry Zorman, Pavel Sumazin, Lauren Rowland, Gino Dettorre, Reid T Powell, Clifford C Stephan, Peter J Davies, Margarita Martinez-Moczygemba, Jun J Yang, Karen R Rabin

Faculty, Staff and Students Publications

No abstract provided.

Dual-Channel Side Channel Attack: Improved Aes Key Decryption By Combining Power And Electromagnetic Side Channels With Convolutional Neural Networks, Sean P. O'Neill

Theses and Dissertations

This research introduces a novel DL approach for SCA that combines power consumption and EM signals to enhance encryption key deduction by leveraging a dual-channel CNN architecture. A new dataset, consisting of simultaneous power and EM signal collections during 128-bitAES encryption, was developed to train and evaluate the model’s effectiveness. The combined approach achieved an 88% reduction in traces needed, from 50 traces to 6, for encryption key classification, outperforming traditional methods such as random forest, DPA, DEMA,and individual side channel CNN models. These findings highlight the potential of integrating multiple side channels in SCA to improve performance without the …

Cadasil: A Notch3-Associated Cerebral Small Vessel Disease, Lamei Yuan, Xiangyu Chen, Joseph Jankovic, Hao Deng

Faculty, Staff and Students Publications

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease (CSVD), pathologically characterized by a non-atherosclerotic and non-amyloid diffuse angiopathy primarily involving small to medium-sized penetrating arteries and leptomeningeal arteries. In 1996, mutation in the notch receptor 3 gene (NOTCH3) was identified as the cause of CADASIL. However, since that time other genetic CSVDs have been described, including the HtrA serine peptidase 1 gene-associated CSVD and the cathepsin A gene-associated CSVD, that clinically mimic the original phenotype. Though NOTCH3-associated CSVD is now a well-recognized hereditary disorder and the number of …

Epinephrine Versus Dopamine In Children, What Is The Current Evidence And What Do We Need? A Systematic Review And Meta-Analysis, Rohit S Loomba, Riddhi D Patel, Enrique G Villarreal, Juan S Farias, Saul Flores

Faculty, Staff and Students Publications

Introduction: Pediatric patients often receive vasoactive agents following cardiothoracic surgery or when in shock. The use of vasoactive agents varies between different settings and has largely changed because of anecdotal observations or small observational studies. Although vasoactive agents are frequently used, there are limited studies in pediatric populations comparing them to one another. The purpose of this systematic review is to quantify the comparative effects of epinephrine and dopamine while identifying gaps in knowledge.

Methods: A systematic review of published manuscripts was completed to identify full-text manuscripts in English using PubMed, Embase, and Cochrane databases. Studies were included if they …

Health Implications Of Racial Differences In Serum Growth Differentiation Factor Levels Among Men With Obesity, Siresha Bathina, Virginia Fuenmayor Lopez, Mia Prado, Elliot Ballato, Georgia Colleluori, Maryam Tetlay, Dennis Tan Villareal, Sanjay Mediwala, Rui Chen, Clifford Qualls, Reina Armamento-Villareal

Faculty, Staff and Students Publications

Growth differentiation factor (GDF15) has been considered a biomarker and recently a hormonal driver for diseases in different populations. However, the role of GDF15 as a biomarker of health outcomes in obese men from different racial/ethnic background has not been evaluated. The objective of this study was to investigate the racial/ethnic differences on the relationship between GDF15 and markers of glucometabolic status, hormonal profile, body composition and bone mineral density (BMD) in obese men. One hundred ninety-three obese men from diverse racial/ethnic backgrounds were enrolled. BMD and body composition were measured by dual energy X-ray absorptiometry. Serum GDF15, osteocalcin, C-terminal …

Infant-Derived Human Nasal Organoids Exhibit Relatively Increased Susceptibility, Epithelial Responses, And Cytotoxicity During Rsv Infection, Gina M Aloisio, Divya Nagaraj, Ashley M Murray, Emily M Schultz, Trevor Mcbride, Letisha Aideyan, Erin G Nicholson, David Henke, Laura Ferlic-Stark, Anubama Rajan, Amal Kambal, Hannah L Johnson, Elina Mosa, Fabio Stossi, Sarah E Blutt, Pedro A Piedra, Vasanthi Avadhanula

Faculty, Staff and Students Publications

Background: Respiratory syncytial virus (RSV) causes significant morbidity and mortality, especially in young children. Why RSV infection in children is more severe compared to healthy adults is not fully understood.

