Digital Commons Network^™

Structural Basis For Polθ-Helicase Dna Binding And Microhomology-Mediated End-Joining, Fumiaki Ito, Ziyuan Li, Leonid Minakhin, Htet A. Khant, Richard T. Pomerantz, Xiaojiang S. Chen

Department of Biochemistry and Molecular Biology Faculty Papers

DNA double-strand breaks (DSBs) present a critical threat to genomic integrity, often precipitating genomic instability and oncogenesis. Repair of DSBs predominantly occurs through homologous recombination (HR) and non-homologous end joining (NHEJ). In HR-deficient cells, DNA polymerase theta (Polθ) becomes critical for DSB repair via microhomology-mediated end joining (MMEJ), also termed theta-mediated end joining (TMEJ). Thus, Polθ is synthetically lethal with BRCA1/2 and other HR factors, underscoring its potential as a therapeutic target in HR-deficient cancers. However, the molecular mechanisms governing Polθ-mediated MMEJ remain poorly understood. Here we present a series of cryo-electron microscopy structures of the Polθ helicase domain (Polθ-hel) …

Partnering With Social Media Influencers To Promote Hpv Vaccination In Diverse Communities, Amy Leader, Amelia Burke-Garcia, Dasha Afanaseva, Erin Cutroneo, Preethi Selvan, Kayla Madden, Joshua Banks, Angela Sustaita-Ruiz

Department of Medical Oncology Faculty Papers

BACKGROUND: While human papillomavirus (HPV) vaccination is one of the most effective ways to prevent HPV-related cancers, many children and adolescents remain unvaccinated. Resistance often stems from parental vaccine hesitancy and mistrust of the health care system, both of which may be higher in communities of color. Partnering with social media influencers may be an effective method for disseminating health messages. We tested the impact of HPV social media posts developed by influencers on outcomes of knowledge, attitudes, and intentions to vaccinate.

METHODS: Ten social media influencers who identified as African American or Hispanic created posts about the HPV vaccine. …

Molecular Mechanism Establishing The Off Pathway In Vision, Florentina Soto, Chin-I Lin, Andrew Jo, Ssu-Yu Chou, Ellen G Harding, Philip A Ruzycki, Gail K Seabold, Ronald S Petralia, Daniel Kerschensteiner

2020-Current year OA Pubs

Parallel ON and OFF (positive- and negative-contrast) pathways fundamental to vision arise at the complex synapse of cone photoreceptors. Cone pedicles form spatially segregated functionally opposite connections with ON and OFF bipolar cells. Here, we discover that mammalian cones express LRFN2, a cell-adhesion molecule, which localizes to the pedicle base. LRFN2 stabilizes basal contacts between cone pedicles and OFF bipolar cell dendrites to guide pathway-specific partner choices, encompassing multiple cell types. In addition, LRFN2 trans-synaptically organizes glutamate receptor clusters, determining the contrast preferences of the OFF pathway. ON and OFF pathways converge in the inner retina to regulate bipolar cell …

Multimeric Transcription Factor Bcl11a Utilizes Two Zinc-Finger Tandem Arrays To Bind Clustered Short Sequence Motifs, John R Horton, Meigen Yu, Jujun Zhou, Melody Tran, Rithvi R Anakal, Yue Lu, Robert M Blumenthal, Xiaotian Zhang, Yun Huang, Xing Zhang, Xiaodong Cheng

Faculty, Staff and Student Publications

BCL11A, a transcription factor, is vital for hematopoiesis, including B and T cell maturation and the fetal-to-adult hemoglobin switch. Mutations in BCL11A are linked to neurodevelopmental disorders. BCL11A contains two DNA-binding zinc-finger arrays, low-affinity ZF2-3 and high-affinity ZF4-6, separated by a 300-amino-acid linker. ZF2-3 and ZF4-5 share 73% identity, including five out of six DNA base-interacting residues. These arrays bind similar short sequence motifs in clusters, with the linker enabling a broader binding span. Crystallographic structures of ZF4-6, in complex with oligonucleotides from the β-globin locus region, reveal DNA sequence recognition by residues Asn756 (ZF4), Lys784 and Arg787 (ZF5). A …

