Digital Commons Network^™

Clonal Hematopoiesis Driven By Mutated Dnmt3a Promotes Inflammatory Bone Loss, Hui Wang, Kimon Divaris, Bohu Pan, Xiaofei Li, Jong-Hyung Lim, Gundappa Saha, Marko Barovic, Danai Giannakou, Jonathan M Korostoff, Yu Bing, Souvik Sen, Kevin Moss, Di Wu, James D Beck, Christie M Ballantyne, Pradeep Natarajan, Kari E North, Mihai G Netea, Triantafyllos Chavakis, George Hajishengallis

Faculty, Staff and Student Publications

Clonal hematopoiesis of indeterminate potential (CHIP) arises from aging-associated acquired mutations in hematopoietic progenitors, which display clonal expansion and produce phenotypically altered leukocytes. We associated CHIP-DNMT3A mutations with a higher prevalence of periodontitis and gingival inflammation among 4,946 community-dwelling adults. To model DNMT3A-driven CHIP, we used mice with the heterozygous loss-of-function mutation R878H, equivalent to the human hotspot mutation R882H. Partial transplantation with Dnmt3a

Parg Is Essential For Polθ-Mediated Dna End-Joining By Removing Repressive Poly-Adp-Ribose Marks, Umeshkumar Vekariya, Leonid Minakhin, Gurushankar Chandramouly, Mrityunjay Tyagi, Tatiana Kent, Katherine Sullivan-Reed, Jessica Atkins, Douglas Ralph, Margaret Nieborowska-Skorska, Anna-Mariya Kukuyan, Hsin-Yao Tang, Richard T. Pomerantz, Tomasz Skorski

Department of Biochemistry and Molecular Biology Faculty Papers

DNA polymerase theta (Polθ)-mediated end-joining (TMEJ) repairs DNA double-strand breaks and confers resistance to genotoxic agents. How Polθ is regulated at the molecular level to exert TMEJ remains poorly characterized. We find that Polθ interacts with and is PARylated by PARP1 in a HPF1- independent manner. PARP1 recruits Polθ to the vicinity of DNA damage via PARylation dependent liquid demixing, however, PARylated Polθ cannot perform TMEJ due to its inability to bind DNA. PARG-mediated de-PARylation of Polθ reactivates its DNA binding and end-joining activities. Consistent with this, PARG is essential for TMEJ and the temporal recruitment of PARG to DNA …

A Crisis In Clinical Research, David S Hong, Patricia Lorusso, Mario Sznol

Faculty, Staff and Student Publications

The clinical research pipeline is critical to ensuring continued development of novel treatments that can offer patients with cancer safe and effective options. Unfortunately, progress has slowed since the COVID-19 pandemic due to uncovered, systemic inefficiencies across critical processes. Towards initiating discussion on how to reinvigorate clinical research, the Society for Immunotherapy of Cancer (SITC) hosted a virtual summit that characterized issues and formed potential solutions. This commentary serves to highlight the crisis facing clinical research as well as stimulate field-wide discussion on how to better serve patients into the future.

Hemodynamics Regulate Spatiotemporal Artery Muscularization In The Developing Circle Of Willis, Siyuan Cheng, Ivan Fan Xia, Renate Wanner, Javier Abello, Amber N Stratman, Stefania Nicoli

2020-Current year OA Pubs

Vascular smooth muscle cells (VSMCs) envelop vertebrate brain arteries and play a crucial role in regulating cerebral blood flow and neurovascular coupling. The dedifferentiation of VSMCs is implicated in cerebrovascular disease and neurodegeneration. Despite its importance, the process of VSMC differentiation on brain arteries during development remains inadequately characterized. Understanding this process could aid in reprogramming and regenerating dedifferentiated VSMCs in cerebrovascular diseases. In this study, we investigated VSMC differentiation on zebrafish circle of Willis (CoW), comprising major arteries that supply blood to the vertebrate brain. We observed that arterial specification of CoW endothelial cells (ECs) occurs after their migration …

