Digital Commons Network^™

Co-Designing A Web-Based And Tablet App To Evaluate Clinical Outcomes Of Early Psychosis Service Users In A Learning Health Care Network: User-Centered Design Workshop And Pilot Study, Kathleen E Burch, Adam B Wilcox, Et Al.

2020-Current year OA Pubs

BACKGROUND: The Early Psychosis Intervention Network of California project, a learning health care network of California early psychosis intervention (EPI) programs, prioritized incorporation of community partner feedback while designing its eHealth app, Beehive. Though eHealth apps can support learning health care network data collection aims, low user acceptance or adoption can pose barriers to successful implementation. Adopting user-centered design (UCD) approaches, such as incorporation of user feedback, prototyping, iterative design, and continuous evaluation, can mitigate these potential barriers.

OBJECTIVE: We aimed to use UCD during development of a data collection and data visualization web-based and tablet app, Beehive, to promote …

Cell Type-Specific Multi-Omics Analysis Of Cocaine Use Disorder In The Human Caudate Nucleus, Lea Zillich, Annasara Artioli, Veronika Pohořalá, Eric Zillich, Laura Stertz, Hanna Belschner, Ammar Jabali, Josef Frank, Fabian Streit, Diana Avetyan, Maja P Völker, Svenja Müller, Anita C Hansson, Thomas D Meyer, Marcella Rietschel, Julia Ladewig, Rainer Spanagel, Ana M M Oliveira, Consuelo Walss-Bass, Rick E Bernardi, Philipp Koch, Stephanie H Witt

Faculty, Staff and Student Publications

Structural and functional alterations in the brain's reward circuitry are present in cocaine use disorder (CocUD), but their molecular underpinnings remain unclear. To investigate these mechanisms, we performed single-nuclei multiome profiling on postmortem caudate nucleus tissue from six individuals with CocUD and eight controls. We profiled 30,030 nuclei, identifying 13 cell types including D1- and D2-medium spiny neurons (MSNs) and glial cells. We observed 1485 differentially regulated genes and 10,342 differentially accessible peaks, with alterations in MSNs and astrocytes related to neurotransmitter activity and synapse organization. Gene regulatory network analysis identified transcription factors including ZEB1 as exhibiting distinct CocUD-specific subclusters, …

Impact Of Perioperative Organ Injury On Morbidity And Mortality In 28 Million Surgical Patients, Felix Kork, Yafen Liang, Adit A Ginde, Xiaoyi Yuan, Rolf Rossaint, Hongfang Liu, Alex S Evers, Holger K Eltzschig

Faculty, Staff and Student Publications

Perioperative organ injury contributes to morbidity and mortality of surgical patients. This cohort study included all elective and emergent surgeries in Germany over 4 years to address the impact of perioperative organ injuries on outcomes. We analyzed 28,350,953 cases. In-hospital mortality was 1.4% (n = 393,157), and 4.4% of cases (n = 1,245,898) experienced perioperative organ injury. Perioperative organ injury was associated with 9-fold higher odds of death and prolonged hospital stay by 11.2 days. Acute kidney injury had the highest incidence (2.0%) and was associated with 25.0% mortality. While delirium had the second highest incidence (1.5%), it was associated …

Geographic Divergence Of Methicillin-Resistant Staphylococcus Aureus St5-Scc Mec I In The Aftermath Of A Major Earthquake And Tsunami: Impact Of A Plasmid Harboring Heavy Metal Resistance Genes, Jose R W Martínez, Manuel Alcalde-Rico, Estefanía Jara-Videla, Jinnethe Reyes, Lina P Carvajal, Sandra Rincon, Rafael Ríos, Lorena Diaz, Ana Quesille-Villalobos, Roberto Riquelme-Neira, Lina Rivas, Ahmed M Moustafa, Blake Hanson, Eduardo A Undurraga, Jorge Olivares-Pacheco, Patricia García, Rafael Araos, Paul J Planet, César A Arias, Jose M Munita

Faculty, Staff and Student Publications

Methicillin-resistant Staphylococcus aureus (MRSA) is a major public health menace. The global spread of MRSA is characterized by successive waves of epidemic clones dominating specific geographical regions. The acquisition of genes encoding resistance to heavy metals (HMRGs) is thought to be a key feature in the geographic divergence of MRSA. However, the cause-effect relationship between the presence of HMRGs and the divergence of MRSA clones remains to be clarified. In this study, we assessed the role that HMRGs may have played in the evolutionary divergence of the MRSA ST5-SCCmecI lineage in Latin America. We conducted a genomic characterization …

