Digital Commons Network^™

Genome-Wide Association Study Meta-Analysis Uncovers Novel Genetic Variants Associated With Olfactory Dysfunction, Mohammed Aslam Imtiaz, Konstantinos Melas, Adrienne Tin, Valentina Talevi, Honglei Chen, Myriam Fornage, Srishti Shrestha, Martin Gögele, David Emmert, Cristian Pattaro, Peter Pramstaller, Franz Förster, Katrin Horn, Thomas H Mosley, Christian Fuchsberger, Markus Scholz, Monique M B Breteler, N Ahmad Aziz

Faculty, Staff and Student Publications

Background: Olfactory dysfunction is among the earliest signs of many age-related neurodegenerative diseases and has been associated with increased mortality in older adults; however, its genetic basis remains largely unknown. Therefore, here we aimed to elucidate its genetic architecture through a genome-wide association study meta-analysis (GWMA).

Methods: This GWMA included the participants of European ancestry (N = 22,730) enrolled in four different large population-based studies followed by a multi-ancestry GWMA including participants of African ancestry (N = 1,030). Olfactory dysfunction was assessed using a 12-item smell identification test.

Results: GWMA revealed a novel genome-wide significant locus (tagged by single nucleotide …

Retraction Of Activation Of Rac1 By Src-Dependent Phosphorylation Of Dock180y1811 Mediates Pdgfrα-Stimulated Glioma Tumorigenesis In Mice And Humans, Haizhong Feng, Bo Hu, Kun-Wei Liu, Yanxin Li, Xinghua Lu, Tao Cheng, Jia-Jean Yiin, Songjian Lu, Susan Keezer, Tim Fenton, Frank B Furnari, Ronald L Hamilton, Kristiina Vuori, Jann N Sarkaria, Motoo Nagane, Ryo Nishikawa, Webster K Cavenee, Shi-Yuan Cheng

Faculty, Staff and Student Publications

No abstract provided.

Elevated Nr2f1 Underlies The Persistence Of Invasive Disease After Treatment Of Braf-Mutant Melanoma, Manoela Tiago, Timothy J Purwin, Casey D Stefanski, Renaira Oliveira Da Silva, Mitchell E Fane, Yash Chhabra, Jelan I Haj, Jessica Lf Teh, Rama Kadamb, Weijia Cai, Sheera R Rosenbaum, Vivian Chua, Nir Hacohen, Michael A Davies, Jessie Villanueva, Inna Chervoneva, Ashani T Weeraratna, Dan A Erkes, Claudia Capparelli, Julio A Aguirre-Ghiso, Andrew E Aplin

Faculty, Staff and Student Publications

Despite the success of targeted inhibitors in cutaneous melanoma, therapeutic responses are limited by the aged tumor microenvironment and drug-tolerant residual cells. Given the similarities between drug tolerance and cellular dormancy, we studied the dormancy marker, nuclear receptor subfamily 2 group F member 1 (NR2F1), in response to BRAF-V600E inhibitors (BRAFi) plus MEK inhibitors (MEKi) in BRAF-mutant melanoma models. Transcriptomic analysis of melanoma patient samples treated with BRAFi + MEKi showed increased NR2F1. NR2F1 was highly expressed in the drug-tolerant invasive cell state of minimal residual disease in patient-derived and mouse-derived xenografts on BRAFi + MEKi. NR2F1 over-expression was sufficient …