Using The Healthy Native Youth Implementation Toolbox To Provide Web-Based Adolescent Health Promotion Decision Support To American Indian And Alaska Native Communities: Implementation Study, Amrita Sidhu, Ross Shegog, Stephanie Craig-Rushing, Nicole Trevino, Michelle Singer, Cornelia Jessen, Gwenda Gorman, Sean Simpson, Melissa Peskin, Belinda Hernandez, Christine Markham

Faculty, Staff and Student Publications

Background: American Indian and Alaska Native (AI/AN) youth experience numerous health inequities, including those in sexual, reproductive, and mental health. Implementation of culturally relevant, age-appropriate evidence-based programs may mitigate these inequities. However, numerous barriers limit the adoption and implementation of evidence-based adolescent health promotion programs in AI/AN communities.

Objective: This study examines user reach and engagement from 2022 to 2024 of web-based decision support (the Healthy Native Youth [HNY] website and the embedded HNY Implementation Toolbox), designed to increase the implementation of evidence-based adolescent health promotion programming in AI/AN communities.

Methods: Promotional strategies were designed for optimal geographic reach to …

Elevated Mitochondrial Membrane Potential Is A Therapeutic Vulnerability In Dnmt3a-Mutant Clonal Hematopoiesis, Kira A Young, Grant A Challen, Et Al.

2020-Current year OA Pubs

The competitive advantage of mutant hematopoietic stem and progenitor cells (HSPCs) underlies clonal hematopoiesis (CH). Drivers of CH include aging and inflammation; however, how CH-mutant cells gain a selective advantage in these contexts is an unresolved question. Using a murine model of CH (Dnmt3a

Developing An Online Community Advisory Board (Cab) Of Parents From Social Media To Co-Design An Human Papillomavirus Vaccine Intervention: Participatory Research Study, Regan M. Murray, Shawn C. Chiang, Ann C. Klassen, Jennifer A. Manganello, Amy E. Leader, Wen-Juo Lo, Philip M. Massey

Department of Medical Oncology Faculty Papers

BACKGROUND: Social media health interventions have grown significantly in recent years. However, researchers are still developing innovative methods to meaningfully engage online communities to inform research activities. Little has been documented describing this approach of using online community advisory boards (CABs) to co-create health communication interventions on social media.

OBJECTIVE: This study describes the formation, engagement, and maintenance of an online CAB focused on co-creating a health education intervention for parents regarding the human papillomavirus (HPV) vaccine. The study provides guiding principles for public health researchers implementing such CABs in future digital health interventions.

METHODS: In May 2020, Twitter was …

A Review Of Recent Studies On The Pathogenesis Of Systemic Sclerosis: Focus On Fibrosis Pathways, Sergio A. Jimenez, Fabian A. Mendoza, Sonsoles Piera-Velazquez

Scleroderma Center Faculty Papers

Systemic Sclerosis (SSc) is a systemic autoimmune disease of unknown etiology characterized by the development of frequently progressive cutaneous and internal organ fibrosis accompanied by severe vascular alterations. The pathogenesis of SSc is highly complex and, despite extensive investigation, has not been fully elucidated. Numerous studies have suggested that unknown etiologic factors cause multiple alterations in genetically receptive hosts, leading to SSc development and progression. These events may be functionally and pathologically interconnected and include: 1) Structural and functional microvascular and endothelial cell abnormalities; 2) Severe oxidative stress and high reactive oxygen species (3); Frequently progressive cutaneous and visceral fibrosis; …

Integrated Analysis Of Molecular And Clinical Features Associated With Overall Survival In Melanoma Patients With Brain Metastasis, Swaminathan Kumar, Meredith S Pelster, Merve Hasanov, Renato A Guerrieri, Courtney W Hudgens, Debora A Ledesma, Fuchenchu Wang, Grant M Fischer, Julie M Simon, Lauren E Haydu, Kalman V Katlowitz, Y N Vashisht Gopal, Jennifer L Mcquade, Lawrence N Kwong, Jason T Huse, Alexander J Lazar, Michael T Tetzlaff, Jeffrey E Gershenwald, Aron Y Joon, Ken Chen, Ziyi Li, Prahlad T Ram, Sherise D Ferguson, Michael A Davies

