Digital Commons Network^™

Intraoperative Cortical Localization Of Music And Language Reveals Signatures Of Structural Complexity In Posterior Temporal Cortex, Meredith J Mccarty, Elliot Murphy, Xavier Scherschligt, Oscar Woolnough, Cale W Morse, Kathryn Snyder, Bradford Z Mahon, Nitin Tandon

Faculty, Staff and Student Publications

Language and music involve the productive combination of basic units into structures. It remains unclear whether brain regions sensitive to linguistic and musical structure are co-localized. We report an intraoperative awake craniotomy in which a left-hemispheric language-dominant professional musician underwent cortical stimulation mapping (CSM) and electrocorticography of music and language perception and production during repetition tasks. Musical sequences were melodic or amelodic, and differed in algorithmic compressibility (Lempel-Ziv complexity). Auditory recordings of sentences differed in syntactic complexity (single vs. multiple phrasal embeddings). CSM of posterior superior temporal gyrus (pSTG) disrupted music perception and production, along with speech production. pSTG and …

Single-Cell Chromatin Accessibility Profiling Of Acute Myeloid Leukemia Reveals Heterogeneous Lineage Composition Upon Therapy-Resistance, Huihui Fan, Feng Wang, Andy Zeng, Alex Murison, Katarzyna Tomczak, Dapeng Hao, Fatima Zahra Jelloul, Bofei Wang, Praveen Barrodia, Shaoheng Liang, Ken Chen, Linghua Wang, Zhongming Zhao, Kunal Rai, Abhinav K Jain, John Dick, Naval Daver, Andy Futreal, Hussein A Abbas

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by high rate of therapy resistance. Since the cell of origin can impact response to therapy, it is crucial to understand the lineage composition of AML cells at time of therapy resistance. Here we leverage single-cell chromatin accessibility profiling of 22 AML bone marrow aspirates from eight patients at time of therapy resistance and following subsequent therapy to characterize their lineage landscape. Our findings reveal a complex lineage architecture of therapy-resistant AML cells that are primed for stem and progenitor lineages and spanning quiescent, activated and late stem cell/progenitor states. Remarkably, …

The Screening Of The Protective Antigens Of Aeromonas Hydrophila Using The Reverse Vaccinology Approach: Potential Candidates For Subunit Vaccine Development, Ting Zhang, Minying Zhang, Zehua Xu, Yang He, Xiaoheng Zhao, Hanliang Cheng, Xiangning Chen, Jianhe Xu, Zhujin Ding

Faculty, Staff and Student Publications

The threat of bacterial septicemia caused by Aeromonas hydrophila infection to aquaculture growth can be prevented through vaccination, but differences among A. hydrophila strains may affect the effectiveness of non-conserved subunit vaccines or non-inactivated A. hydrophila vaccines, making the identification and development of conserved antigens crucial. In this study, a bioinformatics analysis of 4268 protein sequences encoded by the A. hydrophila J-1 strain whole genome was performed based on reverse vaccinology. The specific analysis included signal peptide prediction, transmembrane helical structure prediction, subcellular localization prediction, and antigenicity and adhesion evaluation, as well as interspecific and intraspecific homology comparison, thereby screening …

The Impact Framework And Implementation For Accessible In Silico Clinical Phenotyping In The Digital Era, Andrew Wen, Huan He, Sunyang Fu, Sijia Liu, Kurt Miller, Liwei Wang, Kirk E Roberts, Steven D Bedrick, William R Hersh, Hongfang Liu

Faculty, Staff and Student Publications

Clinical phenotyping is often a foundational requirement for obtaining datasets necessary for the development of digital health applications. Traditionally done via manual abstraction, this task is often a bottleneck in development due to time and cost requirements, therefore raising significant interest in accomplishing this task via in-silico means. Nevertheless, current in-silico phenotyping development tends to be focused on a single phenotyping task resulting in a dearth of reusable tools supporting cross-task generalizable in-silico phenotyping. In addition, in-silico phenotyping remains largely inaccessible for a substantial portion of potentially interested users. Here, we highlight the barriers to the usage of in-silico phenotyping …