33 Unresolved Questions In Nanoscience And Nanotechnology, Chad A Mirkin, Sarah Hurst Petrosko, Natalie Artzi, Koray Aydin, Austin Biaggne, C Jeffrey Brinker, Katherine E Bujold, Y Charles Cao, Rachel R Chan, Chaojian Chen, Peng-Cheng Chen, Xiaodong Chen, Olivier J G L Chevalier, Chung Hang Jonathan Choi, Richard M Crooks, Vinayak P Dravid, Jingshan S Du, Sasha B Ebrahimi, Hongyou Fan, Omar K Farha, C Adrian Figg, Tanner D Fink, Connor M Forsyth, Harald Fuchs, Franz M Geiger, Nathan C Gianneschi, Kyle J Gibson, David S Ginger, Sishi Guo, Justin S Hanes, Liangliang Hao, Jin Huang, Bryan M Hunter, Fengwei Huo, Jeongmin Hwang, Rongchao Jin, Shana O Kelley, Thomas J Kempa, Youngeun Kim, Sergej Kudruk, Sneha Kumari, Kaitlin M Landy, Ki-Bum Lee, Noel J Leon, Jun Li, Yuanwei Li, Zhiwei Li, Bin Liu, Guoliang Liu, Xiaogang Liu, Luis M Liz-Marzán, Jochen H Lorch, Taokun Luo, Robert J Macfarlane, Jill E Millstone, Milan Mrksich, Catherine J Murphy, Rajesh R Naik, Andre E Nel, Christopher Oetheimer, Jenny K Hedlund Orbeck, So-Jung Park, Benjamin E Partridge, Nicholas A Peppas, Michelle L Personick, Arindam Raj, Namrata Ramani, Michael B Ross, Stacey Barnaby Ross, Edward H Sargent, Tanushri Sengupta, George C Schatz, Dwight S Seferos, Tamar Seideman, Soyoung Eileen Seo, Bo Shen, Wooyoung Shim, Donghoon Shin, Ulrich Simon, Andrew J Sinegra, Peter T Smith, Alexander M Spokoyny, Peter J Stang, Alexander H Stegh, J Fraser Stoddart, Dayne F Swearer, Weihong Tan, Michelle H Teplensky, C Shad Thaxton, David R Walt, Mary X Wang, Zhe Wang, Wei David Wei, Paul S Weiss, Peter H Winegar, Younan Xia, Yi Xie, Xiaoyang Xu, Peidong Yang, Yiming Yang, Zihao Ye, Kuk Ro Yoon, Cuizheng Zhang, Hua Zhang, Ke Zhang, Liangfang Zhang, Xiaoyu Zhang, Ye Zhang, Zijian Zheng, Wenjie Zhou, Shengshuang Zhu, Wei Zhu

Faculty, Staff and Student Publications

Significant advances in science and engineering often emerge at the intersections of disciplines. Nanoscience and nanotechnology are inherently interdisciplinary, uniting researchers from chemistry, physics, biology, medicine, materials science, and engineering. This convergence has fostered novel ways of thinking and enabled the development of materials, tools, and technologies that have transformed both basic and applied research, as well as how we address critical societal challenges. In this Nano Focus, we pose and explore 33 questions whose answers could profoundly impact fields such as energy, electronics, the environment, optics, and medicine. These questions highlight the need for deeper foundational understanding, improved tools …

Setd2 Suppresses Tumorigenesis In A Krasg12c-Driven Lung Cancer Model, And Its Catalytic Activity Is Regulated By Histone Acetylation, Ricardo J Mack, Natasha M Flores, Geoffrey C Fox, Hanyang Dong, Metehan Cebeci, Simone Hausmann, Tourkian Chasan, Jill M Dowen, Brian D Strahl, Pawel K Mazur, Or Gozani

Faculty, Staff and Student Publications

Histone H3 trimethylation at lysine 36 (H3K36me3) is a key chromatin modification that regulates fundamental physiological and pathological processes. In humans, SETD2 is the only known enzyme that catalyzes H3K36me3 in somatic cells and is implicated in tumor suppression across multiple cancer types. While there is considerable crosstalk between the SETD2-H3K36me3 axis and other epigenetic modifications, much remains to be understood. Here, we show that Setd2 functions as a potent tumor suppressor in a KRASG12C-driven lung adenocarcinoma (LUAD) mouse model, and that acetylation enhances SETD2 in vitro methylation of H3K36 on nucleosome substrates. In vivo, Setd2 ablation accelerates lethality in …