Faculty, Staff and Student Publications

Melanoma brain metastases (MBMs) are diagnosed in up to 60% of metastatic melanoma patients. Previous studies have identified clinical factors that correlate with overall survival (OS) after MBM diagnosis. However, molecular and immune features associated with OS are poorly understood. An improved understanding of the molecular and immune correlates of OS could provide insights into MBM patient outcomes and guide therapeutic development. Thus, we analyzed clinical features and outcomes of 74 melanoma patients who underwent surgical resection (via craniotomy) between 1991 and 2015 at our institution with RNA-seq data generated from their MBMs. The median post-operative OS was 8.6 months …

Vacuum Erectile Devices For Erectile Dysfunction: Recommendations From The 5th International Consultation On Sexual Medicine, Run Wang, Francisco E Martins, David Ralph, Georgios Hatzichristodoulou, Daniar Osmonov, Justin Parker, Sung Hun Sean Park, Ignacio Moncada, Carlo Bettocchi, Ricardo Munarriz, Tobias Köhler

Faculty, Staff and Student Publications

Introduction: Vacuum erectile device (VED) is 1 of the main approved therapies for erectile dysfunction (ED). The introduction of phosphodiesterase type 5 inhibitor (PDE5i) for ED significantly changed the roles of VED in contemporary sexual medicine.

Objective: To provide updated clinical evidence to inform health care providers on best practices with VED.

Methods: A consensus panel was held with leading sexual medicine experts during the 5th International Consultation on Sexual Medicine (ICSM). Relevant peer-reviewed literature was reviewed with focus on research from the last 10 years, but not limited to the last 10 years. The expert panel generated consensus statements …

Machine Learning To Optimize Use Of Natriuretic Peptides In The Diagnosis Of Acute Heart Failure, Dimitrios Doudesis, Kuan Ken Lee, Mohamed Anwar, Adam J. Singer, Judd E. Hollander, Camille Chenevier-Gobeaux, Yann-Erick Claessens, Desiree Wussler, Dominic Weil, Nikola Kozhuharov, Ivo Strebel, Zaid Sabti, Christopher Defilippi, Stephen Seliger, Evandro Tinoco Mesquita, Jan C. Wiemer, Martin Möckel, Joel Coste, Patrick Jourdain, Komukai Kimiaki, Michihiro Yoshimura, Irwani Ibrahim, Shirley Beng Suat Ooi, Win Sen Kuan, Alfons Gegenhuber, Thomas Mueller, Olivier Hanon, Jean-Sébastien Vidal, Peter Cameron, Louisa Lam, Ben Freedman, Tommy Chung, Sean P. Collins, Christopher J. Lindsell, David E. Newby, Alan G. Japp, Anoop S. V. Shah, Humberto Villacorta, A. Mark Richards, John J V Mcmurray, Christian Mueller, James L. Januzzi, Nicholas L. Mills, Gordon Moe, Carlos Fernando, Hanna K. Gaggin, Antoni Bayes-Genis, Roland Rj Van Kimmenade, Yigal Pinto, Joost H. W. Rutten, Anton H. Van Den Meiracker, Luna Gargani, Nicola R. Pugliese, Pemberton Christopher, Michael Neumaier, Michael Behnes, Ibrahim Akin, Michele Bombelli, Guido Grassi, Peiman Nazerian, Giovanni Albano, Philipp Bahrmann

Department of Emergency Medicine Faculty Papers

AIMS: B-type natriuretic peptide (BNP) and mid-regional pro-atrial natriuretic peptide (MR-proANP) testing are guideline-recommended to aid in the diagnosis of acute heart failure. Nevertheless, the diagnostic performance of these biomarkers is uncertain.