Methods: We used ex-vivo human nasal organoid platforms from infants and adults to investigate the underlying mechanism of this disease disparity at the initial site of RSV replication, the nasal epithelium.

Results: Infant-derived human nasal organoid-air liquid interface (HNO-ALIs) lines were more susceptible to early RSV replication. Moreover, infant-derived HNO-ALIs elicited a statistically significant greater overall cytokine response, enhanced mucous production, and greater cellular damage compared to their adult counterparts. …

Chemogenetic Neuronal Silencing Decouples C-Jun Activation From Cell Death In The Temporal Cortex, Caleb A Wood, Preethi Somasundaram, Jacob M Dundee, Melissa A Rudy, Trent A Watkins, Joanna L Jankowsky

Faculty, Staff and Students Publications

Initial symptoms of neurodegenerative diseases are often defined by the loss of the most vulnerable neural populations specific to each disorder. In the early stages of Alzheimer's disease, vulnerable circuits in the temporal lobe exhibit diminished activity prior to overt degeneration. It remains unclear whether these functional changes contribute to regional vulnerability or are simply a consequence of pathology. We previously found that entorhinal neurons in the temporal cortex undergo cell death following transient suppression of electrical activity, suggesting a causal role for activity disruption in neurodegeneration. Here we demonstrate that electrical arrest of this circuit stimulates the injury-response transcription …

Families’ Experiences Accessing Care After Genomic Sequencing In The Pediatric Cancer Context: “It’S Just Been A Big Juggle”, Blake Vuocolo, Amanda M Gutierrez, Jill O Robinson, Alva M Recinos, Lauren R Desrosiers, Mary A Majumder, Juan Carlos Bernini, Jonathan Gill, Timothy Griffin, Gail E Tomlinson, Kelly Vallance, Amy L Mcguire, D Williams Parsons, Sharon E Plon, Sarah Scollon

Faculty, Staff and Students Publications

Access to genomic sequencing (GS) and resulting recommendations have not been well described in pediatric oncology. GS results may provide a cancer predisposition syndrome (CPS) diagnosis that warrants screening and specialist visits beyond cancer treatment, including testing or surveillance for family members. The Texas KidsCanSeq (KCS) Study evaluated implementation of GS in a diverse pediatric oncology population. We conducted semi-structured interviews (n = 20) to explore experiences of KCS patients' families around learning about a CPS diagnosis and following up on recommended care. We used qualitative content analysis to develop themes and subthemes across families' descriptions of their experiences accessing …

Experiences In Providing A Community Educational Resource For The All Of Us Researcher Workbench, Deborah I Ritter, Jinyoung Byun, Jun Wang, Stephen Richards, Pamela N Luna, Laterrica Williams, Julie R Coleman, Jasmine N Baker, Shamika Ketkar, Ashley M Butler, Latanya Hammonds-Odie, Elizabeth G Atkinson, Kim C Worley, Debra D Murray, Brendan Lee, Steven E Scherer

Faculty, Staff and Students Publications

OBJECTIVE: Educational offerings to fill the bioinformatics knowledge gap are a key component to enhancing access and use of health data from the All of Us Research Program. We developed a Train the Trainer-based, innovative training series including project-based learning, modular on-demand demonstrations, and unstructured tutorial time as a model for educational engagement in the All of Us community.

MATERIALS AND METHODS: We highlight our training modules and content, with training survey data informing cycles of development in the creation of a 6-module training series with modular demonstrations.

