Digital Commons Network^™

De Novo Variants In The Splicing Factor Gene Sf3b1 Are Associated With Neurodevelopmental Disorders, Kevin Uguen, Tiffany Bergot, Marie-Pier Scott-Boyer, Solène Chapalain, Camille Desdouets, Séverine Commet, Changlian Zhu, Yiran Xu, Yangong Wang, Tony Roscioli, Frederic Tran-Mau-Them, Laurence Faivre, Julien Maraval, Julian Delanne, Anne-Sophie Denommé-Pichon, Antonio Vitobello, Céline Jost, Marc Planes, Susan Hiatt, Patricia Wheeler, Claudia Gonzaga-Jauregui, Heng Wang, Baozhong Xin, Valerie Sency, Michael C Kruer, Somayeh Bakhtiari, Patrick Sulem, Cynthia Curry, Trine Prescott, Gertrud Strobl-Wildemann, Theresa Brunet, Martine Doco Fenzy, Thomas Courtin, Céline Poirsier, Trine Bjørg Hammer, Christina D Fenger, Melissa Macpherson, Kosuke Izumi, Jacqueline Leonard, Dong Li, Elaine H Zackai, Ian A Glass, Scott Ward, Philippe M Campeau, Maria Carla Hermida Borroto, Laurence Le Moigno, Hilde Van Esch, Liesbeth De Waele, Daniel G Calame, James R Lupski, Giulia Barcia, Cristina Peduto, Pauline Planté-Bordeneuve, Lucie Dupuis, Roberto Mendoza-Londono, Dimitri J Stavropoulos, Jennifer Gillibert-Duplantier, Thomas Besnard, Laura Do Souto Ferreira, Benjamin Cogné, Stéphane Bézieau, Arnaud Droit, Laurent Corcos, Eric Lippert, Claude Férec, Sebastien Küry, Delphine G Bernard

Faculty, Staff and Students Publications

SF3B1 is an essential and ubiquitous splicing factor that plays a pivotal role in the early steps of pre-mRNA splicing. Recurrent somatic missense mutations in SF3B1 are frequent in cancers, but no constitutional variant has been reported so far. We describe here a cohort of 26 individuals with neurodevelopmental disorders, harbouring SF3B1 constitutional heterozygous variants that appeared mostly de novo. Patients present with a global developmental delay, associated with variable neurological and facial dysmorphic traits. A dichotomy may emerge between patients harbouring predicted loss of function (n = 9) and missense variants (n = 17), the latter being associated with …

Intestinal Epithelial Tlr5 Signaling Promotes Barrier-Supportive Macrophages, Ming-Ting Tsai, Ryann Callaghan, Charles Ng, Lisette Peres-Tintin, Dean B Matthews, Nikketa Stanford, Karuna Ganesh, Mary K Estes, Gretchen E Diehl

Faculty, Staff and Students Publications

Intestinal macrophages are essential for epithelial barrier repair. In homeostasis, macrophages are continuously replenished by recruitment of circulating CCR2+ monocytes into the intestinal lamina propria. This requires the commensal microbiota, however, the specific microbial factors and downstream host pathways that coordinate macrophage replenishment are inadequately understood. Here, we show that colonization with an E. coli isolate increased CCR2+ macrophages in the intestine and ameliorated pathology in a colitis model. Using human colonic organoids, we showed E. coli colonization induced CCL2 secretion by intestinal epithelial stem cells which promoted monocyte migration. In vivo, protection was abolished in the absence of epithelial …

Saga/Atac Complexes Sustain Aberrant Chromatin Regulation And Promote Tumorigenesis In Diffuse Midline Glioma, Rosemary U Richard, Caitlin Bagnetto, Rebecca L Murdaugh, Brittany R Eberl, Alan L Jiao, Adam F Kebede, Barry M Zee, Margaret M Harrington, Mariella G Filbin, Akdes Serin-Harmanci, Yang Shi, Jamie N Anastas