Ragopathies And The Rising Influence Of Raggtpases On Human Diseases, Irene Sambri, Marco Ferniani, Andrea Ballabio

Duncan NRI Faculty and Staff Publications

RagGTPases (Rags) play an essential role in the regulation of cell metabolism by controlling the activities of both mechanistic target of rapamycin complex 1 (mTORC1) and Transcription factor EB (TFEB). Several diseases, herein named ragopathies, are associated to Rags dysfunction. These diseases may be caused by mutations either in genes encoding the Rags, or in their upstream regulators. The resulting phenotypes may encompass a variety of clinical features such as cataract, kidney tubulopathy, dilated cardiomyopathy and several types of cancer. In this review, we focus on the key clinical, molecular and physio-pathological features of ragopathies, aiming to shed light on …

Community-Based Participatory Obesity Prevention Interventions In Rural Communities: A Scoping Review, Saagar Dhanjani, Haley Allen, Beatriz Varman, Chishinga Callender, Jayna M Dave, Debbe Thompson

Library Staff Publications

Child obesity is a worldwide public health concern. In America, children from rural areas have greater odds of obesity in comparison to those from urban areas. Community-engaged research is important for all communities, particularly under-represented communities. This paper reports the results of a scoping review investigating community-engaged research in obesity prevention programs tested with school-aged children in rural America. A literature search of Medline Ovid was conducted to identify interventions reporting the results of obesity prevention interventions that promoted a healthy diet or physical activity (PA) behaviors to school-age children in rural communities of the United States (US). After title …

Tsg-6+ Cancer-Associated Fibroblasts Modulate Myeloid Cell Responses And Impair Anti-Tumor Response To Immune Checkpoint Therapy In Pancreatic Cancer, Swetha Anandhan, Shelley Herbrich, Sangeeta Goswami, Baoxiang Guan, Yulong Chen, Marc Daniel Macaluso, Sonali Jindal, Seanu Meena Natarajan, Samuel W Andrewes, Liangwen Xiong, Ashwat Nagarajan, Sreyashi Basu, Derek Ng Tang, Jielin Liu, Jimin Min, Anirban Maitra, Padmanee Sharma

Faculty, Staff and Student Publications

Resistance to immune checkpoint therapy (ICT) presents a growing clinical challenge. The tumor microenvironment (TME) and its components, namely tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), play a pivotal role in ICT resistance; however, the underlying mechanisms remain under investigation. In this study, we identify expression of TNF-Stimulated Factor 6 (TSG-6) in ICT-resistant pancreatic tumors, compared to ICT-sensitive melanoma tumors, both in mouse and human. TSG-6 is expressed by CAFs within the TME, where suppressive macrophages expressing Arg1, Mafb, and Mrc1, along with TSG-6 ligand Cd44, predominate. Furthermore, TSG-6 expressing CAFs co-localize with the CD44 expressing macrophages in the TME. …

Developing The Openflexure Microscope Towards Medical Use: Technical And Social Challenges Of Developing Globally Accessible Hardware For Healthcare, Joe Knapper, Freya Whiteford, Daniel Rosen, William Wadsworth, Julian Stirling, Catherine Mkindi, Joram Mduda, Valerian L Sanga, Paul T Nyakyi, Thomas Hervé Mboa Nkoudou, Elisée Jafsia, Stephane Fadanka, Kelsey Hummel, Sharmila Anandasabapathy, Richard Bowman

Faculty, Staff and Students Publications

The OpenFlexure Microscope is an accessible, three-dimensional-printed robotic microscope, with sufficient image quality to resolve diagnostic features including parasites and cancerous cells. As access to lab-grade microscopes is a major challenge in global healthcare, the OpenFlexure Microscope has been developed to be manufactured, maintained and used in remote environments, supporting point-of-care diagnosis. The steps taken in transforming the hardware and software from an academic prototype towards an accepted medical device include addressing technical and social challenges, and are key for any innovation targeting improved effectiveness in low-resource healthcare. This article is part of the Theo Murphy meeting issue 'Open, reproducible …