Targeting Polyploid Giant Cancer Cells Potentiates A Therapeutic Response And Overcomes Resistance To Parp Inhibitors In Ovarian Cancer, Xudong Zhang, Jun Yao, Xiaoran Li, Na Niu, Yan Liu, Richard A Hajek, Guang Peng, Shannon Westin, Anil K Sood, Jinsong Liu

Faculty, Staff and Student Publications

To understand the mechanism of acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) olaparib, we induced the formation of polyploid giant cancer cells (PGCCs) in ovarian and breast cancer cell lines, high-grade serous cancer (HGSC)-derived organoids, and patient-derived xenografts (PDXs). Time-lapse tracking of ovarian cancer cells revealed that PGCCs primarily developed from endoreplication after exposure to sublethal concentrations of olaparib. PGCCs exhibited features of senescent cells but, after olaparib withdrawal, can escape senescence via restitutional multipolar endomitosis and other noncanonical modes of cell division to generate mitotically competent resistant daughter cells. The contraceptive drug mifepristone blocked PGCC formation and daughter cell …

Clinical And Functional Correlates Of Parkinsonism In A Population-Based Sample Of Individuals Aged 75 +: The Pietà Study, Thiago Cardoso Vale, Francisco Eduardo Costa Cardoso, Danilo Jorge Da Silva, Elisa De Paula Franca Resende, Débora Palma Maia, Mauro César Quintão Cunningham, Henrique Cerqueira Guimarães, João Carlos Barbosa Machado, Antônio Lúcio Teixeira, Paulo Caramelli, Maira Tonidandel Barbosa

Faculty, Staff and Student Publications

BACKGROUND: Parkinsonism is strongly associated with ageing, and many studies have suggested that parkinsonian signs may affect up to half of older adults and is associated with a wide range of adverse health outcomes. We compared clinical and functional characteristics of oldest-old community-dwelling individuals with parkinsonism (parkinsonian group [PG]) to individuals without parkinsonism (non-parkinsonian group [NPG].

METHODS: The Pietà study is a population-based study conducted in Caeté, southeast Brazil, involving 607 individuals aged 75 + years submitted to an extensive clinical evaluation. A subset of 65 PG individuals (61.5% women, median age of 82 years) was compared to 542 NPG …

Differential Effects Of Bariatric Surgery And Caloric Restriction On Hepatic One-Carbon And Fatty Acid Metabolism, Arnon Haran, Michael Bergel, Doron Kleiman, Liron Hefetz, Hadar Israeli, Sarah Weksler-Zangen, Bella Agranovich, Ifat Abramovich, Rachel Ben-Haroush Schyr, Eyal Gottlieb, Danny Ben-Zvi

Faculty, Staff and Student Publications

Weight loss interventions, including dietary changes, pharmacotherapy, or bariatric surgery, prevent many of the adverse consequences of obesity, and may also confer intervention-specific benefits beyond those seen with decreased weight alone. We compared the molecular effects of different interventions on liver metabolism to understand the mechanisms underlying these benefits. Male rats on a high-fat, high-sucrose diet underwent sleeve gastrectomy (SG) or intermittent fasting with caloric restriction (IF-CR), achieving equivalent weight loss. The interventions were compared to

Genome-Wide Crispr-Cas9 Screen Analyzed By Slider Identifies Network Of Repressor Complexes That Regulate Trim24, Lalit R Patel, Sabrina A Stratton, Megan Mclaughlin, Patrick Krause, Kendra Allton, Andrés López Rivas, Daniela Barbosa, Traver Hart, Michelle C Barton

Faculty, Staff and Student Publications

TRIM24 is an oncogenic chromatin reader that is frequently overexpressed in human tumors and associated with poor prognosis. However, TRIM24 is rarely mutated, duplicated, or rearranged in cancer. This raises questions about how TRIM24 is regulated and what changes in its regulation are responsible for its overexpression. Here, we perform a genome-wide CRISPR-Cas9 screen by fluorescence-activated cell sorting (FACS) that nominated 220 negative regulators and elucidated a regulatory network that includes the KAP1 corepressor, CNOT deadenylase, and GID/CTLH E3 ligase. Knocking out required components of these three complexes caused TRIM24 overexpression, confirming their negative regulation of TRIM24. Our findings …