Faculty, Staff and Students Publications

Diffuse midline gliomas (DMG) are aggressive pediatric brain tumors characterized by chromatin and transcriptional dysregulation induced by H3K27M mutations. Strategies for overcoming epigenetic dysfunction to reduce DMG tumorigenesis remain limited. We identified multiple components of the SAGA and ATAC chromatin regulatory complexes as DMG genetic dependencies and found that genetic or pharmacological inhibition of the SAGA/ATAC-associated chromatin reader SGF29 reduces DMG proliferation. Small molecules targeting SAGA/ATAC-associated histone acetylation, ubiquitination, and methylation similarly suppressed DMG growth. Further chromatin profiling and RNAseq analyses reveal that SGF29 controls H3K9ac and H3K4me3 dynamics at both H3K27M-bound and H3K27M-independent target genes linked to proliferation, differentiation, …

Fyn-Saracatinib Complex Structure Reveals An Active State-Like Conformation, Hai Minh Ta, Banumathi Sankaran, Eric D Roush, Josephine C Ferreon, Allan Chris M Ferreon, Choel Kim

Faculty, Staff and Students Publications

Fyn is a Src-family tyrosine kinase implicated in synaptic dysfunction and neuroinflammation across multiple neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Saracatinib (AZD0530) is a potent Src-family inhibitor that has been explored as a repurposed therapeutic; however, its clinical utility is limited by poor kinase selectivity caused by high sequence conservation within Src-family ATP-binding sites. Here, we combine surface plasmon resonance (SPR) and X-ray crystallography to define saracatinib recognition by the Fyn kinase domain (KD). SPR single-cycle kinetics shows that saracatinib binds the isolated Fyn KD and full-length Fyn with low-nanomolar affinity, whereas dasatinib binds with subnanomolar …

Hiv Vpr Induces Demethylation Of The Snca Antisense Promoter, Leading To Neurocognitive Impairment, Maryline Santerre, Ying Wang, Daniel Kalamarides, Jin Park, Lynn G Kirby, Jeannie Chin, Jaroslav Jelinek, Natalia Shcherbik, Bassel E Sawaya

Faculty, Staff and Students Publications

Human immunodeficiency virus type 1 (HIV-1) alpha-synuclein (α-Syn) aggregation is a hallmark of neurodegenerative diseases. Accumulation and aggregation of α-Syn are often observed in individuals with HIV-1 cognitive impairments. The direct mechanistic link between α-Syn dysregulation and HIV-associated neurocognitive disorders (HAND) remains unclear. Emerging evidence suggests that epigenetic changes, particularly deoxyribonucleic acid (DNA) demethylation, influence α-Syn regulation. We show that the HIV-1 protein viral protein R (Vpr) demethylates the antisense promoter within intron 1 of the alpha-synuclein gene (SNCA), potentially contributing to increased α-Syn expression. Elevated α-Syn promotes aggregation, causing synaptic dysfunction and impaired mitochondrial transport. These processes contribute to …

Single-Cell Atlas Of Human Lung Aging Identifies Cell Type Dyssynchrony And Increased Transcriptional Entropy, Ruben De Man, John E Mcdonough, Taylor S Adams, Fadi Nikola, Reina Rangel, Sabina Anderson, Edward P Manning, Juan Cala Garcia, Benjamin Moss, Alan Waich, Fernando Poli, Rafael Cardenas, Cristian Coarfa, Qi Song, Ziv Bar-Joseph, Bart M Vanaudenaerde, Wim A Wuyts, Laura Niklason, Micha Sam B Raredon, Xiting Yan, Ivan O Rosas, Naftali Kaminski

Faculty, Staff and Students Publications

Age is a major risk factor for lung disease. We characterized the changing cellular, transcriptional, and genomic landscape of human lung aging using single-cell RNA sequencing. We find that lung aging is cell-type dyssynchronous, with alveolar epithelial and endothelial cells exhibiting the greatest transcriptional changes. Among alveolar epithelial cells, aging is associated with a decreased relative proportion of surfactant-expressing SPChigh AT2 cells. Among alveolar capillary cells, we observed loss of differentiation and capillary function. Analysis of somatic mutations called from single-cell data revealed an increase with aging, with alveolar epithelial and endothelial cell types exhibiting greater mutation burdens. Transcriptional entropy …

What Needs To Be Standardized For Reliable, Reproducible, And Robust Tractography?, Jon Haitz Legarreta, Simona Schiavi, Wei Tang, Garrett Banks, Matthew Cieslak, Kurt Schilling, Alberto De Luca, Jacques-Donald Tournier, John Kruper, Francois Rheault, Stamatios N Sotiropoulos, Franco Pestilli, Jelle Veraart, Joseph Yuan-Mou Yang, Maxime Descoteaux, Sarah Heilbronner, Ariel Rokem