METHODS AND RESULTS: We performed a systematic review and individual patient-level data meta-analysis to evaluate the diagnostic performance of BNP and MR-proANP. We subsequently developed and externally validated a decision-support tool called CoDE-HF that combines natriuretic peptide concentrations with clinical variables using machine learning to report the probability of acute heart failure. Fourteen studies from 12 countries provided individual patient-level data in 8493 patients for BNP and 3899 …

Machine Learning To Optimize Use Of Natriuretic Peptides In The Diagnosis Of Acute Heart Failure, Dimitrios Doudesis, Kuan Ken Lee, Mohamed Anwar, Adam J. Singer, Judd Hollander, Md, Camille Chenevier-Gobeaux, Yann-Erick Claessens, Desiree Wussler, Dominic Weil, Nikola Kozhuharov, Ivo Strebel, Zaid Sabti, Christopher Defilippi, Stephen Seliger, Evandro Tinoco Mesquita, Jan C. Wiemer, Martin Möckel, Joel Coste, Patrick Jourdain, Komukai Kimiaki, Michihiro Yoshimura, Irwani Ibrahim, Shirley Beng Suat Ooi, Win Sen Kuan, Alfons Gegenhuber, Thomas Mueller, Olivier Hanon, Jean-Sébastien Vidal, Peter Cameron, Louisa Lam, Ben Freedman, Tommy Chung, Sean P. Collins, Christopher J Lindsell, David E. Newby, Alan G. Japp, Anoop S V Shah, Humberto Villacorta, A Mark Richards, John J V Mcmurray, Christian Mueller, James L. Januzzi, Nicholas L. Mills

Department of Emergency Medicine Faculty Papers

AIMS: B-type natriuretic peptide (BNP) and mid-regional pro-atrial natriuretic peptide (MR-proANP) testing are guideline-recommended to aid in the diagnosis of acute heart failure. Nevertheless, the diagnostic performance of these biomarkers is uncertain.

METHODS AND RESULTS: We performed a systematic review and individual patient-level data meta-analysis to evaluate the diagnostic performance of BNP and MR-proANP. We subsequently developed and externally validated a decision-support tool called CoDE-HF that combines natriuretic peptide concentrations with clinical variables using machine learning to report the probability of acute heart failure. Fourteen studies from 12 countries provided individual patient-level data in 8493 patients for BNP and 3899 …

Large-Scale Multi-Omics Analyses In Hispanic/Latino Populations Identify Genes For Cardiometabolic Traits, Lauren E Petty, Hung-Hsin Chen, Elizabeth G Frankel, Wanying Zhu, Carolina G Downie, Mariaelisa Graff, Phillip Lin, Priya Sharma, Xinruo Zhang, Alyssa C Scartozzi, Rashedeh Roshani, Joshua M Landman, Michael Boehnke, Donald W Bowden, John C Chambers, Anubha Mahajan, Mark I Mccarthy, Maggie C Y Ng, Xueling Sim, Cassandra N Spracklen, Weihua Zhang, Michael Preuss, Erwin P Bottinger, Girish N Nadkarni, Ruth J F Loos, Yii-Der Ida Chen, Jingyi Tan, Eli Ipp, Pauline Genter, Leslie S Emery, Tin Louie, Tamar Sofer, Adrienne M Stilp, Kent D Taylor, Anny H Xiang, Thomas A Buchanan, Kathryn Roll, Chuan Gao, Nicholette D Palmer, Jill M Norris, Lynne E Wagenknecht, Darryl Nousome, Rohit Varma, Roberta Mckean-Cowdin, Xiuqing Guo, Yang Hai, Willa Hsueh, Kevin Sandow, Esteban J Parra, Miguel Cruz, Adan Valladares-Salgado, Niels Wacher-Rodarte, Jerome I Rotter, Mark O Goodarzi, Stephen S Rich, Alain Bertoni, Leslie J Raffel, Jerry L Nadler, Fouad R Kandeel, Ravindranath Duggirala, John Blangero, Donna M Lehman, Ralph A Defronzo, Farook Thameem, Yujie Wang, Sheila Gahagan, Estela Blanco, Raquel Burrows, Alicia Huerta-Chagoya, Jose C Florez, Teresa Tusie-Luna, Clicerio González-Villalpando, Lorena Orozco, Christopher A Haiman, Craig L Hanis, Rebecca Rohde, Eric A Whitsel, Alexander P Reiner, Charles Kooperberg, Yun Li, Qing Duan, Miryoung Lee, Paulina Correa-Burrows, Susan K Fried, Kari E North, Joseph B Mccormick, Susan P Fisher-Hoch, Eric R Gamazon, Andrew P Morris, Josep M Mercader, Heather M Highland, Jennifer E Below