Challenges In Transitioning From Methadone To Buprenorphine-Naloxone For Chronic Pain Management: Two Cases, Jamal Hasoon, Anvinh Nguyen, Omar Viswanath, Alaa Abd-Elsayed

Faculty, Staff and Students Publications

Background: Methadone is frequently used for chronic pain management due to its long half-life and NMDA receptor activity, making it an effective option for opioid-tolerant patients. Buprenorphine-naloxone is increasingly explored as an alternative for chronic pain and opioid use disorder, offering partial opioid agonism with a ceiling effect on respiratory depression. The transition from methadone to buprenorphine-naloxone remains clinically challenging, requiring careful management to prevent withdrawal and ensure adequate pain control.

Case descriptions: Two patients with chronic pain were transitioned from methadone to buprenorphine-naloxone. The first patient, a mid-40s female, was abruptly switched from methadone 10 mg twice daily dosing …

Molecular Subtyping Of Hypertensive Disorders Of Pregnancy, Michal Elovitz, Elaine Gee, Nathaniel Delaney-Busch, Alison Moe, Mitsu Reddy, Arkady Khodursky, Johnny La, Ilma Abbas, Kay Mekaru, Hunter Collins, Farooq Siddiqui, Rory Nolan, Rupsa Boelig, Daniel Kiefer, Pamela Simmons, George Saade, Antonio Saad, Ebony Carter, Thomas Mcelrath, Stephen Quake, Mark Depristo, Carrie Haverty, Manfred Lee, Eugeni Namsaraev, Vincenzo Berghella, Ai-Ris Collier, Antonia Frolova, Esther Park-Hwang, Luis Pacheco, Elizabeth Sutton, Maneesh Jain, Kara Rood, William A Grobman, Joseph Biggio, Cynthia Gyamfi-Bannerman, Arun Jeyabalan, Morten Rasmussen

Department of Obstetrics and Gynecology Faculty Papers

Hypertensive disorders of pregnancy (HDP), including preeclampsia, affect 1 in 6 pregnancies, are major contributors to maternal morbidity and mortality, yet lack precision medicine strategies. Analyzing transcriptomic data from a prospectively-collected diverse cohort (n = 9102), this study reveals distinct RNA subtypes in maternal blood, reclassifying clinical HDP phenotypes like early/late-onset preeclampsia. The placental gene PAPPA2 strongly predicts the most severe forms of preeclampsia in individuals without pre-existing high risk factors, months before symptoms, and its overexpression correlates with earlier delivery in a dose-dependent manner. Further, molecular subtypes characterized by immune genes are upregulated in less severe forms of HDP. …

Differential Antibody Response To Ebv Proteome Following Ebvst Immunotherapy In Ebv-Associated Lymphomas, Yomani D Sarathkumara, Nathan W Van Bibber, Zhiwei Liu, Helen E Heslop, Rayne H Rouce, Anna E Coghill, Cliona M Rooney, Carla Proietti, Denise L Doolan

Faculty, Staff and Students Publications

Epstein-Barr virus (EBV) is associated with a diverse range of lymphomas. EBV-specific T-cell (EBVST) infusions have shown promise in safety and clinical effectiveness in treating EBV-associated lymphomas; however, not all patients respond to T-cell immunotherapies. To identify EBV antigen–specific antibody responses associated with clinical outcomes, we comprehensively characterized antibody responses to the complete EBV proteome using a custom protein microarray in 56 patients with EBV-associated lymphoma who received EBVST infusions in phase 1 clinical trials. Responders (nonprogressors) and nonresponders (progressors) had distinct antibody profiles against EBV. Twenty-five immunoglobulin G (IgG) antibodies were significantly elevated in higher levels in nonresponders than …

The Cardiovascular Care Of The Pediatric Athlete, Peter N Dean, Julie A Brothers, Kristin Burns, Jonathan B Edelson, Susan Etheridge, Dermot M Phelan, Keri Shafer, Chris Snyder, Silvana Molossi, Alfred Danielian, Eli M Friedman, Jeff Hsu, Mustafa Husaini, Eugene H Chung, Matthew W Martinez, Aaron L Baggish, Benjamin D Levine, Jonathan H Kim, American College Of Cardiology Sports & Exercise Cardiology Council