Faculty, Staff and Students Publications

Tractography is a key component of efforts to map brain connectivity. As a rapidly evolving field of neuroscience, current tractography methods are diverse, often varying across research laboratories and different software pipelines. Therefore, it suffers from a lack of standardization, leading to inconsistencies in results, which can limit reproducibility and affect the robustness needed for research and clinical applications of these methods. Variability in data acquisition procedures, inconsistencies in spatial referencing schemes and implementations, and anatomical heterogeneity-at the individual level, across the lifespan, and across species-hinder comparative analyses. Additionally, the lack of consensus on best practices complicates the development of …

Maturity-Onset Diabetes Of The Young (Mody) In A Racially/Ethnically Diverse Pediatric Population, Shilpi Relan, Guido Alarcon, Danielle Guffey, Charles G Minard, Mary E Fang, Kelly Timmons, Rona Y Sonabend, Mustafa Tosur, Maria J Redondo, Jennifer E Posey

Faculty, Staff and Students Publications

Context: Current practice guidelines recommend considering a diagnosis of maturity-onset diabetes of the young (MODY) in patients with diabetes with an affected parent but without typical features of type 1 or type 2 diabetes.

Objective: To test if these criteria apply to a real-world cohort of racially/ethnically diverse children with diabetes.

Methods: We performed a retrospective case review of electronic medical records of youth diagnosed with MODY in a large academic pediatric hospital in Southwestern United States. Cases were ascertained based on the identification of a molecular diagnosis of MODY.

Results: We studied 50 genetically confirmed cases of MODY: 60% …

The Use Of Artificial Intelligence In Decreasing Vaccine Skepticism And Hesitancy, Nathaniel Wolf, Nhan Nguyen, Rojelio Mejia

Faculty, Staff and Students Publications

Purpose of review: Recent advances in artificial intelligence (AI) coincide with decreases in confidence in vaccines. This review examines studies that analyze and mitigate vaccine skepticism by implementing artificial intelligence strategies in various ways.

Recent findings: Studies have explored public attitudes towards vaccines using AI to analyze language in social media postings and interactions, scrutinize AI responses to vaccine-related queries, and attempt to use AI to directly influence vaccine hesitancy. Findings show that AI can be effective in addressing vaccine hesitancy in various ways, including, but not limited to, directly interacting with vaccine-hesitant groups, identifying reasons for vaccine hesitancy, and …

B Lymphocytes Impede Tregs To Erode Islet Tolerance In Type 1 Diabetes, Christopher S Wilson, Blair T Stocks, Alexander C Falk, Daniel J Moore

Faculty, Staff and Students Publications

B lymphocytes are thought to drive β-cell destruction in type 1 diabetes (T1D) by activating anti-islet T cells. However, the observation that autoreactive T-cell activation and disease progression can occur without B cells challenges this view. Still, preclinical and clinical studies have shown that B-cell depletion alleviates β-cell destruction, suggesting a critical role for B cells in T1D. Our findings propose an alternative function for B cells, impairing regulatory T cells (Tregs) that would otherwise protect islets. In the NOD islet transplant model, we show that B-cell absence enables transplant tolerance, allowing Tregs to become responsive to immune therapy and …

The Evolution Of Public Health Statistical Modeling Approaches And How To Advance Their Incorporation Into Modern Arboviral Surveillance, Maggie Mccarter, Stella C W Self, Alex Ewing, Mufaro Kanyangarara, Sarah M Gunter, Melissa S Nolan

Faculty, Staff and Students Publications

Statistical modeling of infectious disease transmission patterns has been in existence since the mid-1700s, evolving in their utility as the scientific and technological revolutions progressed. Despite the expansion of emerging mathematical and statistical methodologies over the past 250 yr, their usage has largely remained restricted to academic settings. This forum article will discuss the evolution of disease modeling techniques, the most common types of models in use today, and recommendations on how key archetypes can be incorporated into future public health practice. With the recent global impetus to predict and forecast novel pathogens, this article raises the question: Why are …