Bayesian Clustering Prior With Overlapping Indices For Effective Use Of Multisource External Data, Xuetao Lu, J Jack Lee

Faculty, Staff and Student Publications

The use of external data in clinical trials offers numerous advantages, such as reducing enrollment, increasing study power, and shortening trial duration. In Bayesian inference, information in external data can be transferred into an informative prior for future borrowing (i.e. prior synthesis). However, multisource external data often exhibits heterogeneity, which can cause information distortion during the prior synthesizing. Clustering helps identifying the heterogeneity, enhancing the congruence between synthesized prior and external data. Obtaining optimal clustering is challenging due to the trade-off between congruence with external data and robustness to future data. We introduce two overlapping indices: the overlapping clustering index …

Preclinical Perspectives On Disorders Of The Temporomandibular Joint: Tracing The Past, Navigating The Present, And Shaping The Future, John K Neubert, Kyle Allen, Tamara Alliston, Alejandro J Almarza, Kyriacos A Athanasiou, Basak Donertas-Ayaz, Bruna Balbino De Paula, Roxanne Bavarian, Nidhi Bhutani, Brian E Cairns, Robert M Caudle, Yang Chai, Jian-Fu Chen, Yong Chen, Glenn T Clark, Yenisel Cruz-Almeida, Alexandre F Dasilva, Paul L Durham, Airam Vivanco Estela, Millie Embree, Roger Fillingim, Fernando Guastaldi, Shruti Handa, Sunil D Kapila, David Keith, Keith L Kirkwood, Phillip Kramer, Katherine T Martucci, Niall P Murphy, Andrea G Nackley, Richard Ohrbach, Benedikt Sagl, Shad B Smith, Feng Tao, Beth Winkelstein, Hai Yao, Simon Young, Michael S Gold

Faculty, Staff and Student Publications

Temporomandibular disorders (TMDs) are complex conditions characterized by orofacial pain and dysfunction, affecting a significant portion of the population. TMDs may involve joint and/or muscle pain, dysfunction (e.g., noise, limited or altered jaw movements), or both, leading to a marked decrease in quality of life. Patients often experience functional limitations that hinder eating, speaking, and daily activities. Additionally, TMDs are frequently associated with psychological distress, including anxiety and depression, which further impacts overall well-being. Despite the profound individual and societal impact of TMDs, effective therapies remain elusive, partly due to deficiencies in translational research. A primary limitation in the TMD …

Infusion Of Blood From Young And Old Mice Modulates Amyloid Pathology, Matias Pizarro, Ruben Gomez-Gutierrez, Ariel Caviedes, Catalina Valdes, Ute Woehlbier, Cristian Vargas, Mauricio Hernandez, Claudia Duran-Aniotz, Rodrigo Morales

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the accumulation of misfolded proteins in the brain. Recently, the impact of blood components in the progression of this disease has come to attention. This study investigates the effects of infusing blood from young and old wild-type mice into transgenic mice that model AD brain amyloidosis. Impaired memory and Aβ accumulation were observed in mice infused with blood from old donors. A proteomic analysis in the brain of these mice identified alterations in components related to synaptogenesis and the endocannabinoid system. The α2δ2 protein, associated with neuronal calcium regulation, was validated …

Loss Of Ptdss1 In Tumor Cells Improves Immunogenicity And Response To Anti-Pd-1 Therapy, Jielin Liu, Shelley Herbrich, Sreyashi Basu, Yulong Chen, Ashwat Nagarajan, Swetha Anandhan, Sangeeta Goswami, Liangwen Xiong, Baoxiang Guan, Padmanee Sharma