Faculty, Staff and Student Publications

Here, we present a multi-omics study of type 2 diabetes and quantitative blood lipid and lipoprotein traits conducted to date in Hispanic/Latino populations (nmax = 63,184). We conduct a meta-analysis of 16 type 2 diabetes and 19 lipid trait GWAS, identifying 20 genome-wide significant loci for type 2 diabetes, including one novel locus and novel signals at two known loci, based on fine-mapping. We also identify sixty-one genome-wide significant loci across the lipid/lipoprotein traits, including nine novel loci, and novel signals at 19 known loci through fine-mapping. Next, we analyze genetically regulated expression, perform Mendelian randomization, and analyze association with …

Whole Genome Sequencing Analysis Of Body Mass Index Identifies Novel African Ancestry-Specific Risk Allele, Xinruo Zhang, Jennifer A Brody, Mariaelisa Graff, Heather M Highland, Nathalie Chami, Hanfei Xu, Zhe Wang, Kendra R Ferrier, Geetha Chittoor, Navya Shilpa Josyula, Mariah Meyer, Shreyash Gupta, Xihao Li, Zilin Li, Matthew A Allison, Diane M Becker, Lawrence F Bielak, Joshua C Bis, Meher Preethi Boorgula, Donald W Bowden, Jai G Broome, Erin J Buth, Christopher S Carlson, Kyong-Mi Chang, Sameer Chavan, Yen-Feng Chiu, Lee-Ming Chuang, Matthew P Conomos, Dawn L Demeo, Mengmeng Du, Ravindranath Duggirala, Celeste Eng, Alison E Fohner, Barry I Freedman, Melanie E Garrett, Xiuqing Guo, Chris Haiman, Benjamin D Heavner, Bertha Hidalgo, James E Hixson, Yuk-Lam Ho, Brian D Hobbs, Donglei Hu, Qin Hui, Chii-Min Hwu, Rebecca D Jackson, Deepti Jain, Rita R Kalyani, Sharon L R Kardia, Tanika N Kelly, Ethan M Lange, Michael Lenoir, Changwei Li, Loic Le Marchand, Merry-Lynn N Mcdonald, Caitlin P Mchugh, Alanna C Morrison, Take Naseri, Jeffrey O'Connell, Christopher J O'Donnell, Nicholette D Palmer, James S Pankow, James A Perry, Ulrike Peters, Michael H Preuss, D C Rao, Elizabeth A Regan, Sefuiva M Reupena, Dan M Roden, Jose Rodriguez-Santana, Colleen M Sitlani, Jennifer A Smith, Hemant K Tiwari, Ramachandran S Vasan, Zeyuan Wang, Daniel E Weeks, Jennifer Wessel, Kerri L Wiggins, Lynne R Wilkens, Peter W F Wilson, Lisa R Yanek, Zachary T Yoneda, Wei Zhao, Sebastian Zöllner, Donna K Arnett, Allison E Ashley-Koch, Kathleen C Barnes, John Blangero, Eric Boerwinkle, Esteban G Burchard, April P Carson, Daniel I Chasman, Yii-Der Ida Chen, Joanne E Curran, Myriam Fornage, Victor R Gordeuk, Jiang He, Susan R Heckbert, Lifang Hou, Marguerite R Irvin, Charles Kooperberg, Ryan L Minster, Braxton D Mitchell, Mehdi Nouraie, Bruce M Psaty, Laura M Raffield, Alexander P Reiner, Stephen S Rich, Jerome I Rotter, M Benjamin Shoemaker, Nicholas L Smith, Kent D Taylor, Marilyn J Telen, Scott T Weiss, Yingze Zhang, Nancy Heard-Costa, Yan V Sun, Xihong Lin, L Adrienne Cupples, Leslie A Lange, Ching-Ti Liu, Ruth J F Loos, Kari E North, Anne E Justice