Successful Bacteriophage Treatment Of A Recalcitrant Intra-Abdominal Infection Caused By Multi-Drug-Resistant Pseudomonas Aeruginosa In A 2-Year-Old Child, Sanchi Malhotra, Keiko C Salazar, Neema Pithia, Ishminder Kaur, Kristina Adachi, Nanda Ramachandar, Austin L Terwilliger, Anthony Maresso, Robert S Venick, Suzanne V Mcdiarmid, John S Bradley

Faculty, Staff and Students Publications

Antimicrobial resistance is life-threatening to complex pediatric patients who receive multiple courses of broad-spectrum antibiotics. Bacteriophages offer a safe treatment alternative when our antibiotic armamentarium is no longer sufficient. We describe successful use of bacteriophage therapy on a patient with a recalcitrant Pseudomonas aeruginosa infection after receiving a multi-organ transplant.

Onset And Exacerbation Of Obsessive-Compulsive Disorder In The Perinatal Period, Jack Samuels, Mary Kimmel, Janice Krasnow, Rashelle Musci, Paul S Nestadt, Lauren M Osborne, Eric A Storch, Jonathan S Abramowitz, Gerald Nestadt

Faculty, Staff and Students Publications

Purpose: Obsessive-compulsive disorder (OCD) can emerge during pregnancy and the postpartum and may adversely affect mother and newborn. However, little is known about potential risk factors for the onset of OCD in the perinatal period. Therefore, we investigated the onset of diagnosed DSM-5 OCD in women followed from the second trimester of pregnancy to 6-months postpartum.

Methods: We followed 256 women from the 20-24th week of pregnancy to 6-month postpartum. Participants had psychiatric diagnostic interviews at baseline and 6-month postpartum and completed self-report instruments. We compared women with and without incident OCD on sociodemographic characteristics and clinical features.

Results: Of …

Effects Of Icosapent Ethyl On Risk And Duration Of Hospitalizations And Death In Reduce-It, Michael Szarek, Deepak L Bhatt, Michael Miller, Eliot A Brinton, Jean-Claude Tardif, Christie M Ballantyne, Steven B Ketchum, Mandeep R Mehra, Ph Gabriel Steg

Faculty, Staff and Students Publications

Aims: Among statin-treated participants with elevated triglycerides and known cardiovascular disease or with diabetes and other risk factors, icosapent ethyl reduced the risk of cardiovascular events in the REDUCE-IT study. In this post hoc analysis of REDUCE-IT, we quantified the effects of icosapent ethyl on total hospitalizations and days lost to hospitalization and death.

Methods: Randomization to treatment with 2 g twice daily of icosapent ethyl or matching placebo was performed among 8179 participants receiving statin therapy with established cardiovascular disease or age ≥50 years with diabetes and ≥1 additional risk factor, fasting triglyceride 1.69-5.63 mmol/L, and low-density lipoprotein cholesterol …

Associations Of Arsenic Exposure And Folate In Maternal Leukocyte Dna Methylation: A Case-Control Study Of Mothers With Spina-Bifida Affected Children, Amy M Inkster, Anne K Bozack, Bernardo Lemos, Tabitha Lumour-Mensah, Sudipta Kumar Mukherjee, Shekh Muhammad Ekramullah, D M Arman, Joynul Islam, Xingyan Wang, Liming Liang, Richard H Finnell, Maitreyi Mazumdar, Andres Cardenas

Faculty, Staff and Students Publications

No abstract provided.

Rnai-Based Screen For Pigmentation In Drosophila Melanogaster Reveals Regulators Of Brain Dopamine And Sleep, Samantha L Deal, Danqing Bei, Shelley B Gibson, Harim Delgado-Seo, Yoko Fujita, Kyla Wilwayco, Elaine S Seto, Amita Sehgal, Shinya Yamamoto

Faculty, Staff and Students Publications

The dopaminergic system has a large role in behavior and neurological disease, and understanding dopamine level regulation in vivo is critical. To identify dopamine regulators, we utilized Drosophila melanogaster cuticle pigmentation, where dopamine is a precursor to melanin. We measured dopamine from known pigmentation mutants (e.g., tan, ebony, black) and performed an RNAi-based screen to identify additional regulators. We found 153 hits, enriched for developmental signaling pathways and mitochondria-associated proteins. From 35 prioritized candidates, 11 affected head dopamine levels. Effects on brain dopamine were mild, even knocking down the rate-limiting synthesis enzyme Tyrosine hydroxylase (TH), suggesting …