Single-Cell Sequencing Reveals The Landscape Of The Human Brain Metastatic Microenvironment, Qianqian Song, Jimmy Ruiz, Fei Xing, Hui-Wen Lo, Lou Craddock, Ashok K Pullikuth, Lance D Miller, Michael H Soike, Stacey S O'Neill, Kounosuke Watabe, Michael D Chan, Jing Su

Faculty, Staff and Student Publications

Brain metastases is the most common intracranial tumor and account for approximately 20% of all systematic cancer cases. It is a leading cause of death in advanced-stage cancer, resulting in a five-year overall survival rate below 10%. Therefore, there is a critical need to identify effective biomarkers that can support frequent surveillance and promote efficient drug guidance in brain metastasis. Recently, the remarkable breakthroughs in single-cell RNA-sequencing (scRNA-seq) technology have advanced our insights into the tumor microenvironment (TME) at single-cell resolution, which offers the potential to unravel the metastasis-related cellular crosstalk and provides the potential for improving therapeutic effects mediated …

Study Of Polytopic Membrane Protein Topological Organization As A Function Of Membrane Lipid Composition, Takefumi Morizumi, Kyumhyuk Kim, Hai Li, Elena G Govorunova, Oleg A Sineshchekov, Yumei Wang, Lei Zheng, Éva Bertalan, Ana-Nicoleta Bondar, Azam Askari, Leonid S Brown, John L Spudich, Oliver P Ernst

Faculty, Staff and Student Publications

Kalium channelrhodopsin 1 from Hyphochytrium catenoides (HcKCR1) is a light-gated channel used for optogenetic silencing of mammalian neurons. It selects K+ over Na+ in the absence of the canonical tetrameric K+ selectivity filter found universally in voltage- and ligand-gated channels. The genome of H. catenoides also encodes a highly homologous cation channelrhodopsin (HcCCR), a Na+ channel with >100-fold larger Na+ to K+ permeability ratio. Here, we use cryo-electron microscopy to determine atomic structures of these two channels embedded in peptidiscs to elucidate structural foundations of their dramatically different cation selectivity. Together with structure-guided mutagenesis, we show that K+ versus Na+ …

Multi-Campaign Ship And Aircraft Observations Of Marine Cloud Condensation Nuclei And Droplet Concentrations, Kevin J Sanchez, David Painemal, Matthew D Brown, Ewan C Crosbie, Francesca Gallo, Johnathan W Hair, Chris A Hostetler, Carolyn E Jordan, Claire E Robinson, Amy Jo Scarino, Taylor J Shingler, Michael A Shook, Kenneth L Thornhill, Elizabeth B Wiggins, Edward L Winstead, Luke D Ziemba, Scott Chambers, Alastair Williams, Ruhi S Humphries, Melita D Keywood, Jason P Ward, Luke Cravigan, Ian M Mcrobert, Connor Flynn, Gourihar R Kulkarni, Lynn M Russell, Gregory C Roberts, Greg M Mcfarquhar, Athanasios Nenes, Sarah F Woods, Jeffery S Reid, Jennifer Small-Griswold, Sarah Brooks, Simon Kirschler, Christianne Voigt, Jian Wang, David J Delene, Patricia K Quinn, Richard H Moore

Faculty, Staff and Student Publications

In-situ marine cloud droplet number concentrations (CDNCs), cloud condensation nuclei (CCN), and CCN proxies, based on particle sizes and optical properties, are accumulated from seven field campaigns: ACTIVATE; NAAMES; CAMP2EX; ORACLES; SOCRATES; MARCUS; and CAPRICORN2. Each campaign involves aircraft measurements, ship-based measurements, or both. Measurements collected over the North and Central Atlantic, Indo-Pacific, and Southern Oceans, represent a range of clean to polluted conditions in various climate regimes. With the extensive range of environmental conditions sampled, this data collection is ideal for testing satellite remote detection methods of CDNC and CCN in marine environments. Remote measurement methods are vital to …