Leukocyte Immunoglobulin-Like Receptor B1 (Lilrb1) Protects Human Multiple Myeloma Cells From Ferroptosis By Maintaining Cholesterol Homeostasis, Miao Xian, Qiang Wang, Liuling Xiao, Ling Zhong, Wei Xiong, Lingqun Ye, Pan Su, Chuanchao Zhang, Yabo Li, Robert Z Orlowski, Fenghuang Zhan, Siddhartha Ganguly, Youli Zu, Jianfei Qian, Qing Yi

Faculty, Staff and Student Publications

Multiple myeloma (MM) is a hematologic malignancy characterized by uncontrolled proliferation of plasma cells in the bone marrow. MM patients with aggressive progression have poor survival, emphasizing the urgent need for identifying new therapeutic targets. Here, we show that the leukocyte immunoglobulin-like receptor B1 (LILRB1), a transmembrane receptor conducting negative immune response, is a top-ranked gene associated with poor prognosis in MM patients. LILRB1 deficiency inhibits MM progression in vivo by enhancing the ferroptosis of MM cells. Mechanistic studies reveal that LILRB1 forms a complex with the low-density lipoprotein receptor (LDLR) and LDLR adapter protein 1 (LDLRAP1) to facilitate LDL/cholesterol …

Identification Of An H-Ras Nanocluster Disrupting Peptide, Candy Laura Steffen, Ganesh Babu Manoharan, Karolina Pavic, Alejandro Yeste-Vázquez, Matias Knuuttila, Neha Arora, Yong Zhou, Harri Härmä, Anthoula Gaigneaux, Tom N Grossmann, Daniel Kwaku Abankwa

Faculty, Staff and Student Publications

Hyperactive Ras signalling is found in most cancers. Ras proteins are only active in membrane nanoclusters, which are therefore potential drug targets. We previously showed that the nanocluster scaffold galectin-1 (Gal1) enhances H-Ras nanoclustering via direct interaction with the Ras binding domain (RBD) of Raf. Here, we establish that the B-Raf preference of Gal1 emerges from the divergence of the Raf RBDs at their proposed Gal1-binding interface. We then identify the L5UR peptide, which disrupts this interaction by binding with low micromolar affinity to the B- and C-Raf-RBDs. Its 23-mer core fragment is sufficient to interfere with H-Ras nanoclustering, modulate …

Predictors Of Aneurysm Obliteration In Patients Treated With The Web Device: Results Of A Multicenter Retrospective Study, Panagiotis Mastorakos, Kareem El Naamani, Nimer Adeeb, Mathews Lan, James Castiglione, Omaditya Khanna, Ritam Ghosh, Jose Danilo Bengzon Diestro, Mahmoud Dibas, Rachel M Mclellan, Oktay Algin, Sherief Ghozy, Nicole M Cancelliere, Assala Aslan, Hugo H Cuellar-Saenz, Sovann V Lay, Adrien Guenego, Leonardo Renieri, Joseph Carnevale, Guillaume Saliou, Eimad Shotar, Kevin Premat, Markus Möhlenbruch, Michael Kral, Justin E Vranic, Charlotte Chung, Mohamed M Salem, Ivan Lylyk, Paul M Foreman, Jay A Vachhani, Hamza Shaikh, Vedran Župančić, Muhammad U Hafeez, Joshua Catapano, Muhammad Waqas, Vincent M Tutino, Mohamed K Ibrahim, Marwa A Mohammed, James D Rabinov, Yifan Ren, Clemens M Schirmer, Mariangela Piano, Maria Bres Bullrich, Michael Mayich, Anna L Kühn, Caterina Michelozzi, Stéphanie Elens, Robert M Starke, Ameer E Hassan, Mark Ogilvie, Anh Nguyen, Jesse Jones, Waleed Brinjikji, Marios Psychogios, Christian Ulfert, Julian Spears, Brian T Jankowitz, Jan-Karl Burkhardt, Ricardo A Domingo, Thien Huynh, Rabih G Tawk, Boris Lubicz, Marie T Nawka, Pietro Panni, Ajit S Puri, Guglielmo Pero, Erez Nossek, Eytan Raz, Monika Killer-Oberpfalzer, M Ozgur Ozates, Giyas Ayberk, Robert W Regenhardt, Christoph J Griessenauer, Hamed Asadi, Adnan Siddiqui, Andrew F Ducruet, Felipe C Albuquerque, Nirav J Patel, Christopher J Stapleton, Peter Kan, Vladimir Kalousek, Pedro Lylyk, Srikanth Boddu, Jared Knopman, Mohammad A Aziz-Sultan, Frédéric Clarençon, Nicola Limbucci, Mario Zanaty, Juan Carlos Martinez-Gutierrez, Sunil Sheth, Gary Spiegel, Rawad Abbas, Abdelaziz Amllay, Stavropoula I Tjoumakaris, Michael R Gooch, Nabeel A Herial, Robert H Rosenwasser, Hekmat Zarzour, Richard F Schmidt, Vitor Mendes Pereira, Aman B Patel, Pascal M Jabbour, Adam A Dmytriw