RESULTS: We have conducted 2 public iterations of the Train the Trainer …

A Reproducible Pipeline For Parcellation Of The Anterior Limb Of The Internal Capsule, Karianne Sretavan, Henry Braun, Zoe Liu, Daniel Bullock, Tara Palnitkar, Remi Patriat, Jayashree Chandrasekaran, Samuel Brenny, Matthew D Johnson, Alik S Widge, Noam Harel, Sarah R Heilbronner

Faculty, Staff and Students Publications

Background: The anterior limb of the internal capsule (ALIC) is a white matter structure that connects the prefrontal cortex (PFC) to the brainstem, thalamus, and subthalamic nucleus. It is a target for deep brain stimulation for obsessive-compulsive disorder. There is strong interest in improving deep brain stimulation targeting by using diffusion tractography to reconstruct and target specific ALIC fiber pathways, but this methodology is susceptible to errors and lacks validation. To address these limitations, we developed a novel diffusion tractography pipeline that generates reliable and biologically validated ALIC white matter reconstructions.

Methods: Following algorithm development and refinement, we analyzed 43 …

A New Ex Vivo Model System To Analyze Factors Affecting The Integrity Of Fetal Membranes In Fetoscopic Surgery, Serjosha Robmann, Raoul Hopf, Costanza Giampietro, Lukas Moser, Alexandra Dolder, Magdalena Sanz Cortes, Martin Ehrbar, Nicole Ochsenbein, Jan Deprest, Edoardo Mazza

Faculty, Staff and Students Publications

We developed an ex vivo model system to analyze the influence of relevant environmental and mechanical factors potentially affecting the integrity of fetal membranes during fetoscopic surgery. The set-up exposes amniochorion membranes to insufflation at predefined levels of gas pressure, flow, humidity, and temperature. Change in fetal membranes stiffness is quantified during the phase mimicking surgery through measurement of membranes' strain in response to cyclic overpressure. The trocar induced perforation creates a mechanical weakness whose stability is assessed by increasing the insufflation pressure until membrane rupture. Damage of the epithelial cells lining the amnion is assessed through live-dead staining. Initial …

Bioindicators Of Mercury In Riverine Systems, Kathryn Mudica

All-Inclusive List of Electronic Theses and Dissertations

This study focuses on the bioaccumulation and biomagnification of mercury in freshwater food webs, with emphasis on bioindicators, such as macroinvertebrates, crayfish, and river otters. Despite regulatory efforts and advancements in monitoring, significant gaps remain in understanding mercury dynamics in freshwater systems—especially regarding its transport, methylation, and bioavailability across different ecosystems. To address these knowledge gaps, this study adopts a biocentric approach, emphasizing the role of living organisms in their environment. By utilizing macroinvertebrates, crayfish, and river otters as bioindicators, we aim to assess mercury bioavailability and distribution. These organisms provide varying temporal and spatial scales of mercury accumulation, offering …

Food Insecurity Knowledge And Training Among College Students In Health Majors, Virginia B. Gray, Cara Cuite, Megan Patton-López, Rickelle Richards, Mateja Savoie-Roskos, Stephanie Machado, Emily Heying, Matthew Landry, Susan Chen, Rebecca L. Hagedorn-Hatfield, Georgianna Mann, Zubaida Qamar, Kendra Oonorasak, Victoria A. Zigmont

Faculty Research, Scholarly, and Creative Activity

Objective: To describe current food insecurity (FI)-related training among nutrition/dietetics, public health, and social work students. Methods: A cross-sectional online survey was used among students (n = 306) enrolled in health-related programs at 12 US universities. Participants reported FI-related course-based and extracurricular experiences and rated confidence to address FI on a scale of 1–3. Open-ended questions investigated perceived definitions of FI and impactful course activities. Descriptive statistics and thematic analysis were used for data analysis. Results: Participants’ FI definitions were multifaceted. Most (80.6%) reported FI being covered in at least 1 course. The overall mean confidence to address FI was …

Testosterone Acts Through The Membrane Protein Gprc6a To Cause Cardiac Edema In Zebrafish Embryos, Vahid Zadmajid, Shayan Shahriar, Daniel A Gorelick