The Impact Of Indigenous American-Like Ancestry On The Risk Of Acute Lymphoblastic Leukemia In Hispanic/Latino Children, Jalen Langie, Tsz Fung Chan, Wenjian Yang, Alice Y Kang, Libby Morimoto, Daniel O Stram, Nicholas Mancuso, Xiaomei Ma, Catherine Metayer, Philip J Lupo, Karen R Rabin, Michael E Scheurer, Joseph L Wiemels, Jun J Yang, Adam J De Smith, Charleston W K Chiang

Faculty, Staff and Students Publications

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, with Hispanic/Latino children having a higher incidence of ALL than other racial/ethnic groups. Among the genetic variants previously implicated in ALL risk, a number of them were found to be enriched in Indigenous American (IA)-like ancestries and inherited by many Hispanic/Latino individuals. However, due to potential confounding from environmental factors, the association between IA-like ancestry and risk for ALL has remained unclear. In this study, we characterized the impact of IA-like ancestry on overall ALL risk and on the frequency and effect size of known risk alleles, while accounting for …

Resolution Of A Human Chromosomal Mystery: Evolutionary Complexity Revealed, Jeffrey Rogers

Faculty, Staff and Students Publications

The human complement of chromosomes differs from our closest primate relatives by virtue of a unique chromosome fusion event. In this issue of Cell Genomics, Yang et al. provide the first detailed analysis of the site of chromosome fusion and reconstruct the complex evolutionary relationships among the genomic elements within the human fusion site and their related sequences in our great ape relatives.

Ophiobolin A Impacts Mitochondrial Redox Biology In An Epithelial-Mesenchymal Transition (Emt)-Specific Manner, Haleigh N Parker, Yongfeng Tao, Jenna Tobin, Kayla L Haberman, Samantha Davis, Emily York, Alysia Martinez, Nobuyuki Matsumoto, Jaquelin Aroujo, Jun Hyoung Park, Bernd Zechmann, Benny Abraham Kaipparettu, Angela Boari, Christie M Sayes, Antonio Evidente, Alexander Kornienko, Benjamin Cravatt, Daniel Romo, Joseph H Taube

Faculty, Staff and Students Publications

Breast cancer progression is facilitated by the epithelial to mesenchymal transition (EMT), generating cancer cells with enhanced metastatic capacity and resistance to chemotherapeutics. The fungus-derived sesterterpenoid natural produce compound, ophiobolin A (OpA), possesses nanomolar cytotoxic activity and a high therapeutic index, although its molecular targets and mechanism of action are not well characterized. Herein, we utilized a model of mammary epithelial cells and breast cancer cell lines with and without EMT features to characterize the mechanism of selectivity towards EMT(+) cells by OpA. Proteins interacting with OpA in EMT(+) cells, including mitochondrial glutathione transporter SLC25A40, were identified through via mass …

Egfr Inhibitor-Resistant Lung Cancers Exhibit Collateral Sensitivity To A Covalent, Cysteine-Independent Keap1 Oligomerizing Molecular Bridge, Christopher F Bassil, Kerry Dillon, Gray R Anderson, Benjamin Mayro, Kayleigh N Askin, Peter S Winter, Stefan Harry, Samuel Gruber, Tierney M Hall, Jacob P Hoj, Christian Cerda-Smith, Haley M Hutchinson, Shane T Killarney, Ava Heffernan, Caroline Teddy, Katherine R Singleton, Li Qin, Kévin Jubien-Girard, Cécile Favreau, Guillaume Robert, Barr Tivon, Ella Livnah, Nir London, Rachid Benhida, Patrick Auberger, Ann Marie Pendergast, Liron Bar-Peled, David M Lonard, Anthony R Martin, Alexandre Puissant, Kris C Wood