Faculty, Staff and Student Publications

Background and purpose: Despite the numerous studies evaluating the occlusion rates of aneurysms following WEB embolization, there are limited studies identifying predictors of occlusion. Our purpose was to identify predictors of aneurysm occlusion and the need for retreatment.

Materials and methods: This is a review of a prospectively maintained database across 30 academic institutions. We included patients with previously untreated cerebral aneurysms embolized using the WEB who had available intraprocedural data and long-term follow-up.

Results: We studied 763 patients with a mean age of 59.9 (SD, 11.7) years. Complete aneurysm occlusion was observed in 212/726 (29.2%) cases, and contrast stasis …

How Can Interventions More Directly Address Drivers Of Unprofessional Behaviour Between Healthcare Staff?, Justin A Aunger, Ruth Abrams, Russell Mannion, Johanna I Westbrook, Aled Jones, Judy M Wright, Mark Pearson, Jill Maben

School of Nursing and Midwifery

Unprofessional behaviours (UBs) between healthcare staff are widespread and have negative impacts on patient safety, staff well-being and organisational efficiency. However, knowledge of how to address UBs is lacking. Our recent realist review analysed 148 sources including 42 reports of interventions drawing on different behaviour change strategies and found that interventions insufficiently explain their rationale for using particular strategies. We also explored the drivers of UBs and how these may interact. In our analysis, we elucidated both common mechanisms underlying both how drivers increase UB and how strategies address UB, enabling the mapping of strategies against drivers they address. For …

Self-Explainable Graph Neural Network For Alzheimer Disease And Related Dementias Risk Prediction: Algorithm Development And Validation Study, Xinyue Hu, Zenan Sun, Yi Nian, Yichen Wang, Yifang Dang, Fang Li, Jingna Feng, Evan Yu, Cui Tao

Faculty, Staff and Student Publications

Background: Alzheimer disease and related dementias (ADRD) rank as the sixth leading cause of death in the United States, underlining the importance of accurate ADRD risk prediction. While recent advancements in ADRD risk prediction have primarily relied on imaging analysis, not all patients undergo medical imaging before an ADRD diagnosis. Merging machine learning with claims data can reveal additional risk factors and uncover interconnections among diverse medical codes.

Objective: The study aims to use graph neural networks (GNNs) with claim data for ADRD risk prediction. Addressing the lack of human-interpretable reasons behind these predictions, we introduce an innovative, self-explainable method …

Unveiling Novel Genetic Variants In 370 Challenging Medically Relevant Genes Using The Long Read Sequencing Data Of 41 Samples From 19 Global Populations, Yanfeng Ji, Junfan Zhao, Jiao Gong, Fritz J Sedlazeck, Shaohua Fan

Faculty, Staff and Students Publications

Background: A large number of challenging medically relevant genes (CMRGs) are situated in complex or highly repetitive regions of the human genome, hindering comprehensive characterization of genetic variants using next-generation sequencing technologies. In this study, we employed long-read sequencing technology, extensively utilized in studying complex genomic regions, to characterize genetic alterations, including short variants (single nucleotide variants and short insertions and deletions) and copy number variations, in 370 CMRGs across 41 individuals from 19 global populations.