Faculty, Staff and Students Publications

Androgens are classically thought to act through intracellular androgen receptors (AR/NR3C4), but they can also trigger non-genomic effects via membrane proteins. Although several membrane androgen receptors have been characterized in vitro, their functions in vivo remain unclear. Using a chemical-genetic screen in zebrafish, we found that GPRC6A, a G-protein-coupled receptor, mediates non-genomic androgen actions during embryonic development. Exposure to androgens (androstanedione, DHT and testosterone) caused cardiac edema or tail curvature in wild-type embryos, as well as in ar mutants, suggesting AR-independent pathways. We then mutated putative membrane androgen receptors [gprc6a, hcar1-4 and zip9 (slc39a9)] and found that only gprc6a mutants …

Inhibitory Activities Of Phytoconstituents From Azadirachta Indica And Murraya Koenigii As Potential Drugs For Secondary Infection Of Atopic Eczema Disease - In Silico Study, Mikidadi S. Gurisha, Pulapa V. Kanaka Rao, Laxmikanth Cherupally

Tanzania Journal of Science

Atopic Eczema (AE) disease is a chronic inflammatory skin condition that is caused by a person’s inability to repair damage to the skin barrier. Staphylococcus aureus (SA) is a virulent pathogen that plays an important role in the progression of secondary infection in AE patients, thus intensifying the disease's virulence. In this study, the inhibitory activities of phytoconstituents from Azadirachta indica and Murraya koenigii against the SA (Protein Data Bank ID: 7TIO) using an in silico approach are presented. Site-specific docking analysis was carried out on the virulent pathogen with the docking center at X: 1.65044, Y: 1.7980, Z: 3.1878, …

The Effects Of Mosaicism On Biological And Clinical Markers Of Alzheimer's Disease In Adults With Down Syndrome, Laura Xicota, Rachel L Henson, Beau Ances, Et Al.

2020-Current year OA Pubs

BACKGROUND: Individuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21.

METHODS: We examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium-Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma …

Quantifying Brain Development In The Healthy Brain And Child Development (Hbcd) Study: The Magnetic Resonance Imaging And Spectroscopy Protocol, Douglas C Dean 3rd, Chad M Sylvester, Michael P Harms, Christopher D Smyser, Et Al.

2020-Current year OA Pubs

The HEALthy Brain and Child Development (HBCD) Study, a multi-site prospective longitudinal cohort study, will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. The acquisition of multimodal magnetic resonance-based brain development data is central to the study's core protocol. However, application of Magnetic Resonance Imaging (MRI) methods in this population is complicated by technical challenges and difficulties of imaging in early life. Overcoming these challenges requires an innovative and harmonized approach, combining age-appropriate acquisition protocols together with specialized pediatric neuroimaging strategies. The HBCD MRI Working Group aimed to establish a core acquisition …

The Sodium-Proton Exchangers Snhe And Nhe1 Control Plasma Membrane Hyperpolarization In Mouse Sperm, Analia G Novero, Celia M Santi, Et Al.

2020-Current year OA Pubs

Sperm capacitation is a complex process that takes place in the female reproductive tract and empowers mammalian sperm with the competence to fertilize an egg. It consists of an intricate cascade of events that can be mimicked in vitro through incubation in a medium containing essential components, such as bicarbonate, albumin, Ca

Cxcr3-Cxcl11 Signaling Restricts Angiogenesis And Promotes Pericyte Recruitment, Jihui Lee, Megan E. Goeckel, Allison Levitas, Sarah Colijn, Jimann Shin, Anna Hindes, Geonyoung Mun, Zarek Burton, Bharadwaj Chintalapati, Ying Yin, Javier Abello, Lilianna Solnica-Krezel, Amber N. Stratman

2020-Current year OA Pubs

BACKGROUND: Endothelial cell (EC)-pericyte interactions are known to remodel in response to hemodynamic forces; yet there is a lack of mechanistic understanding of the signaling pathways that underlie these events. Here, we have identified a novel signaling network regulated by blood flow in ECs-the chemokine receptor CXCR3 (CXC motif chemokine receptor 3) and one of its ligands, CXCL11 (CXC motif chemokine ligand 11)-that delimits EC angiogenic potential and promotes pericyte recruitment to ECs during development.