Faculty, Staff and Students Publications

Targeted therapies have revolutionized cancer care. Unfortunately, most patients develop refractory, multifocal resistance to these therapies within a matter of months. Here, we demonstrate that the evolution of resistance to EGFR inhibitors in EGFR-mutant non-small cell lung cancer endows cells with hypersensitivity to a PAINS-like small molecule, MCB-613. Systematic proteomic, functional genomic, and biochemical studies revealed that MCB-613 binds KEAP1 in a covalent, cysteine-independent fashion, acting as a divalent molecular bridge that relies upon lysine residues in the KEAP1 dimerization domain to join monomers of KEAP1 together. Oligomerization of KEAP1 by MCB-613 sets into motion a fatal cascade of KEAP1 …

Progress And Challenges In Profiling Protein-Rna And Protein-Associated Rna-Rna Interactions, Zhuoyi Song, Eric L Van Nostrand

Faculty, Staff and Students Publications

RNA binding proteins (RBPs) play essential roles in post-transcriptional gene regulation by interacting with a wide range of RNA targets. In addition to regulating RNA processing via individual RBP-RNA interactions, there is a growing appreciation of the regulatory impact of protein-associated RNA-RNA interactions that include both well-studied examples of small regulatory RNAs (e.g. microRNAs, snRNAs, snoRNAs, piRNAs) guiding ribonucleoprotein complexes to their targets as well as structured RNA elements defining the interaction landscape for an RBP. To elucidate the full scope of RBP-RNA interactions, CLIP ( crosslinking and immunoprecipitation)-based methods have emerged as powerful tools. Even with the wide application …

Efficacy And Safety Of Oral Pcsk9 Inhibitor Enlicitide In Adults With Heterozygous Familial Hypercholesterolemia: A Randomized Clinical Trial, Christie M Ballantyne, Laura Gellis, Jean-Claude Tardif, Puja Banka, Ann Marie Navar, Emil Andreas Asprusten, Russell Scott, Erik S G Stroes, Samar Froman, Geraldine Mendizabal, Fan Wang, Alberico L Catapano

Faculty, Staff and Students Publications

Importance: Persons with heterozygous familial hypercholesterolemia (HeFH) are at increased risk of atherosclerotic cardiovascular disease due to lifelong elevated levels of low-density lipoprotein cholesterol (LDL-C). Many patients with HeFH do not achieve guideline-recommended LDL-C goals with the currently available lipid-lowering therapies.

Objective: To evaluate the efficacy of enlicitide decanoate (an oral proprotein convertase subtilisin/kexin type 9 inhibitor) vs placebo in adults with HeFH requiring further lowering of LDL-C levels despite use of statin therapy.

Design, setting, and participants: This phase 3, randomized clinical trial included persons aged 18 years or older with HeFH currently using lipid-lowering therapy (taking at least …

Tumor-Specific Immune Responses And Biomarkers In Pediatric Patients With High-Risk Hodgkin Lymphoma, Keri Toner, Lindsay A Renfro, Hema Dave, Gloria Pezzella, Qinglin Pei, Lisa Giulino-Roth, Terzah Horton, Frank G Keller, Kara M Kelly, Sharon M Castellino, Catherine M Bollard

Faculty, Staff and Students Publications

There is an unmet need to examine antitumor immune responses and predictive biomarkers in the peripheral blood to guide effective combination immunotherapies in classical Hodgkin lymphoma (cHL). We sought to evaluate T-cell specific immune responses as well as cytokine and chemokine profiles including levels of soluble CD30 (sCD30), sCD163, and thymus and activation-regulated chemokine (TARC) in relation to event-free survival in patients with cHL. The Children’s Oncology Group (COG) clinical trial AHOD1331 was a randomized phase 3 trial for patients with newly diagnosed high-risk cHL, aged 2 to 21 years, which compared standard chemotherapy and doxorubicin, bleomycin, vincristine, etoposide, prednisone, …

The Biomedical Landscape Of Genomic Structural Variation In The Qatari Population, Elbay Aliyev, Najeeb Syed, Alessia Visconti, Taghi Aliyev, Aziz Belkadi, Mohammadmersad Ghorbani, Niccolò Rossi, Haroon Naeem, Geethanjali Devadoss Gandhi, Gaurav Thareja, Aljazi Al-Maraghi, Waleed Aamer, Amal Abdulsalam Ibrahim, Rulan Shaath, Farooq Omar Al-Ajli, Rozaimi Mohamad Razali, Fritz J Sedlazeck, Sonia Davila, Ammira Akil, Karsten Suhre, Younes Mokrab, Mario Falchi, Khalid A Fakhro