Results: Our analysis revealed high levels of genetic variants in CMRGs, with 68.73% exhibiting copy number variations and 65.20% containing short variants that may …

Broadcasters, Receivers, Functional Groups Of Metabolites, And The Link To Heart Failure By Revealing Metabolomic Network Connectivity, Azam Yazdani, Raul Mendez-Giraldez, Akram Yazdani, Rui-Sheng Wang, Daniel J Schaid, Sek Won Kong, M Reza Hadi, Ahmad Samiei, Esmat Samiei, Clemens Wittenbecher, Jessica Lasky-Su, Clary B Clish, Jochen D Muehlschlegel, Francesco Marotta, Joseph Loscalzo, Samia Mora, Daniel I Chasman, Martin G Larson, Sarah H Elsea

Faculty, Staff and Students Publications

Background and objective: Blood-based small molecule metabolites offer easy accessibility and hold significant potential for insights into health processes, the impact of lifestyle, and genetic variation on disease, enabling precise risk prevention. In a prospective study with records of heart failure (HF) incidence, we present metabolite profiling data from individuals without HF at baseline.

Methods: We uncovered the interconnectivity of metabolites using data-driven and causal networks augmented with polygenic factors. Exploring the networks, we identified metabolite broadcasters, receivers, mediators, and subnetworks corresponding to functional classes of metabolites, and provided insights into the link between metabolomic architecture and regulation in health. …

Genetic Diversity Of 1,845 Rhesus Macaques Improves Genetic Variation Interpretation And Identifies Disease Models, Jun Wang, Meng Wang, Ala Moshiri, R Alan Harris, Muthuswamy Raveendran, Tracy Nguyen, Soohyun Kim, Laura Young, Keqing Wang, Roger Wiseman, David H O'Connor, Zach Johnson, Melween Martinez, Michael J Montague, Ken Sayers, Martha Lyke, Eric Vallender, Tim Stout, Yumei Li, Sara M Thomasy, Jeffrey Rogers, Rui Chen

Faculty, Staff and Students Publications

Understanding and treating human diseases require valid animal models. Leveraging the genetic diversity in rhesus macaque populations across eight primate centers in the United States, we conduct targeted-sequencing on 1845 individuals for 374 genes linked to inherited human retinal and neurodevelopmental diseases. We identify over 47,000 single nucleotide variants, a substantial proportion of which are shared with human populations. By combining rhesus and human allele frequencies with established variant prediction methods, we develop a machine learning-based score that outperforms established methods in predicting missense variant pathogenicity. Remarkably, we find a marked number of loss-of-function variants and putative deleterious variants, which …

Shp2 As A Primordial Epigenetic Enzyme Expunges Histone H3 Ptyr-54 To Amend Androgen Receptor Homeostasis, Surbhi Chouhan, Dhivya Sridaran, Cody Weimholt, Jingqin Luo, Tiandao Li, Kiran Mahajan, Nupam P Mahajan, Et Al.

2020-Current year OA Pubs

Mutations that decrease or increase the activity of the tyrosine phosphatase, SHP2 (encoded by PTPN11), promotes developmental disorders and several malignancies by varying phosphatase activity. We uncovered that SHP2 is a distinct class of an epigenetic enzyme; upon phosphorylation by the kinase ACK1/TNK2, pSHP2 was escorted by androgen receptor (AR) to chromatin, erasing hitherto unidentified pY54-H3 (phosphorylation of histones H3 at Tyr54) epigenetic marks to trigger a transcriptional program of AR. Noonan Syndrome with Multiple Lentigines (NSML) patients, SHP2 knock-in mice, and ACK1 knockout mice presented dramatic increase in pY54-H3, leading to loss of AR transcriptome. In contrast, prostate tumors …