Faculty, Staff and Students Publications

Sports cardiology broadly encompasses the cardiovascular care of individuals who place a high premium on habitual exercise, sports performance, and/or sports competition. Some of the essential aspects within sports cardiology include the preparticipation cardiac evaluation and the management of cardiac diseases in athletes. Although most sports cardiology practitioners are trained in adult cardiology, a significant number of individuals who participate in sports are pediatric-aged, < 18 years old. Up to two-thirds of children in middle and high school participate in organized sports or are involved in nonorganized recreational sports. The cardiovascular care of pediatric-aged athletes can be challenging because many of the classic tenets and principles in adult sports cardiology do not fully generalize to pediatrics, and there is a lack of the evidence base that may be present for adult athletes. The epidemiology, presentation, and progression of cardiovascular diseases can be significantly different between pediatric and adult athletes. The evaluation of potential diseases and management considerations may also differ between pediatric and adult athletes. Similar to adults, there are "gray zones" where it is difficult to differentiate between normal exercise-induced cardiac remodeling and true cardiac pathology, but the additional lack of normative standards further complicates assessments in pediatric athletes. Management decisions for pediatric athletes are generally based on limited data but carry substantial short- and long-term implications. Thus, shared decision-making as part of the determination of clinical management strategies and for sports participation is critical and requires the participation of the parents or guardian(s). In this state-of-the-art review, key differences between pediatric and adult-aged athletes are highlighted. Specifically, how to define the "pediatric athlete," consider cardiovascular adaptations observed among pediatric athletes, determine preparticipation screening options and optimal symptom-driven evaluations in children, and consider best practices for pediatric athletes with several key cardiac conditions are detailed. The purpose of this document is to represent the first primary reference available to providers who care for pediatric athletes with cardiovascular concerns.

Tumor-Derived Arachidonic Acid Reprograms Neutrophils To Promote Immune Suppression And Therapy Resistance In Triple-Negative Breast Cancer, Liqun Yu, Keziah Liebenberg, Yichao Shen, Fengshuo Liu, Zhan Xu, Xiaoxin Hao, Ling Wu, Weijie Zhang, Hilda L Chan, Bo Wei, Philip L Lorenzi, Yang Gao, Igor Bado, Luis Becerra-Dominguez, Charlotte Helena Rivas, Sergio Aguirre, Bradley C Pingel, Yi-Hsuan Wu, Yunfeng Ding, Jun Liu, David G Edwards, Livia S Eberlin, Xiang H-F Zhang

Faculty, Staff and Students Publications

The combination of immune checkpoint blockade and chemotherapies is the standard of care for triple-negative breast cancer (TNBC). However, initially, responsive tumors can still develop recurrences, suggesting acquired resistance mechanisms that remain poorly understood. Herein, we discover that TNBC cells surviving anti-programmed cell death protein-1 (anti-PD-1) and chemotherapy treatment accumulate neutral lipids. Disrupting lipid droplet formation in cancer cells reverses resistance and mitigates the immunosuppressive microenvironment. Single-cell RNA sequencing reveals a subset of neutrophils exhibiting a lipid-laden phenotype similar to adjacent tumor cells. Mechanistically, tumor-derived extracellular vesicles carrying lipids, including arachidonic acid (AA), mediate neutrophil reprogramming. Blocking dietary intake of …

Leveraging Llms To Understand Narratives In Maude Reports, Yuheng Shi, Yang Gong

Faculty, Staff and Student Publications

Interest in using the MAUDE database to investigate adverse events linked to medical devices has been growing. Yet, the narrative sections of these reports remain largely unexplored, leaving valuable insights unutilized and creating an incomplete understanding of these events. To bridge this gap, we employ large language models (LLMs) to analyze and interpret these narratives. Using OpenAI's GPT-4-turbo model, we focused on MAUDE reports involving endoscopic clips to identify uncoded surgical procedures and uncover additional insights. This approach showcases the potential of LLMs in processing narrative content, offering a more efficient and cost-effective alternative to previous methods and supporting the …

Mechanistic Insights Into The Structure-Based Design Of A Cspz-Targeting Lyme Disease Vaccine, Kalvis Brangulis, Jill Malfetano, Ashley L Marcinkiewicz, Alan Wang, Yi-Lin Chen, Jungsoon Lee, Zhuyun Liu, Xiuli Yang, Ulrich Strych, Dagnija Tupina, Inara Akopjana, Maria-Elena Bottazzi, Utpal Pal, Ching-Lin Hsieh, Wen-Hsiang Chen, Yi-Pin Lin