Genome-Wide Identification And Phenotypic Characterization Of Seizure-Associated Copy Number Variations In 741,075 Individuals, Ludovica Montanucci, David Lewis-Smith, Ryan L Collins, Lisa-Marie Niestroj, Shridhar Parthasarathy, Julie Xian, Shiva Ganesan, Marie Macnee, Tobias Brünger, Rhys H Thomas, Michael Talkowski, Epi25 Collaborative, Ingo Helbig, Costin Leu, Dennis Lal

Faculty, Staff and Student Publications

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, …

A Novel Statistical Method For Decontaminating T-Cell Receptor Sequencing Data, Ruoxing Li, Mehmet Altan, Alexandre Reuben, Ruitao Lin, John V Heymach, Hai Tran, Runzhe Chen, Latasha Little, Shawna Hubert, Jianjun Zhang, Ziyi Li

Faculty, Staff and Student Publications

The T-cell receptor (TCR) repertoire is highly diverse among the population and plays an essential role in initiating multiple immune processes. TCR sequencing (TCR-seq) has been developed to profile the T cell repertoire. Similar to other high-throughput experiments, contamination can happen during several steps of TCR-seq, including sample collection, preparation and sequencing. Such contamination creates artifacts in the data, leading to inaccurate or even biased results. Most existing methods assume 'clean' TCR-seq data as the starting point with no ability to handle data contamination. Here, we develop a novel statistical model to systematically detect and remove contamination in TCR-seq data. …

Measuring And Enhancing The Ionic Conductivity Of Chloroaluminate Electrolytes For Al-Ion Batteries, Anthony J Lucio, Iwan Sumarlan, Elena Bulmer, Igor Efimov, Stephen Viles, A Robert Hillman, Christopher J Zaleski, Karl S Ryder

Faculty, Staff and Student Publications

At the core of the aluminum (Al) ion battery is the liquid electrolyte, which governs the underlying chemistry. Optimizing the rheological properties of the electrolyte is critical to advance the state of the art. In the present work, the chloroaluminate electrolyte is made by reacting AlCl3 with a recently reported acetamidinium chloride (Acet-Cl) salt in an effort to make a more performant liquid electrolyte. Using AlCl3:Acet-Cl as a model electrolyte, we build on our previous work, which established a new method for extracting the ionic conductivity from fitting voltammetric data, and in this contribution, we validate the method across a …

Asian Americans In Stem Are Not A Monolith, Zer Vue, Chia Vang, Neng Vue, Vijayvardhan Kamalumpundi, Taylor Barongan, Bryanna Shao, Sunny Huang, Larry Vang, Mein Vue, Nancy Vang, Jianqiang Shao, Coohleenann Coombes, Prasanna Katti, Kaihua Liu, Kailee Yoshimura, Michelle Biete, Dao-Fu Dai, Mark A Phillips, Richard R Behringer

Faculty, Staff and Student Publications

Despite tremendous diversity, Asian Americans in STEM are grouped and viewed as a homogeneous monolith, facing stereotypes and disparities. We propose solutions that include disaggregating the Asian American grouping and recognizing the diverse individual ethnic subgroups that comprise Americans of Asian ancestry to implement change within the STEM field.

Structures Of Channelrhodopsin Paralogs In Peptidiscs Explain Their Contrasting K+ And Na+ Selectivities, Takefumi Morizumi, Kyumhyuk Kim, Hai Li, Elena G Govorunova, Oleg A Sineshchekov, Yumei Wang, Lei Zheng, Éva Bertalan, Ana-Nicoleta Bondar, Azam Askari, Leonid S Brown, John L Spudich, Oliver P Ernst

Faculty, Staff and Student Publications

Kalium channelrhodopsin 1 from Hyphochytrium catenoides (HcKCR1) is a light-gated channel used for optogenetic silencing of mammalian neurons. It selects K+ over Na+ in the absence of the canonical tetrameric K+ selectivity filter found universally in voltage- and ligand-gated channels. The genome of H. catenoides also encodes a highly homologous cation channelrhodopsin (HcCCR), a Na+ channel with >100-fold larger Na+ to K+ permeability ratio. Here, we use cryo-electron microscopy to determine atomic structures of these two channels embedded in peptidiscs to elucidate structural foundations of their dramatically different cation selectivity. Together with structure-guided mutagenesis, we show …