Hur Controls Glutaminase Rna Metabolism, Douglas Adamoski, Larissa M Dos Reis, Ana Carolina Paschoalini Mafra, Felipe Corrêa-Da-Silva, Pedro Manoel Mendes De Moraes-Vieira, Ioana Berindan-Neagoe, George A Calin, Sandra Martha Gomes Dias

Faculty, Staff and Student Publications

Glutaminase (GLS) is directly related to cell growth and tumor progression, making it a target for cancer treatment. The RNA-binding protein HuR (encoded by the ELAVL1 gene) influences mRNA stability and alternative splicing. Overexpression of ELAVL1 is common in several cancers, including breast cancer. Here we show that HuR regulates GLS mRNA alternative splicing and isoform translation/stability in breast cancer. Elevated ELAVL1 expression correlates with high levels of the glutaminase isoforms C (GAC) and kidney-type (KGA), which are associated with poor patient prognosis. Knocking down ELAVL1 reduces KGA and increases GAC levels, enhances glutamine anaplerosis into the TCA cycle, and …

Reported Incidence Of Infections Caused By Pathogens Transmitted Commonly Through Food: Impact Of Increased Use Of Culture-Independent Diagnostic Tests - Foodborne Diseases Active Surveillance Network, 1996-2023, Hazel J. Shah, Rachel H. Jervis, Katie Wymore, Tamara Rissman, Bethany Laclair, Michelle M. Boyle, Kirk Smith, Sarah Lathrop, Suzanne Mcguire, Rosalie Trevejo, Marcy Mcmillian, Stic Harris, Joanna Zablotsky Kufel, Kennedy Houck, Carey E. Lau, Carey J. Devine, Dave Boxrud, Daniel L. Weller

Pathology Research and Scholarship

Reducing foodborne disease incidence is a public health priority. This report summarizes preliminary 2023 Foodborne Diseases Active Surveillance Network (FoodNet) data and highlights efforts to increase the representativeness of FoodNet. During 2023, incidences of domestically acquired campylobacteriosis, Shiga toxin-producing Escherichia coli infection, yersiniosis, vibriosis, and cyclosporiasis increased, whereas those of listeriosis, salmonellosis, and shigellosis remained stable compared with incidences during 2016-2018, the baseline used for tracking progress towards federal disease reduction goals. During 2023, the incidence and percentage of infections diagnosed by culture-independent diagnostic tests (CIDTs) reported to FoodNet continued to increase, and the percentage of cases that yielded an …

Context-Dependent T-Box Transcription Factor Family: From Biology To Targeted Therapy, Siwen Li, Xiangyuan Luo, Mengyu Sun, Yijun Wang, Zerui Zhang, Junqing Jiang, Dian Hu, Jiaqian Zhang, Zhangfan Wu, Yufei Wang, Wenjie Huang, Limin Xia

Faculty, Staff and Student Publications

T-BOX factors belong to an evolutionarily conserved family of transcription factors. T-BOX factors not only play key roles in growth and development but are also involved in immunity, cancer initiation, and progression. Moreover, the same T-BOX molecule exhibits different or even opposite effects in various developmental processes and tumor microenvironments. Understanding the multiple roles of context-dependent T-BOX factors in malignancies is vital for uncovering the potential of T-BOX-targeted cancer therapy. We summarize the physiological roles of T-BOX factors in different developmental processes and their pathological roles observed when their expression is dysregulated. We also discuss their regulatory roles in tumor …

O-Glcnacylation Of Mitf Regulates Its Activity And Cdk4/6 Inhibitor Resistance In Breast Cancer, Yi Zhang, Shuyan Zhou, Yan Kai, Ya-Qin Zhang, Changmin Peng, Zhuqing Li, Muhammad Jameel Mughal, Belmar Julie, Xiaoyan Zheng, Junfeng Ma, Cynthia X Ma, Min Shen, Matthew D Hall, Shunqiang Li, Wenge Zhu