Faculty, Staff and Student Publications

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P <  5 × 10

Natural Killer Cells’ Functional Impairment Drives The Immune Escape Of Pre-Malignant Clones In Early-Stage Myelodysplastic Syndromes, Juan Jose Rodriguez-Sevilla, Irene Ganan-Gomez, Bijender Kumar, Natthakan Thongon, Feiyang Ma, Kelly S Chien, Yi J Kim, Hui Yang, Sanam Loghavi, Roselyn Tan, Vera Adema, Zongrui Li, Tomoyuki Tanaka, Hidetaka Uryu, Rashmi Kanagal-Shamanna, Gheath Al-Atrash, Rafael Bejar, Pinaki Prosad Banerjee, Sophia Lynn Cha, Guillermo Montalban-Bravo, Max Dougherty, Maria Claudina Fernandez Laurita, Noelle Wheeler, Baosen Jia, Eirini P Papapetrou, Franco Izzo, Daniela E Dueñas, Salome Mcallen, Yiqian Gu, Gabriele Todisco, Francesca Ficara, Matteo Giovanni Della Porta, Abhinav Jain, Koichi Takahashi, Karen Clise-Dwyer, Stephanie Halene, Maria Teresa Sabrina Bertilaccio, Guillermo Garcia-Manero, May Daher, Simona Colla

Faculty, Staff and Student Publications

Dissecting the preneoplastic disease states' biological mechanisms that precede tumorigenesis can lead to interventions that can slow down disease progression and/or mitigate disease-related comorbidities. Myelodysplastic syndromes (MDS) cannot be cured by currently available pharmacological therapies, which fail to eradicate aberrant hematopoietic stem cells (HSCs), most of which are mutated by the time of diagnosis. Here, we sought to elucidate how MDS HSCs evade immune surveillance and expand in patients with clonal cytopenias of undetermined significance (CCUS), the pre-malignant stage of MDS. We used multi-omic single-cell approaches and functional in vitro studies to show that immune escape at disease initiation is …

Whole Genome Sequencing Analysis Of Body Mass Index Identifies Novel African Ancestry-Specific Risk Allele, Xinruo Zhang, D C Rao, Et Al.

2020-Current year OA Pubs

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P <  5 × 10

The Human Brainstem's Red Nucleus Was Upgraded To Support Goal-Directed Action, Samuel R Krimmel, Timothy O Laumann, Roselyne J Chauvin, Tamara Hershey, Jarod L Roland, Joshua S Shimony, Jon T Willie, Scott A Norris, Scott Marek, Andrew N Van, Anxu Wang, Julia Monk, Kristen M Scheidter, Forrest I Whiting, Nadeshka Ramirez-Perez, Athanasia Metoki, Noah J Baden, Benjamin P Kay, Hadas Nahman-Averbuch, Abraham Z Snyder, Marcus E Raichle, Evan M Gordon, Nico U F Dosenbach, Et Al.

2020-Current year OA Pubs

The red nucleus, a large brainstem structure, coordinates limb movement for locomotion in quadrupedal animals. In humans, its pattern of anatomical connectivity differs from that of quadrupeds, suggesting a different purpose. Here, we apply our most advanced resting-state functional connectivity based precision functional mapping in highly sampled individuals (n = 5), resting-state functional connectivity in large group-averaged datasets (combined n ~ 45,000), and task based analysis of reward, motor, and action related contrasts from group-averaged datasets (n > 1000) and meta-analyses (n > 14,000 studies) to precisely examine red nucleus function. Notably, red nucleus functional connectivity with motor-effector networks (somatomotor hand, foot, …

Effects Of Metformin Use On Aneurysmal Subarachnoid Hemorrhage Outcomes, Angel Bueno, Andrea Becerril-Gaitan, Collins Mokua, Kristina Ramirez-Garcia, Justin Nguyen, Faris Shaker, Tien Nguyen, Antonio Dono, Spiros Blackburn, Peng Roc Chen, Mark Dannenbaum, H Alex Choi, Arthur L Day, Jacques J Morcos, Ching-Jen Chen

Faculty, Staff and Student Publications

Background: Metformin is widely prescribed and has neuroprotective effects in animals, but its impact on brain injury after aneurysmal subarachnoid hemorrhage (aSAH) in humans is unclear.