China Stroke Surveillance Report 2021, Wen-Jun Tu, Long-De Wang, Special Writing Group Of China Stroke Surveillance Report

Faculty, Staff and Student Publications

Since 2015, stroke has become the leading cause of death and disability in China, posing a significant threat to the health of its citizens as a major chronic non-communicable disease. According to the China Stroke High-risk Population Screening and Intervention Program, an estimated 17.8 million [95% confidence interval (CI) 17.6–18.0 million] adults in China had experienced a stroke in 2020, with 3.4 million (95% CI 3.3–3.5 million) experiencing their first-ever stroke and another 2.3 million (95% CI 2.2–2.4 million) dying as a result. Additionally, approximately 12.5% (95% CI 12.4–12.5%) of stroke survivors were left disabled, as defined by a modified …

Metastatic Infiltration Of Nervous Tissue And Periosteal Nerve Sprouting In Multiple Myeloma-Induced Bone Pain In Mice And Human, Marta Diaz-Delcastillo, Oana Palasca, Tim T Nemler, Didde M Thygesen, Norma A Chávez-Saldaña, Juan A Vázquez-Mora, Lizeth Y Ponce Gomez, Lars Juhl Jensen, Holly Evans, Rebecca E Andrews, Aritri Mandal, David Neves, Patrick Mehlen, James P Caruso, Patrick M Dougherty, Theodore J Price, Andrew Chantry, Michelle A Lawson, Thomas L Andersen, Juan M Jimenez-Andrade, Anne-Marie Heegaard

Faculty, Staff and Student Publications

Multiple myeloma (MM) is a neoplasia of B plasma cells that often induces bone pain. However, the mechanisms underlying myeloma-induced bone pain (MIBP) are mostly unknown. Using a syngeneic MM mouse model, we show that periosteal nerve sprouting of calcitonin gene-related peptide (CGRP+) and growth associated protein 43 (GAP43+) fibers occurs concurrent to the onset of nociception and its blockade provides transient pain relief. MM patient samples also showed increased periosteal innervation. Mechanistically, we investigated MM induced gene expression changes in the dorsal root ganglia (DRG) innervating the MM-bearing bone of male mice and found alterations in pathways associated with …

Early Non-Response As A Predictor Of Later Non-Response To Antipsychotics In Schizophrenia: A Randomized Trial, Yujun Long, Qiongqiong Wu, Ye Yang, Jingda Cai, Jingmei Xiao, Zhaoqian Liu, Yifeng Xu, Ying Chen, Manli Huang, Ruiguo Zhang, Xijia Xu, Jian Hu, Zhifen Liu, Fang Liu, Yingjun Zheng, Huaqing Meng, Zhimin Wang, Yanqing Tang, Xueqin Song, Yunchun Chen, Xueyi Wang, Tiebang Liu, Xiaoli Wu, Maosheng Fang, Chunling Wan, Jingping Zhao, Renrong Wu

Faculty, Staff and Student Publications

BACKGROUND: It remains a challenge to predict the long-term response to antipsychotics in patients with schizophrenia who do not respond at an early stage. This study aimed to investigate the optimal predictive cut-off value for early non-response that would better predict later non-response to antipsychotics in patients with schizophrenia.

METHODS: This multicenter, 8-week, open-label, randomized trial was conducted at 19 psychiatric centers throughout China. All enrolled participants were assigned to olanzapine, risperidone, amisulpride, or aripiprazole monotherapy for 8 weeks. The positive and negative syndrome scale (PANSS) was evaluated at baseline, week 2, week 4, and week 8. The main outcome …