Faculty, Staff and Students Publications

Borrelia burgdorferi (Bb) causes Lyme disease (LD), one of the most common vector-borne diseases in the Northern Hemisphere. Here, we solve the crystal structure of a mutated Bb vaccine antigen, CspZ-YA that lacks the ability to bind to host complement factor H (FH). We generate point mutants of CspZ-YA and identify CspZ-YAI183Y and CspZ-YAC187S to trigger more robust bactericidal responses. Compared to CspZ-YA, these CspZ-YA mutants require a lower immunization frequency to protect mice from LD-associated inflammation and bacterial colonization. Antigenicity of wild-type and mutant CspZ-YA proteins are similar, as measured using sera from infected people or immunized …

Structural Updates To The Implant And Refill Needle Of The Port Delivery Platform, Dante J. Pieramici, Peter A. Campochiaro, Margaret Chang, Ian Pearce, Carl D. Regillo, Shamika Gune, Nancy Holekamp, Carlos Quezada-Ruiz, Shrirang V. Ranade, Natasha Singh, Geoffrey Wise, Joshua Horvath

Wills Eye Hospital Papers

PURPOSE: The purpose of this study was to report the impact of component-level changes and manufacturing process improvements on septum durability in the ocular implant of the Port Delivery Platform (PD-P), more commonly known as the Port Delivery System with ranibizumab (PDS) with its current formulation.

METHODS: Laboratory tests were conducted to determine (1) the bond strength of the septum to the overmold, (2) the amount of force utilized for the refill needle to puncture the septum, and (3) septum durability over 50 years. To simulate multiple refill-exchanges over long-term clinical use, implants were aged at elevated temperature in saline …

Association Of Age, Sex And Education With Access To The Intravenous Thrombolysis For Acute Ischemic Stroke, Yoona Ko, Beom Joon Kim, Youngran Kim, Jong-Moo Park, Kyusik Kang, Jae Guk Kim, Jae-Kwan Cha, Tai Hwan Park, Kyungbok Lee, Jun Lee, Keun-Sik Hong, Byung-Chul Lee, Kyung-Ho Yu, Dong-Eog Kim, Joon-Tae Kim, Jay Chol Choi, Jee Hyun Kwon, Wook-Joo Kim, Kyu Sun Yum, Sung-Il Sohn, Hyungjong Park, Sang-Hwa Lee, Kwang-Yeol Park, Chi Kyung Kim, Sung Hyuk Heo, Moon-Ku Han, Anjail Z Sharrief, Sunil A Sheth, Hee-Joon Bae

Faculty, Staff and Student Publications

Background: Barriers to treatment with intravenous thrombolysis (IVT) for patients with acute ischemic stroke (AIS) in South Korea remain incompletely characterized. We analyze a nationwide prospective cohort to determine patient-level features associated with delayed presentation and non-treatment of potential IVT-eligible patients.

Methods: We identified consecutive patients with AIS from 01/2011 to 08/2023 from a multicenter and prospective acute stroke registry in Korea. Patients were defined as IVT candidates if they presented within 4.5 hours from the last known well, had no lab evidence of coagulopathy, and had National Institute of Health Stroke Scale (NIHSS) ≥ 4. Multivariable generalized linear mixed …

Pediatric And Congenital Cardiac Services: An Innovative And Empowering Approach To Global Training And Equitable Care, Wyman W. Lai, Dominique Vervoort, David Bradley, Antonio G. Cabrera, Casey Culbertson, Alejandro Floh, Saurabh K. Gupta, Babar S. Hasan, Adrian Holloway, Jeffrey P. Jacobs, Kathy J. Jenkins, R. K. Kumar, L.A. Larrazabal, Colin J. Mcmahon, Daniel J. Penny, Alistair Phillips, Emilio Quezada, Craig A. Sable, Shubhika Srivastava, Sandra L. Staveski, Patcharapong Suntharos, David F. Teitel, Betsy Tirado, Brian C. Tran, Bistra Zheleva, Liesl Zuhkle, Anthony C. Chang

Division of Cardiology Faculty Papers

Congenital heart disease is a leading cause of preventable death in children, with a disproportionate impact on low- and middle-income countries. Despite progress in treating congenital heart disease globally, significant challenges remain in accessing specialized cardiovascular care, particularly cardiac surgery, in low- and middle-income countries. This review examines current models of assistance and proposes a novel global training program to address these inequities. Key challenges identified include building program infrastructure, training health care providers, ensuring financial sustainability, and promoting local engagement. The proposed program, structured under a new international organization, will leverage emerging technologies to deliver accessible and rigorously assessed …