Methods: This single-center retrospective review assessed patients with aSAH from 2009 to 2023, categorizing them based on pre-admission metformin use. The primary outcome was delayed cerebral ischemia (DCI), while secondary outcomes included in-hospital mortality, rebleeding, angiographic cerebral vasospasm (CVS), and favorable modified Rankin Scale (mRS) scores at discharge and the 3-month follow-up. Outcomes were analyzed using logistic regression. Sensitivity analysis was performed after excluding patients receiving comfort care.

Results: A total of 900 patients …

Allosteric Targeted Drug Delivery For Enhanced Blood-Brain Barrier Penetration Via Mimicking Transmembrane Domain Interactions, Kaicheng Tang, Zhongjie Tang, Miaomiao Niu, Zuyin Kuang, Weiwei Xue, Xinyu Wang, Xinlong Liu, Yang Yu, Seongdong Jeong, Yifan Ma, Annette Wu, Betty Y S Kim, Wen Jiang, Zhaogang Yang, Chong Li

Faculty, Staff and Student Publications

Current strategies for active targeting in the brain are entirely based on the effective interaction of the ligand with the orthosteric sites of specific receptors on the blood-brain barrier (BBB), which is highly susceptible to various pathophysiological factors and limits the efficacy of drug delivery. Here, we propose an allosteric targeted drug delivery strategy that targets classical BBB transmembrane receptors by designing peptide ligands that specifically bind to their transmembrane domains. This strategy prevents competitive interference from endogenous ligands and antibodies by using the insulin receptor and integrin α

Sociodemographic Differences In Logins And Engagement With The Electronic Health Coach Messaging Feature Of A Mobile App To Support Opioid And Stimulant Use Recovery: Results From A 1-Month Observational Study, Lindsey M Filiatreau, Hannah Szlyk, Alex T Ramsey, Erin Kasson, Xiao Li, Zhuoran Zhang, Patricia Cavazos-Rehg

2020-Current year OA Pubs

BACKGROUND: Mobile health apps can serve as a critical tool in supporting the overall health of uninsured and underinsured individuals and groups who have been historically marginalized by the medical community and may be hesitant to seek health care. However, data on uptake and engagement with specific app features (eg, in-app messaging) are often lacking, limiting our ability to understand nuanced patterns of app use.

OBJECTIVE: This study aims to characterize sociodemographic differences in uptake and engagement with a smartphone app (uMAT-R) to support recovery efforts in a sample of individuals with opioid and stimulant use disorders in the Greater …

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 …

Gramd1b Is A Regulator Of Lipid Homeostasis, Autophagic Flux And Phosphorylated Tau, Diana Acosta Ingram, Jacob Marsh, Celeste M Karch, Et Al.

2020-Current year OA Pubs

Lipid dyshomeostasis and tau pathology are present in frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). However, the relationship between lipid dyshomeostasis and tau pathology remains unclear. We report that GRAM Domain Containing 1B (GRAMD1B), a nonvesicular cholesterol transporter, is increased in excitatory neurons of human neural organoids (HNOs) with the MAPT R406W mutation. Human FTLD, AD cases, and PS19 tau mice also have increased GRAMD1B expression. We show that overexpression of GRAMD1B increases levels of free cholesterol, lipid droplets, and impairs autophagy flux. Modulating GRAMD1B in iPSC-derived neurons also alters key autophagy-related components such as PI3K, phospho-AKT, and p62, …

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

2020-Current year OA Pubs

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 …

Activation Of Endoplasmic Reticulum-Localized Metabotropic Glutamate Receptor 5 (Mglu5) Triggers Calcium Release Distinct From Cell Surface Counterparts In Striatal Neurons, Yuh-Jiin I Jong, Steven K Harmon, Karen L O'Malley

2020-Current year OA Pubs

Metabotropic glutamate receptor 5 (mGlu

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 …

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. …

Molecular Subtyping Of Hypertensive Disorders Of Pregnancy, Michal A Elovitz, Antonia I Frolova, Et Al.

2020-Current year OA Pubs

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. …

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 …

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 …