Metastatic Infiltration Of Nervous Tissue And Periosteal Nerve Sprouting In Multiple Myeloma-Induced Bone Pain In Mice And Human, Marta Diaz-Delcastillo, Oana Palasca, Tim T Nemler, Didde M Thygesen, Norma A Chávez-Saldaña, Juan A Vázquez-Mora, Lizeth Y Ponce Gomez, Lars Juhl Jensen, Holly Evans, Rebecca E Andrews, Aritri Mandal, David Neves, Patrick Mehlen, James P Caruso, Patrick M Dougherty, Theodore J Price, Andrew Chantry, Michelle A Lawson, Thomas L Andersen, Juan M Jimenez-Andrade, Anne-Marie Heegaard

Faculty, Staff and Student Publications

Multiple myeloma (MM) is a neoplasia of B plasma cells that often induces bone pain. However, the mechanisms underlying myeloma-induced bone pain (MIBP) are mostly unknown. Using a syngeneic MM mouse model, we show that periosteal nerve sprouting of calcitonin gene-related peptide (CGRP+) and growth associated protein 43 (GAP43+) fibers occurs concurrent to the onset of nociception and its blockade provides transient pain relief. MM patient samples also showed increased periosteal innervation. Mechanistically, we investigated MM induced gene expression changes in the dorsal root ganglia (DRG) innervating the MM-bearing bone of male mice and found alterations in pathways associated with …

Proteomics Analysis Of Plasma From Middle-Aged Adults Identifies Protein Markers Of Dementia Risk In Later Life, Keenan A Walker, Jingsha Chen, Liu Shi, Yunju Yang, Myriam Fornage, Linda Zhou, Pascal Schlosser, Aditya Surapaneni, Morgan E Grams, Michael R Duggan, Zhongsheng Peng, Gabriela T Gomez, Adrienne Tin, Ron C Hoogeveen, Kevin J Sullivan, Peter Ganz, Joni V Lindbohm, Mika Kivimaki, Alejo J Nevado-Holgado, Noel Buckley, Rebecca F Gottesman, Thomas H Mosley, Eric Boerwinkle, Christie M Ballantyne, Josef Coresh

Faculty, Staff and Student Publications

A diverse set of biological processes have been implicated in the pathophysiology of Alzheimer's disease (AD) and related dementias. However, there is limited understanding of the peripheral biological mechanisms relevant in the earliest phases of the disease. Here, we used a large-scale proteomics platform to examine the association of 4877 plasma proteins with 25-year dementia risk in 10,981 middle-aged adults. We found 32 dementia-associated plasma proteins that were involved in proteostasis, immunity, synaptic function, and extracellular matrix organization. We then replicated the association between 15 of these proteins and clinically relevant neurocognitive outcomes in two independent cohorts. We demonstrated that …

Timigp: Inferring Cell-Cell Interactions And Prognostic Associations In The Tumor Immune Microenvironment Through Gene Pairs, Chenyang Li, Baoyi Zhang, Evelien Schaafsma, Alexandre Reuben, Linghua Wang, Mary Jo Turk, Jianjun Zhang, Chao Cheng

Faculty, Staff and Student Publications

Determining the prognostic association of different immune cell types in the tumor microenvironment is critical for understanding cancer biology and developing new therapeutic strategies. However, this is challenging in certain cancer types, where the abundance of different immune subsets is highly correlated. In this study, we develop a computational method named TimiGP to overcome this challenge. Based on bulk gene expression and survival data, TimiGP infers cell-cell interactions that reveal the association between immune cell relative abundance and prognosis. As demonstrated in metastatic melanoma, TimiGP prioritizes immune cells critical in prognosis based on the identified cell-cell interactions. Highly consistent results …

Integrating Genetics And Metabolomics From Multi-Ethnic And Multi-Fluid Data Reveals Putative Mechanisms For Age-Related Macular Degeneration, Xikun Han, Ines Lains, Jun Li, Jinglun Li, Yiheng Chen, Bing Yu, Qibin Qi, Eric Boerwinkle, Robert Kaplan, Bharat Thyagarajan, Martha Daviglus, Charlotte E Joslin, Jianwen Cai, Marta Guasch-Ferré, Deirdre K Tobias, Eric Rimm, Alberto Ascherio, Karen Costenbader, Elizabeth Karlson, Lorelei Mucci, A Heather Eliassen, Oana Zeleznik, John Miller, Demetrios G Vavvas, Ivana K Kim, Rufino Silva, Joan Miller, Frank Hu, Walter Willett, Jessica Lasky-Su, Peter Kraft, J Brent Richards, Stuart Macgregor, Deeba Husain, Liming Liang