Life On The Dry Side: A Roadmap To Understanding Desiccation Tolerance And Accelerating Translational Applications, R A Marks, J T B Ekwealor, M A S Artur, L Bondi, T C Boothby, O M S Carmo, D C Centeno, K K Coe, H J W Dace, S Field, A Hutt, S Porembski, A Thalhammer, L Van Der Pas, A J Wood, P Alpert, D Bartels, S Boeynaems, M N Datar, T Giese, W I Seidou, S M Kirchner, J Köhler, U G V S S Kumara, J Kyung, R Lyall, B D Mishler, J B V T Ndongmo, M S Otegui, V Reddy, J Rexroth, S M Tebele, R Vanburen, J Verdier, U C Vothknecht, M F Wittenberg, E Zokov, M J Oliver, S Y Rhee

Duncan NRI Faculty and Staff Publications

To thrive in extreme conditions, organisms have evolved a diverse arsenal of adaptations that confer resilience. These species, their traits, and the mechanisms underlying them comprise a valuable resource that can be mined for numerous conceptual insights and applied objectives. One of the most dramatic adaptations to water limitation is desiccation tolerance. Understanding the mechanisms underlying desiccation tolerance has important potential implications for medicine, biotechnology, agriculture, and conservation. However, progress has been hindered by a lack of standardization across sub-disciplines, complicating the integration of data and slowing the translation of basic discoveries into practical applications. Here, we synthesize current knowledge …

Benchmarking Large Language Models For Biomedical Natural Language Processing Applications And Recommendations, Qingyu Chen, Yan Hu, Xueqing Peng, Qianqian Xie, Qiao Jin, Aidan Gilson, Maxwell B Singer, Xuguang Ai, Po-Ting Lai, Zhizheng Wang, Vipina K Keloth, Kalpana Raja, Jimin Huang, Huan He, Fongci Lin, Jingcheng Du, Rui Zhang, W Jim Zheng, Ron A Adelman, Zhiyong Lu, Hua Xu

Faculty, Staff and Student Publications

The rapid growth of biomedical literature poses challenges for manual knowledge curation and synthesis. Biomedical Natural Language Processing (BioNLP) automates the process. While Large Language Models (LLMs) have shown promise in general domains, their effectiveness in BioNLP tasks remains unclear due to limited benchmarks and practical guidelines. We perform a systematic evaluation of four LLMs-GPT and LLaMA representatives-on 12 BioNLP benchmarks across six applications. We compare their zero-shot, few-shot, and fine-tuning performance with the traditional fine-tuning of BERT or BART models. We examine inconsistencies, missing information, hallucinations, and perform cost analysis. Here, we show that traditional fine-tuning outperforms zero- or …

Parasite Contamination Of Soil In Different Peruvian Locations And Outside Built Environments, Carlos Pineda, Maritza Dalí Camones Rivera, Eddyson Montalva Sabino, Lucia Estela Mejia, Katherine Elizabeth Keegan, Lizbet Pilar Patricio Alvarez, Javier Jorge Mora, Fernanda Espinoza Vega, Emilio Rey Mejia, Patrick Olivas Herrera, Elisa Palomino Pando, Zhen Zeng, Athos Silva De Oliveira, Maria Jose Villar Mondragon, Barton Slatko, Eric J Wetzel, Rojelio Mejia

Faculty, Staff and Students Publications

Background: Soil is a reservoir for many parasites that can affect human and animal health, especially in tropical regions where soil-transmitted helminths and protozoa thrive. Understanding how environmental factors influence parasite distribution will provide a basis for relating how climate changes may intensify their impacts, altering parasite habitats and increasing transmission risks. We surveyed soil parasite prevalence, burden, and diversity in several different Peruvian environmental ecologies to catalog current parasite presence and provide a baseline for future surveys.

Methods: A total of 198 soil samples from 43 locations across three Peruvian regions-Tingo María (TM) (Amazon rainforest), Andabamba/Marabamba (A/M) (Andean highlands), …

Protocol For A Multisite, Observational Clinical Study Of The Association Between Skin Colour And Pulse Oximeter Accuracy In Children Undergoing Cardiac Catheterisation (Pach Study), Halley Ruppel, Liming Huang, Christopher J Petit, Athar M Qureshi, Christopher P Bonafide, Elizabeth E Foglia, Jeffery Feldman, Meghan B Lane-Fall, Jennifer M Lynch, Anna Chien, Michelle Dunn, Michael L O'Byrne

Faculty, Staff and Students Publications

Introduction: Prospective, real-world clinical studies of the association between skin color and pulse oximeter (SpO2) accuracy in children are needed to address the limitations of previous research. Such studies are essential for generating evidence for clinicians, regulators and industry. This is the protocol for a multisite study funded by the National Heart, Lung, and Blood Institute (R01HL171313; 1 January 2024-31 December 2028).