METHODS: We investigated the role of CXCR3 on vascular development using both 2- and 3-dimensional in vitro assays, to study EC-pericyte interactions and EC behavioral …

Dysfunctional Alpha Modulation As A Mechanism Of Working Memory Impairment In Serious Mental Illness, Molly A Erickson, Megan A Boudewyn, Kurt Winsler, Charlotte Li, Deanna M Barch, Cameron S Carter, Michael J Frank, James M Gold, Angus W Macdonald 3rd, John D Ragland, Steven M Silverstein, Andrew Yonelinas, Steven J Luck

2020-Current year OA Pubs

BACKGROUND: People with psychosis and mood disorders experience disruptions in working memory; however, the underlying mechanism remains unknown. We focused on 2 potential mechanisms: poor attentional engagement should be associated with elevated levels of prestimulus alpha-band activity within the electroencephalogram (EEG), whereas impaired working memory encoding should be associated with reduced poststimulus alpha suppression.

METHODS: We collected EEG data from 68 people with schizophrenia, 43 people with bipolar disorder with a history of psychosis, 53 people with major depressive disorder, and 90 healthy comparison subjects while they completed a spatial working memory task. We quantified attention lapsing, memory precision, and …

Solid-State Nmr Compositional Analysis Of Sputum From People With Cystic Fibrosis, Kathy Duong, Evan Moss, Courtney Reichhardt

2020-Current year OA Pubs

People with the genetic disease cystic fibrosis (CF) often have chronic airway infections and produce airway secretions called sputum. A better understanding of sputum composition is desired in order to track changes in response to CF therapeutics and to improve laboratory models for the study of CF airway infections. The glycosylated protein mucin is a primary component. Along with extracellular DNA, mucin gives rise to the high viscoelasticity of sputum, which inhibits airway clearance and is thought to promote chronic airway infections in people with CF. Past studies of sputum composition identified additional biomolecular components of sputum including other proteins, …

Development And Validation Of A Prechiasmatic Mouse Model Of Subarachnoid Hemorrhage To Measure Long-Term Cognitive Deficits, Deepti Diwan, Jogender Mehla, James W Nelson, James D Quirk, Sheng-Kwei Song, Sarah Cao, Benjamin Meron, Aminah Mostofa, Gregory J Zipfel

2020-Current year OA Pubs

Controllable and reproducible animal models of aneurysmal subarachnoid hemorrhage (SAH) are crucial for the systematic study of the pathophysiology and treatment of this debilitating condition. However, current animal models have not been successful in replicating the pathology and disabilities seen in SAH patients, especially the long-term neurocognitive deficits that affect the survivor's quality of life. Therefore, there is an unmet need to develop experimental models that reliably replicate the long-term clinical ramifications of SAH - especially in mice where genetic manipulations are straightforward and readily available. To address this need, a standardized mouse SAH model is developed that reproducibly produced …

Emergent Microenvironments Of Nucleoli, Matthew R King, Kiersten M Ruff, Rohit V Pappu

2020-Current year OA Pubs

In higher eukaryotes, the nucleolus harbors at least three sub-phases that facilitate multiple functionalities including ribosome biogenesis. The three prominent coexisting sub-phases are the fibrillar center (FC), the dense fibrillar component (DFC), and the granular component (GC). Here, we review recent efforts in profiling sub-phase compositions that shed light on the types of physicochemical properties that emerge from compositional biases and territorial organization of specific types of macromolecules. We highlight roles played by molecular grammars which refers to protein sequence features including the substrate binding domains, the sequence features of intrinsically disordered regions, and the multivalence of these distinct types …

High-Country Currents: Wonder, Never Cease, Lucille Stott

Appalachia

No abstract provided.

Appalachia Summer/Fall 2004: Complete Issue

Appalachia

No abstract provided.

Accidents

Appalachia

No abstract provided.

Tundra Frogs: Previously Unrecorded Amphibian Life In The Northeast's Alpine Zone, Michael Jones

Appalachia

No abstract provided.

High-Country Currents: Leaving The Journal But Not The Pack, Lucille Stott

Appalachia

No abstract provided.

Appalachia Winter/Spring 2006: Complete Issue

Appalachia

No abstract provided.