Faculty, Staff and Student Publications

PTDSS1 (phosphatidylserine synthase 1) encodes an enzyme that facilitates production of phosphatidylserine (PS), which mediates a global immunosuppressive signal. Here, based on in vivo CRISPR screen, we identified PTDSS1 as a target to improve anti-PD-1 therapy. Depletion of Ptdss1 in tumor cells increased expression of interferon-γ (IFN-γ)-regulated genes, including B2m, Cxcl9, Cxcl10, and Stat1, even in the absence of IFN-γ stimulation in vitro. Loss of Ptdss1 in tumor cells also led to increased expression of MHC-I, enhanced cytotoxicity of CD8+ T cells, and increased frequency of an iNOS+ myeloid subset. A gene signature derived from the …

Mesenchymal Stem Cells In Socket Healing And Mronj, Yuki Arai, Chiaki Tsutsumi-Arai, Jeryl D English, Noriaki Ono, Wanida Ono

Faculty, Staff and Student Publications

This review aims to summarise the current understanding of the biological processes involved in socket healing after tooth extraction and the contribution of mesenchymal stem/progenitor cells (MSCs) during these processes. Additionally, it seeks to explore the mechanisms underlying medication-related osteonecrosis of the jaw (MRONJ), often linked to tooth extraction, to provide insights for future research directions. Socket healing is a complex biological process consisting of three phases: inflammatory, proliferative and modelling/remodelling. MSCs, particularly those derived from periodontal ligament (PDL) cells and bone lining cells, are known to play a significant role in the initial and subsequent stages of healing. However, …

Nmr-Based Metabolomic Profiling For Brain Cancer Diagnosis And Treatment Guidance, Julia R Zickus, José S Enriquez, Paytience Smith, Bill T Sun, Muxin Wang, Aldo Morales, Pratip K Bhattacharya, Shivanand Pudakalakatti

Faculty, Staff and Student Publications

Nuclear magnetic resonance (NMR) spectroscopy is a routinely used analytical tool for studying chemical entities of varying molecular sizes, ranging from approximately 20 Da to ~45 kDa, and in some cases even larger. Over the past two decades, the use of NMR spectroscopy has significantly expanded to the study of metabolomics. In this medium-sized review, the application of NMR-based metabolomics in the diagnosis, therapeutic intervention, and guidance of therapy for various types of brain cancer is discussed.

Ubiquitination-Targeted Therapies Improve Bmd Ipsc Myogenic Cell Engraftment And Dystrophin Expression In Vivo, Muchen Liu, Somik Chatterjee, Jianbo Wu, Zeinab Kashaniasl, Ashok Kumar, Chunru Lin, Radbod Darabi

Faculty, Staff and Student Publications

Becker muscular dystrophy (BMD) is caused by in-frame mutations in dystrophin gene, leading to progressive muscle weakness, and cardiac and respiratory complications. Currently, there is no cure. We have recently identified the importance of poly-ubiquitination in regulating dystrophin stability through the binding of lncRNA H19 to the dystrophin C-terminal zinc-finger domain (ZNF), inhibiting TRIM63-mediated poly-ubiquitination. We also demonstrated that BMD mutations lead to conformational changes in ZNF domain, reduced lncRNA H19 binding and increased dystrophin ubiquitination. Here we used BMD iPSCs to investigate the in vitro myogenic potential of BMD myogenic cells, as well as in vitro and in vivo …

Complete Genome Sequence Of Actinomyces Oris Strain Mg-1: An Oral Commensal Critical For Dental Plaque Formation, Bibek G C, Kexin Tan, Chenggang Wu

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Actinomyces oris MG-1 is a key oral commensal involved in dental plaque formation. We report its complete genome sequence, generated using Illumina and Oxford Nanopore sequencing. The genome consists of a single circular chromosome of 3,042,829 bp, providing a resource for future functional studies.