Methods and analysis: In this pragmatic, observational study conducted in three large paediatric cardiac catheterisation centres in the USA, children undergoing cardiac catheterisation with directly measured arterial oxygen saturation will be prospectively enrolled. The outcome variable (SpO2 bias) …

K-Mer Analysis Of Long-Read Alignment Pileups For Structural Variant Genotyping, Adam C English, Fabio Cunial, Ginger A Metcalf, Richard A Gibbs, Fritz J Sedlazeck

Faculty, Staff and Students Publications

Accurately genotyping structural variant (SV) alleles is crucial to genomics research. We present a novel method (kanpig) for genotyping SVs that leverages variant graphs and k-mer vectors to rapidly generate accurate SV genotypes. Benchmarking against the latest SV datasets shows kanpig achieves a single-sample genotyping concordance of 82.1%, significantly outperforming existing tools, which average 66.3%. We explore kanpig's use for multi-sample projects by testing on 47 genetically diverse samples and find kanpig accurately genotypes complex loci (e.g. SVs neighboring other SVs), and produces higher genotyping concordance than other tools. Kanpig requires only 43 seconds to process a single sample's 20x …

Alpha-Synuclein Seed Amplification Assays: Data Sharing, Standardization Needed For Clinical Use, Hilal A Lashuel, D James Surmeier, Tanya Simuni, Kalpana Merchant, Byron Caughey, Claudio Soto, Mohamed-Bilal Fares, Roland G Heym, Ronald Melki

Faculty, Staff and Student Publications

Alpha-synuclein seed amplification assays can improve neurodegenerative disease diagnosis and care, but widespread use depends on a framework that standardizes protocols and encourages data sharing.

Findings From A Qualitative Analysis: Social Media Influencers Of Color As Trusted Messengers Of Hpv Vaccination Messages, Amelia Burke-Garcia, Erin Cutroneo, Dasha Afanaseva, Kayla Madden, Angela Sustaita-Ruiz, Preethi Selvan, Estefany Rivera Sanchez, Amy Leader

Department of Medical Oncology Faculty Papers

BACKGROUND: Despite HPV vaccination reducing the prevalence of cervical cancer by 90%, vaccination rates remain lower among communities of color due to vaccine hesitancy and mistrust in traditional public health messengers. The emergence of social media influencers, a newer kind of messenger, presents a unique opportunity to share immunization messages in new ways with a variety of communities. This paper reviews the qualitative findings from a study aimed at assessing influencers' perceptions of and approaches to sharing messaging about the HPV vaccine.

METHODS: Guided by several theories (Theory of Planned Behavior, Narrative Theory, and Opinion Leader Theory), the study team …

Bright And Photostable Yellow Fluorescent Proteins For Extended Imaging, Jihwan Lee, Shujuan Lai, Shuyuan Yang, Shiqun Zhao, Francisco A Blanco, Anne C Lyons, Raquel Merino-Urteaga, John F Ahrens, Nathan A Nguyen, Haixin Liu, Zhuohe Liu, Gerard G Lambert, Nathan C Shaner, Liangyi Chen, Kimberley F Tolias, Jin Zhang, Taekjip Ha, François St-Pierre

Faculty, Staff and Students Publications

Fluorescent proteins are indispensable molecular tools for visualizing biological structures and processes, but their limited photostability restricts the duration of dynamic imaging experiments. Yellow fluorescent proteins (YFPs), in particular, photobleach rapidly. Here, we introduce mGold2s and mGold2t, YFPs with up to 25-fold greater photostability than mVenus and mCitrine, two commonly used YFPs, while maintaining comparable brightness. These variants were identified using a high-throughput pooled single-cell platform, simultaneously screening for high brightness and photostability. Compared with our previous benchmark, mGold, the mGold2 variants display a ~4-fold increase in photostability without sacrificing brightness. mGold2s and mGold2t extend imaging durations across diverse modalities, …

De Novo Variants In Cdkl1 And Cdkl2 Are Associated With Neurodevelopmental Symptoms, Ali H Bereshneh, Jonathan C Andrews, Daniel F Eberl, Guney Bademci, Nicholas A Borja, Stephanie Bivona, Wendy K Chung, Shinya Yamamoto, Michael F Wangler, Shane Mckee, Mustafa Tekin, Hugo J Bellen, Oguz Kanca