2020-Current year OA Pubs

Cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in cell cycle and cancer development. Targeting CDK4/6 has demonstrated promising effects against breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i), such as palbociclib, remains a substantial challenge in clinical settings. Using high-throughput combinatorial drug screening and genomic sequencing, we find that the microphthalmia-associated transcription factor (MITF) is activated via O-GlcNAcylation by O-GlcNAc transferase (OGT) in palbociclib-resistant breast cancer cells and tumors. Mechanistically, O-GlcNAcylation of MITF at Serine 49 enhances its interaction with importin α/β, thus promoting its translocation to nuclei, where it suppresses palbociclib-induced senescence. Inhibition of MITF or …

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

2020-Current year OA Pubs

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

Baseline Levels And Longitudinal Changes In Plasma Aβ42/40 Among Black And White Individuals, Chengjie Xiong, Jingqin Luo, Rachel L Henson, Tammie L S Benzinger, Quoc Bui, Folasade Agboola, Elizabeth Grant, Emily N Gremminger, Krista L Moulder, Ganesh Babulal, Carlos Cruchaga, David M Holtzman, Randall J Bateman, John C Morris, Suzanne E Schindler, Et Al.

2020-Current year OA Pubs

Blood-based biomarkers of Alzheimer disease (AD) may facilitate testing of historically under-represented groups. The Study of Race to Understand Alzheimer Biomarkers (SORTOUT-AB) is a multi-center longitudinal study to compare AD biomarkers in participants who identify their race as either Black or white. Plasma samples from 324 Black and 1,547 white participants underwent analysis with C

Identification Of Unique Cell Type Responses In Pancreatic Islets To Stress, Marlie M Maestas, Matthew Ishahak, Punn Augsornworawat, Daniel A Veronese-Paniagua, Kristina G Maxwell, Leonardo Velazco-Cruz, Erica Marquez, Jiameng Sun, Mira Shunkarova, Sarah E Gale, Fumihiko Urano, Jeffrey R Millman

2020-Current year OA Pubs

Diabetes involves the death or dysfunction of pancreatic β-cells. Analysis of bulk sequencing from human samples and studies using in vitro and in vivo models suggest that endoplasmic reticulum and inflammatory signaling play an important role in diabetes progression. To better characterize cell type-specific stress response, we perform multiplexed single-cell RNA sequencing to define the transcriptional signature of primary human islet cells exposed to endoplasmic reticulum and inflammatory stress. Through comprehensive pair-wise analysis of stress responses across pancreatic endocrine and exocrine cell types, we define changes in gene expression for each cell type under different diabetes-associated stressors. We find that …

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

2020-Current year OA Pubs

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

Addressing Disparities In Pediatric Congenital Heart Disease: A Call For Equitable Health Care, Devyani Chowdhury, Pietro A Elliott, S Yukiko Asaki, Shahnawaz Amdani, Quang-Tuyen Nguyen, Christina Ronai, Seda Tierney, Victor Y Levy, Kriti Puri, Carolyn A Altman, Jonathan N Johnson, Julie S Glickstein

Faculty, Staff and Students Publications

While significant progress has been made in reducing disparities within the US health care system, notable gaps remain. This article explores existing disparities within pediatric congenital heart disease care. Congenital heart disease, the most common birth defect and a leading cause of infant death, has garnered substantial attention, revealing certain disparities within the US health care system. Factors such as race, ethnicity, insurance coverage, socioeconomic status, and geographic location are all commonalities that significantly affect health disparities in pediatric congenital heart disease. This comprehensive review sheds light on disparities from diverse perspectives in pediatric care, demonstrates the inequities and inequalities …