Neuroengineering Approaches Assessing Structural And Functional Changes Of Motor Descending Pathways In Stroke, Jordan N Williamson, Rita Huan-Ting Peng, Joohwan Sung, Mahmood Rajabtabar Darvish, Xiaoxi Chen, Mehreen Ali, Sheng Li, Yuan Yang

Faculty, Staff and Student Publications

Stroke is a leading cause of adult disability worldwide, with approximately 101 million survivors globally. Over 60% of these individuals live with from long-term, often lifelong, movement impairments that significantly hinder their ability to perform essential daily activities and maintain independence. Post-stroke movement disabilities are highly associated with structural and functional changes in motor descending pathways, particularly the corticospinal tract and other indirect motor pathways via the brainstem. For decades, neuroengineers have been working to quantitively evaluate the post-stroke changes of motor descending pathways, aiming to establish a precision prognosis and tailoring treatments to post-stroke motor impairment. However, a clear …

Neurotransmitter Signaling In Molecular And Behavioral Immune Responses To Pathogens In C Elegans, Benson Otarigho, Alejandro Aballay

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Neurotransmitter signaling pathways play major roles in both molecular and behavioral defenses against pathogen invasion, shaping the ability of Caenorhabditis elegans to sense and respond to environmental challenges. Given the conservation of neurotransmitter signaling pathways, their understanding may not only provide insights into the neurobiology of C. elegans but also has broader implications for our understanding of neural-immune interactions and host defense mechanisms in higher organisms. In this review, we discussed the literature on various neurotransmitter signaling pathways, including serotonergic, dopaminergic/octopaminergic, GABAergic, and glutamatergic pathways, and how these pathways modulate molecular and behavioral immune defense against pathogens.

The Glutaminase Activity Of Asns Fuels Glutamine Metabolism In Leukemia, Wai-Kin Chan, Lin Tan, Sara A Martinez, Di Du, Thomas D Horvath, Michael Pontikos, Leona A Rusling, Yulun Chiu, Bao Q Tran, Susan B Rempe, Sergei Sukharev, John N Weinstein, Philip L Lorenzi

Faculty, Staff and Student Publications

Not available.

Health Systems Responsiveness In Low And Middle-Income Countries (L&Mics): Revisiting Its Scope, Meesha Iqbal, Robert Morgan, Cici Bauer, Cecilia Ganduglia Cazaban, Sameen Siddiqi

Faculty, Staff and Student Publications

Introduction: Health systems responsiveness (HSR) addresses the legitimate non-health expectations of the population and plays a vital role in strengthening health systems and enhancing population health. Identifying specific constructs or domains within HSR is particularly important in the context of low and middle-income countries (L&MICs) to facilitate targeted improvement. Following a comprehensive systematic review of the literature, we developed a conceptual framework for HSR. This study was designed to validate our proposed framework through a Delphi process.

Methods: Global HSR experts were contacted via email to participate in the study, and a copy of the proposed framework (12 domains, 53 …

The "Secret Of Seven Stones": Short-Term Efficacy Of An Online Intergenerational Sexual Health Education Game For Early Adolescents And Their Parents, Ross Shegog, Christine Markham, Melissa Peskin, Robert C Addy, Sara Dube, Diane Santa Maria, Susan Tortolero Emery, Johnny M Wilkerson, Elizabeth Baumler, Laura Armistead, Pooja Chaudhary, Hsing-Yi Song, Angela Spencer, Jeffery Mclaughlin

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Objectives: Intergenerational games offer a potential channel to impact parent-youth sexual health communication. The "Secret of Seven Stones" (SSS) is an 18-level online adventure game and parent website designed to engage parents and youth (11-14 years) in conversations about healthy dating relationships and sexual behavior and to provide sexual health skills training to youth. Study hypotheses were that SSS exposure would increase sexual health parent-child communication, increase youth intentions to delay sexual debut, and reduce youth exposure to situations that promote sexual activity.

Materials and Methods: SSS was evaluated in the homes of parent-youth dyads randomly assigned to intervention ( …

Neurobehavioral Symptom Profiles For The Behavioral Assessment Screening Tool In Chronic Traumatic Brain Injury, Shannon B Juengst, Brittany Wright, Annalyn Demello, Leia Vos, Fedora Biney, Luis Leon Novelo, Michael Williams

Faculty, Staff and Student Publications

Objective: To identify neurobehavioral symptom profiles among persons with chronic traumatic brain injury (TBI) using the Behavioral Assessment Screening Tool (BAST) and to consider participant characteristics that differ between profile groups.