Faculty, Staff and Student Publications

Age-related macular degeneration (AMD) is a leading cause of blindness in older adults. Investigating shared genetic components between metabolites and AMD can enhance our understanding of its pathogenesis. We conduct metabolite genome-wide association studies (mGWASs) using multi-ethnic genetic and metabolomic data from up to 28,000 participants. With bidirectional Mendelian randomization analysis involving 16,144 advanced AMD cases and 17,832 controls, we identify 108 putatively causal relationships between plasma metabolites and advanced AMD. These metabolites are enriched in glycerophospholipid metabolism, lysophospholipid, triradylcglycerol, and long chain polyunsaturated fatty acid pathways. Bayesian genetic colocalization analysis and a customized metabolome-wide association approach prioritize putative causal …

Women With Large Vessel Occlusion Acute Ischemic Stroke Are Less Likely To Be Routed To Comprehensive Stroke Centers, Muhammad Bilal Tariq, Iman Ali, Sergio Salazar-Marioni, Ananya S Iyyangar, Hussain M Azeem, Swapnil Khose, Victor Lopez, Rania Abdelkhaleq, Louise D Mccullough, Sunil A Sheth, Youngran Kim

Faculty, Staff and Student Publications

Background Prehospital routing of patients with large vessel occlusion (LVO) acute ischemic stroke (AIS) to centers capable of performing endovascular therapy may improve clinical outcomes. Here, we explore whether distance to comprehensive stroke centers (CSCs), stroke severity, and sex are associated with direct-to-CSC prehospital routing in patients with LVO AIS. Methods and Results In this cross-sectional study, we identified consecutive patients with LVO AIS from a prospectively collected multihospital registry throughout the greater Houston area from January 2019 to June 2020. Primary outcome was prehospital routing to CSC and was compared between men and women using modified Poisson regression including …

Psychosocial Impacts Of The Covid-19 Pandemic On Women With Spinal Cord Injury, Heather B Taylor, Rosemary B Hughes, Diana Gonzalez, Muna Bhattarai, Susan Robinson-Whelen

Faculty, Staff and Student Publications

This study represents the first known research addressing the impact of the COVID-19 pandemic on women with spinal cord injury (SCI) in the United States. Women in this population face unique barriers that put them at elevated risk for compromised quality of life, risk that was magnified by physical and social restrictions imposed during the pandemic. This qualitative study examined the perceptions of women with SCI and the effect of the pandemic on their lives. The predominantly White and relatively well-educated sample of 105 women with traumatic SCI was diverse in age, injury characteristics, and geographic representation. Recruited across the …

Reversal Of Dual Epigenetic Repression Of Non-Canonical Wnt-5a Normalises Diabetic Corneal Epithelial Wound Healing And Stem Cells, Ruchi Shah, Tanya M Spektor, Daniel J Weisenberger, Hui Ding, Rameshwar Patil, Cynthia Amador, Xue-Ying Song, Steven T Chun, Jake Inzalaco, Sue Turjman, Sean Ghiam, Jiho Jeong-Kim, Sasha Tolstoff, Sabina V Yampolsky, Onkar B Sawant, Yaron S Rabinowitz, Ezra Maguen, Pedram Hamrah, Clive N Svendsen, Mehrnoosh Saghizadeh, Julia Y Ljubimova, Andrei A Kramerov, Alexander V Ljubimov

Faculty, Staff and Student Publications

AIMS/HYPOTHESIS: Diabetes is associated with epigenetic modifications including DNA methylation and miRNA changes. Diabetic complications in the cornea can cause persistent epithelial defects and impaired wound healing due to limbal epithelial stem cell (LESC) dysfunction. In this study, we aimed to uncover epigenetic alterations in diabetic vs non-diabetic human limbal epithelial cells (LEC) enriched in LESC and identify new diabetic markers that can be targeted for therapy to normalise corneal epithelial wound healing and stem cell expression.