Faculty, Staff and Students Publications

We present a large-scale study of structural variation (SV) in the Qatari population, based on short-read whole-genome sequencing (WGS) of 6,141 individuals, identifying 153,946 variants across 5 classes reflecting the region's diversity and evolutionary history. Leveraging consanguinity and biobank phenotypes, we identify >180 putative gene knockouts, and use proteomics to show functional consequences in homozygotes. Conversely, 52 genes show significant depletion of homozygous deletions, eight of which cause severe pediatric disease or murine embryonic lethality. Examining phenotypic extremes uncovers several non-exonic homozygous deletions with large effect, including in SPIRE2 (creatinine), MAGI2 (leanness) and a chr19 microRNA cluster (extreme obesity). Further, …

Identifying Priority Research Questions For Decentralized Wastewater, Bryan W Brooks, Timothy Callahan, Jacob K Stanley, Jamie Holodak, Kevin M Stroski, Alissa H Cox, Thomas W Groves, Anish Jantrania, Jeff C Moeller, Kris Neset, Christopher Walker, Harry Zhang, Amal Bakchan, Kelly D Alley, Jim Bell, Allison Blodig, Eric Casey, Donna Cosper, Victor D'Amato, Mark A Elliott, Greg Graves, Roxanne Groover, Robert Himschoot, Mary G Lusk, Jillian Maxcy-Brown, David Meints, Rojelio Mejia, Matt Pace, Benjamin J Ryan, Brian Scheffe, Tom Schimelfenig, June E Wolfe, Sara F Heger

Faculty, Staff and Students Publications

Decentralized wastewater treatment and reuse represent critical infrastructure across the rural-periurban-urban continuum around the world. Effective, efficient, resilient, and equitable implementation of on-premise technologies and management systems is part of a One Water approach and necessary to protect public health and the environment, yet inconsistent delivery of essential public health services persists in many regions, including across states, tribes, and territories of the United States. We initiated a groundbreaking effort to understand challenges and to identify research opportunities related to the science and practice of decentralized wastewater. A horizon scanning exercise using a bottom up and transparent key questions approach …

Dynamic Fib-4 Score Changes And Hcc Risk In Patients With Masld And Elevated Liver Enzymes: A Nationwide Cohort Study, Yee Hui Yeo, Hsiu J Ho, Tsai-Wei Huang, Teng-Yu Lee, Ju Dong Yang, George Cholankeril, Chien-Jen Chen, Hawi-I Yang, Chuen-Fei Chen, Hung-Chuen Chang, Chun-Ying Wu

Faculty, Staff and Students Publications

Introduction: Hepatocellular carcinoma (HCC) can develop in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) without cirrhosis, especially in those with elevated liver enzymes. However, there is currently no low-cost, scalable screening tool for this population. To address this need, we investigated the association between serial changes in FIB-4 (fibrosis-4) scores over a 3-year period and the risk of developing HCC in a large, diverse cohort of patients with MASLD without cirrhosis.

Methods: This study utilized a nationwide cohort from the National Health Insurance Research Database (NHIRD), including 810,698 patients with MASLD who had demographic and laboratory data at baseline …

Germline Hla Heterozygosity Is Associated With Decreased Lung Cancer Risk, Taotao Tan, Vikram R Shaw, Jinyoung Byun, Hyun-Sung Lee, Younghun Han, Yafang Li, Rayjean J Hung, David C Christiani, Xin-An Wang, Mattias Johansson, Xiangjun Xiao, David Zaridze, Stig Egil Bojesen, Sanjay Shete, Demetrios Albanes, Melinda C Aldrich, Adonina Tardon, Guillermo Fernandez-Tardon, Loïc Le Marchand, Gad Rennert, Heike Bickeböller, H-Erich Wichmann, Angela Risch, John K Field, Michael Davies, Penella Woll, Lambertus A Kiemeney, Aage Haugen, Shanbeh Zienolddiny, Stephen Lam, Mikael Johansson, Kjell Grankvist, Matthew B Schabath, Angeline Andrew, Philip Lazarus, Susanne M Arnold, Dakai Zhu, Maria Teresa Landi, James Mckay, Christopher Amos, Chao Cheng