Duncan NRI Faculty and Staff Publications

The CDKL (cyclin-dependent kinase-like) family consists of five members in humans, CDKL1-5, that encode serine-threonine kinases. The only member that has been associated with a Mendelian disorder is CDKL5, and variants in CDKL5 cause developmental and epileptic encephalopathy type 2 (DEE2). Here, we study four de novo variants in CDKL2 identified in five individuals, including three unrelated probands and monozygotic twins. These individuals present with overlapping symptoms, including global developmental delay, intellectual disability, childhood-onset epilepsy, dyspraxia, and speech deficits. We also identified two individuals with de novo missense variants in CDKL1 in the published Deciphering Developmental Disorders (DDD) and GeneDx …

Biochemical Profiling And Structural Basis Of Adar1-Mediated Rna Editing, Xiangyu Deng, Lina Sun, Min Zhang, Rashmi Basavaraj, Jin Wang, Yi-Lan Weng, Yang Gao

Faculty, Staff and Students Publications

ADAR1 regulates RNA-induced immune responses by converting adenosine to inosine in double-stranded RNA. Mutations in ADAR1 are associated with human autoimmune disease, and targeting ADAR1 has been proposed for cancer immunotherapy. However, the molecular mechanisms underlying ADAR1-mediated editing remain unclear. Here, we provide detailed biochemical and structural characterizations of human ADAR1. Our biochemical profiling reveals that ADAR1 editing is both sequence and RNA-duplex-length dependent but can well tolerate mismatches near the editing site. High-resolution ADAR1-RNA complex structures, combined with mutagenesis, elucidate RNA binding, substrate selection, dimerization, and the essential role of RNA-binding domain 3. The ADAR1 structures also help explain …

Open Access Dataset And Common Data Model For Pulse Oximeter Performance Data, Nicholas Fong, Michael S Lipnick, Ella Behnke, Yu Chou, Seif Elmankabadi, Lily Ortiz, Christopher S Almond, Isabella Auchus, Garrett W Burnett, Ronald Bisegerwa, Desireé R Conrad, Carolyn M Hendrickson, Shubhada Hooli, Robert Kopotic, Gregory Leeb, Daniel Martin, Eric D Mccollum, Ellis P Monk, Kelvin L Moore, Leonid Shmuylovich, J Brady Scott, An-Kwok Ian Wong, Tianyue Zhou, Romain Pirracchio, Philip E Bickler, John Feiner, Tyler J Law

Faculty, Staff and Students Publications

The OpenOximetry Dataset stores clinical and lab pulse oximetry data. It supports measurements of arterial oxygen saturation (SaO2) by arterial blood gas co-oximetry and pulse oximetry (SpO2), alongside processed and unprocessed photoplethysmography (PPG) data and other metadata. This includes skin color measurements, finger diameter, vital signs (e.g., arterial blood pressure, end-tidal carbon dioxide), and arterial blood gas parameters (e.g., acid-base balance, hemoglobin concentration). All data, from desaturation studies to clinical trials, are collected prospectively to ensure accuracy. A common data model and standardized protocols for consistent archival and interpretation ensure consistent data archival and interpretation. The dataset aims to facilitate …

Widespread Variation In Molecular Interactions And Regulatory Properties Among Transcription Factor Isoforms, Luke Lambourne, Kaia Mattioli, Clarissa Santoso, Gloria Sheynkman, Sachi Inukai, Babita Kaundal, Anna Berenson, Kerstin Spirohn-Fitzgerald, Anukana Bhattacharjee, Elisabeth Rothman, Shaleen Shrestha, Florent Laval, Brent S Carroll, Stephen P Plassmeyer, Ryan J Emenecker, Zhipeng Yang, Deepa Bisht, Jared A Sewell, Guangyuan Li, Anisa Prasad, Sabrina Phanor, Ryan Lane, Devlin C Moyer, Toby Hunt, Dawit Balcha, Marinella Gebbia, Jean-Claude Twizere, Tong Hao, Alex S Holehouse, Adam Frankish, Josh A Riback, Nathan Salomonis, Michael A Calderwood, David E Hill, Nidhi Sahni, Marc Vidal, Martha L Bulyk, Juan I Fuxman Bass

Faculty, Staff and Students Publications

Most human transcription factor (TF) genes encode multiple protein isoforms differing in DNA-binding domains, effector domains, or other protein regions. The global extent to which this results in functional differences between isoforms remains unknown. Here, we systematically compared 693 isoforms of 246 TF genes, assessing DNA binding, protein binding, transcriptional activation, subcellular localization, and condensate formation. Relative to reference isoforms, two-thirds of alternative TF isoforms exhibit differences in one or more molecular activities, which often could not be predicted from sequence. We observed two primary categories of alternative TF isoforms: "rewirers" and "negative regulators," both of which were associated with …