METHODS: Human LEC were isolated, or organ-cultured corneas were obtained, from autopsy eyes from non-diabetic (59.87±20.89 years) and diabetic (71.93±9.29 years) donors. The …

Impact Of Mir196a-2 Genotypes On Colorectal Cancer Risk In Taiwan, Te-Cheng Yueh, Yun-Chi Wang, Yu-Ting Chin, Yi-Chih Hung, Mei-Chin Mong, Ya-Chen Yang, Jen-Sheng Pei, Jian Gu, Chia-Wen Tsai, Da-Tian Bau, Wen-Shin Chang

Faculty, Staff and Student Publications

We aimed to investigate the association between genotypes for

Efficacy And Safety Of Elamipretide In Individuals With Primary Mitochondrial Myopathy: The Mmpower-3 Randomized Clinical Trial, Amel Karaa, Enrico Bertini, Valerio Carelli, Bruce H Cohen, Gregory M Enns, Marni J Falk, Amy Goldstein, Gráinne Siobhan Gorman, Richard Haas, Michio Hirano, Thomas Klopstock, Mary Kay Koenig, Cornelia Kornblum, Costanza Lamperti, Anna Lehman, Nicola Longo, Maria Judit Molnar, Sumit Parikh, Han Phan, Robert D S Pitceathly, Russell Saneto, Fernando Scaglia, Serenella Servidei, Mark Tarnopolsky, Antonio Toscano, Johan L K Van Hove, John Vissing, Jerry Vockley, Jeffrey S Finman, David A Brown, James A Shiffer, Michelango Mancuso, Mmpower-3 Trial Investigators

Faculty, Staff and Student Publications

BACKGROUND AND OBJECTIVES: Primary mitochondrial myopathies (PMMs) encompass a group of genetic disorders that impair mitochondrial oxidative phosphorylation, adversely affecting physical function, exercise capacity, and quality of life (QoL). Current PMM standards of care address symptoms, with limited clinical impact, constituting a significant therapeutic unmet need. We present data from MMPOWER-3, a pivotal, phase-3, randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of elamipretide in participants with genetically confirmed PMM.

METHODS: After screening, eligible participants were randomized 1:1 to receive either 24 weeks of elamipretide at a dose of 40 mg/d or placebo subcutaneously. Primary efficacy endpoints …

New Insights About Immune Populations In Gastrointestinal Gvhd, Eiko Hayase, Robert R Jenq

Faculty, Staff and Student Publications

Jarosch et al.have deeply characterized immune cell infiltrates in gastrointestinal (GI) biopsies from individuals with GI graft-versus-host disease (GI-GvHD) using single-cell RNA sequencing and ChipCytometry. Individuals with severe GI-GvHD demonstrated increased clonally expanded cytotoxic CD8 T cells in GI biopsies.

Ancestry-Driven Metabolite Variation Provides Insights Into Disease States In Admixed Populations, Kaylia M Reynolds, Andrea R V R Horimoto, Bridget M Lin, Ying Zhang, Nuzulul Kurniansyah, Bing Yu, Eric Boerwinkle, Qibin Qi, Robert Kaplan, Martha Daviglus, Lifang Hou, Laura Y Zhou, Jianwen Cai, Saame Raza Shaikh, Tamar Sofer, Sharon R Browning, Nora Franceschini

Faculty, Staff and Student Publications

BACKGROUND: Metabolic pathways are related to physiological functions and disease states and are influenced by genetic variation and environmental factors. Hispanics/Latino individuals have ancestry-derived genomic regions (local ancestry) from their recent admixture that have been less characterized for associations with metabolite abundance and disease risk.

METHODS: We performed admixture mapping of 640 circulating metabolites in 3887 Hispanic/Latino individuals from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Metabolites were quantified in fasting serum through non-targeted mass spectrometry (MS) analysis using ultra-performance liquid chromatography-MS/MS. Replication was performed in 1856 nonoverlapping HCHS/SOL participants with metabolomic data.

RESULTS: By leveraging local ancestry, this …