Faculty, Staff and Students Publications

Heterozygosity at human leukocyte antigen (HLA) loci may improve lung cancer immunosurveillance by increasing recognition of the tumor by the immune system. Previous studies utilizing data from population-level biobanks, such as the United Kingdom Biobank and FinnGen, have identified an association between germline HLA class-II heterozygosity and reduced lung cancer risk in smokers. In the present study, we evaluate the association between HLA heterozygosity and lung cancer in a large case-control study (15,302 cases; 14,580 controls) with imputed HLA allele-type information, comparing differences in HLA heterozygosity between smokers and non-smokers, amongst lung cancer subtypes, and at 2- and 4-digit HLA …

Chek2 Loss Endows Chemotherapy Resistance To Hematopoietic Stem Cells, Jing Zhou, Tianyuan Hu, Dian Li, Sanming Li, Minhua Li, Xiangguo Shi, Daisuke Nakada

Faculty, Staff and Students Publications

Individuals with history of chemo- or radiotherapy frequently exhibit somatic mosaicism in the blood, often involving mutations in genes responsible for DNA damage responses (DDR), such as CHEK2. However, the mechanisms by which CHEK2 mutations promote the expansion of mutant cells following chemo- or radiotherapy remain poorly understood. Here, we demonstrate that loss of CHEK2 confers resistance to chemotherapy in hematopoietic stem and progenitor cells (HSPCs). Through a CRISPR-based screen, we identified CHEK2 as a gene whose loss enhances resistance to cytotoxic chemotherapies. A complementary drug screen revealed that CHEK2-mutant cells are also resistant to DNA hypomethylating agents. Chek2-deficient HSPCs …

Plasma Proteomics And Incident Coronary Heart Disease, Matthew P Huber, Jennifer A Brody, Colleen M Sitlani, Thomas R Austin, Usman A Tahir, Shuliang Deng, Devendra Meena, Jingsha Chen, Kunihiro Matsushita, Christie M Ballantyne, Josef Coresh, Robert E Gerszten, Russell P Tracy, Ting Ye, Bruce M Psaty, Joshua C Bis, James S Floyd

Faculty, Staff and Students Publications

Background: Systematic profiling of plasma proteins in population studies offers a complementary approach to discovery of novel risk factors and may provide new insights into the causes of coronary heart disease.

Methods: To explore relationships between the circulating proteome and coronary heart disease (CHD), we evaluated associations of 4780 plasma proteins with incident CHD in the Cardiovascular Health Study (CHS, N=2856, 575 CHD events) and replicated significant associations in the Atherosclerosis Risk in Communities Study (ARIC, N = 10456; 1375 events).

Results: We find that 11 proteins significantly associate with incident CHD after adjusting for risk factors; and eight significantly …

Il-18 Metabolically Reprograms Car-Expressing Natural Killer T Cells And Enhances Their Antitumor Activity, Gabriel A Barragán Bravo, David A De La Cerda, Elisa Landoni, Kshiti Dholakia, Piotr Humeniuk, Leidy D Caraballo Galva, Ying Wang, Gengwen Tian, Boning Yang, Linjie Guo, Michael S Wood, Xavier Rios, Xin Xu, Amy N Courtney, Erica J Di Pierro, Joan Jacob, Yi-Han Li, Akshaya Adaikkalavan, Norihiro Watanabe, Sufeng Mao, George Miles, Gianpietro Dotti, Leonid S Metelitsa

Faculty, Staff and Students Publications

Invariant natural killer T cells (NKTs) have intrinsic anti-tumor properties that make them promising candidates for chimeric antigen receptor (CAR) immunotherapies. Transgenic cytokine expression can enhance cellular therapy potency, and we hypothesized that co-expressing IL-18 alone or with IL-15 would boost CAR-NKT therapeutic potential. To test this, we generated retroviral constructs expressing IL-15 and/or IL-18 with an inducible caspase 9 safety switch and co-transduced them with a GD2-specific CAR into human NKTs. Co-expression of IL-18 or IL-15/IL-18 increased CAR-NKT cytotoxicity, proliferation, and cytokine secretion in vitro compared to IL-15 alone. IL-18 also enhanced GPC3.CAR and CD19.CAR NKT activity against hepatocellular …