Clinical Validation Of Rna Sequencing For Mendelian Disorder Diagnostics, Sen Zhao, Kristina Macakova, Jefferson C Sinson, Hongzheng Dai, Jill Rosenfeld, Gladys E Zapata, Shenglan Li, Patricia A Ward, Christiana Wang, Chunjing Qu, Becky Maywald, Brendan Lee, Christine Eng, Pengfei Liu

Faculty, Staff and Students Publications

Despite rapid advancements in clinical sequencing, over half of diagnostic evaluations still lack definitive results. RNA sequencing (RNA-seq) has shown promise in research settings for bridging this gap by providing essential functional data for accurate interpretation of diagnostic sequencing results. However, despite advanced research pipelines, clinical translation of diagnostic RNA-seq has not yet been realized. We have developed and validated a clinical diagnostic RNA-seq test for individuals with suspected genetic disorders who have existing or concurrent comprehensive DNA diagnostic testing. This diagnostic RNA-seq test processes RNA samples from fibroblasts or blood and derives clinical interpretations based on the analytical detection …

A Mapping Review And Critique Of The Literature On Translation, Dissemination, And Implementation Capacity Building Initiatives For Different Audiences, Ana A Baumann, Danielle R Adams, Laura-Mae Baldwin, Rachel G Tabak, Sara Malone, Maura M Kepper, Anita D Misra-Hebert, Kathleen R Stevens, Maria E Fernandez, Sunil Kripalani

Faculty, Staff and Student Publications

Background: Capacity building is critical for research and practice as the fields of dissemination, implementation and translation science continue to grow. Some scholars state that capacity building should be grounded in competencies. However, the fields are unclear in determining which competencies are relevant for whom, including the content and appropriate level of information and skills for different roles. The goal of this study was to catalogue competencies across current D&I capacity building initiatives.

Methods: We conducted a mapping review to examine to what extent are theories or frameworks used to guide capacity building, who is being trained, to what extent …

Polygenic Score Analysis Identifies Distinct Genetic Risk Profiles In Alzheimer’S Disease Comorbidities, Carlos F Hernández, Camilo Villaman, Costin Leu, Dennis Lal, Ignacio Mata, Andrés D Klein, Eduardo Pérez-Palma

Faculty, Staff and Student Publications

Alzheimer’s disease (AD) is usually accompanied by comorbidities such as type 2 diabetes (T2D), epilepsy, major depressive disorder (MDD), and migraine headaches (MH) that can significantly affect patient management and progression. As AD, these comorbidities have their own cumulative common genetic risk component that can be explored in a single individual through polygenic scores. Utilizing data from the UK Biobank, we investigated the correlation between polygenic scores (PGS) for these comorbidities and their actual presentation in AD patients. We show that individuals with higher PGS values showed an elevated risk of developing T2D (OR 2.1, p = 1.07 × 10−11) …

Bone-Induced Her2 Promotes Secondary Metastasis In Hr+/Her2- Breast Cancer, Rahat Alam, Anna Reva, David G Edwards, Bree M Lege, Laura S Munoz-Arcos, Carolina Reduzzi, Swarnima Singh, Xiaoxin Hao, Yi-Hsuan Wu, Zeru Tian, Laura M Natalee, Gargi Damle, Deniz Demircioglu, Yixian Wang, Ling Wu, Elisabetta Molteni, Dan Hasson, Bora Lim, Zbigniew Gugala, Jerry E Chipuk, Julie E Lang, Joseph A Sparano, Chonghui Cheng, Massimo Cristofanilli, Han Xiao, Xiang H-F Zhang, Igor L Bado

Faculty, Staff and Students Publications

Bone metastases can disseminate to secondary sites and promote breast cancer progression creating additional clinical challenges. The mechanisms contributing to secondary metastasis are barely understood. Here, we evaluate the prediction power of Her2-expressing (Her2E) circulating tumor cells (CTCs) after analyzing over 13,000 CTCs from a cohort of 137 metastatic breast cancer (MBC) patients with initial HR+/Her2− status and employ preclinical models of bone metastasis (BM) to validate the role of Her2E CTCs in multi-organ metastases. While Her2 expression was higher in patients with bone metastasis, experimental analyses revealed that Her2E CTCs derived from bone lesions were more dependent on Her2 …