Experiences From Patients In Mental Healthcare Accessing Their Electronic Health Records: Results From A Cross-National Survey In Estonia, Finland, Norway, And Sweden, A. J. Fagerlund, Annika Bärkås, A. Kharko, C. R. Blease, J. Hagström, I. Huvila, I. Hörhammer, B. Kane, E. Kristiansen, S. Kujala, J. Moll, H. Rexhepi, I. Scandurra, S. Simola, H. Soone, B. Wang, R. M. Åhlfeldt, M. Hägglund, M. A. Johansen

School of Psychology

Background: Patients’ online record access (ORA) enables patients to read and use their health data through online digital solutions. One such solution, patient-accessible electronic health records (PAEHRs) have been implemented in Estonia, Finland, Norway, and Sweden. While accumulated research has pointed to many potential benefits of ORA, its application in mental healthcare (MHC) continues to be contested. The present study aimed to describe MHC users’ overall experiences with national PAEHR services. Methods: The study analysed the MHC-part of the NORDeHEALTH 2022 Patient Survey, a large-scale multi-country survey. The survey consisted of 45 questions, including demographic variables and questions related to …

Fedgmmat: Federated Generalized Linear Mixed Model Association Tests, Wentao Li, Han Chen, Xiaoqian Jiang, Arif Harmanci

Faculty, Staff and Student Publications

Increasing genetic and phenotypic data size is critical for understanding the genetic determinants of diseases. Evidently, establishing practical means for collaboration and data sharing among institutions is a fundamental methodological barrier for performing high-powered studies. As the sample sizes become more heterogeneous, complex statistical approaches, such as generalized linear mixed effects models, must be used to correct for the confounders that may bias results. On another front, due to the privacy concerns around Protected Health Information (PHI), genetic information is restrictively protected by sharing according to regulations such as Health Insurance Portability and Accountability Act (HIPAA). This limits data sharing …

Trans-Ancestral Genetic Risk Factors For Treatment-Related Type 2 Diabetes Mellitus In Survivors Of Childhood Cancer, Cindy Im, Achal Neupane, Jessica L Baedke, Brian Lenny, Angela Delaney, Stephanie B Dixon, Eric J Chow, Sogol Mostoufi-Moab, Tianzhong Yang, Melissa A Richard, M Monica Gramatges, Philip J Lupo, Noha Sharafeldin, Smita Bhatia, Gregory T Armstrong, Melissa M Hudson, Kirsten K Ness, Leslie L Robison, Yutaka Yasui, Carmen L Wilson, Yadav Sapkota

Center for Medical Ethics and Health Policy Staff Publications

Purpose: Type 2 diabetes mellitus (T2D) is a prevalent long-term complication of treatment in survivors of childhood cancer, with marked racial/ethnic differences in burden. In this study, we investigated trans-ancestral genetic risks for treatment-related T2D.

Patients and methods: Leveraging whole-genome sequencing data from the St Jude Lifetime Cohort (N = 3,676, 304 clinically ascertained cases), we conducted ancestry-specific genome-wide association studies among survivors of African and European genetic ancestry (AFR and EUR, respectively) followed by trans-ancestry meta-analysis. Trans-/within-ancestry replication including data from the Childhood Cancer Survivor Study (N = 5,965) was required for prioritization. Three external general population T2D polygenic …

Lethal Phenotypes In Mendelian Disorders, Pilar Cacheiro, Samantha Lawson, Ignatia B Van Den Veyver, Gabriel Marengo, David Zocche, Stephen A Murray, Michael Duyzend, Peter N Robinson, Damian Smedley

Center for Medical Ethics and Health Policy Staff Publications

Purpose: Existing resources that characterize the essentiality status of genes are based on either proliferation assessment in human cell lines, viability evaluation in mouse knockouts, or constraint metrics derived from human population sequencing studies. Several repositories document phenotypic annotations for rare disorders; however, there is a lack of comprehensive reporting on lethal phenotypes.

Methods: We queried Online Mendelian Inheritance in Man for terms related to lethality and classified all Mendelian genes according to the earliest age of death recorded for the associated disorders, from prenatal death to no reports of premature death. We characterized the genes across these lethality categories, …