Setting: Community.

Participants: Participants (n = 615) were English-speaking adults (≥18) and had a self-reported history of at least one TBI of any severity.

Design: Secondary analysis of cross-sectional data.

Main measures: The BAST measures neurobehavioral symptoms in the domains of Negative Affect, Fatigue, Executive Dysfunction, Impulsivity, and Substance Misuse.

Results: Using latent profile analysis (LPA), we identified 3 different neurobehavioral profiles. Overall symptom frequency and differences in the …

Structure Of The T9ss Porkn Ring Complex Reveals Conformational Plasticity Based On The Repurposed Fge Fold, Xiangan Liu, John D Perpich, Liqiang Song, Christian Cambillau, Thierry Doan, Lei Zheng, Richard J Lamont, Eric Cascales, Bo Hu

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The type IX secretion system (T9SS) is a protein secretion machinery unique to the Bacteroidetes-Chlorobi-Fibrobacteres superphylum, which plays crucial roles in bacterial pathogenesis and gliding motility. It is composed of >15 proteins, including the proton-motive force-dependent PorLM motor, the PorKN ring anchored to the outer membrane, and the Sov translocon. Here, we present the cryo-electron microscopy (EM) structure of the PorKN ring complex from Porphyromonas gingivalis at 3.2 Å resolution. Our structural analysis reveals that PorK contains a repurposed formylglycine-generating enzyme-like fold, which serves as a structural hub for complex assembly rather than enzymatic activity. The complex exhibits a 33-fold …

Retinoid-X-Receptor As A Mediator Of Poststroke Recovery By Reversing Age-Associated Phenotypes Of Microglia/Hematogenous Macrophages, Shun-Ming Ting, Xiurong Zhao, Guanghua Sun, Mercedes Ricote, Jaroslaw Aronowski

Faculty, Staff and Student Publications

After stroke, microglia and hematogenous macrophages, together referred to as MΦ, clear dead cells and cellular debris in the infarcted brain through phagocytosis as an essential part of the recovery process. However, the phagocytic capability of MΦ declines with age. Furthermore, aged MΦ become overactivated in response to stroke, enhancing secondary brain injury. In this study, we demonstrated that by reversing the age-related dysfunctions in MΦ through activating the retinoid X receptor (RXR), the recovery after stroke in the aged brain could be improved. Using RNA-sequencing, we compared the transcriptomes between MΦ isolated from the brains of young and aged …

Innate And Adaptive Immune Features Associated With Immune-Related Adverse Events, Shaheen Khan, Venkat S Malladi, Mitchell S Von Itzstein, Hong Mu-Mosley, Farjana J Fattah, Yang Liu, Mary E Gwin, Jason Y Park, Suzanne M Cole, Sheena Bhalla, Jay Lohrey, David Hsiehchen, Angela Moses, Tao Wang, Yaming Xue, Angela B Mobley, J David Farrar, Marjaan Imam, Michelle Wu, Quan-Zhen Li, Edward K Wakeland, Yang Xie, Jeffrey A Sorelle, David E Gerber

Faculty, Staff and Student Publications

Background: While highly efficacious for numerous cancers, immune checkpoint inhibitors (ICIs) can cause unpredictable and potentially severe immune-related adverse events (irAEs), underscoring the need to understand irAE biology.

Methods: We used a multidimensional approach incorporating single-cell RNA sequencing, mass cytometry, multiplex cytokine assay, and antinuclear antibody (ANA) profiling to characterize the peripheral immune landscape of patients receiving ICI therapy according to irAE development.

Results: Analysis of 162 patients revealed that individuals who developed clinically significant irAEs exhibited a baseline proinflammatory, autoimmune-like state characterized by a significantly higher abundance of CD57+ T and natural killer (NK) T cells, plasmablasts, proliferating and …

Bypassing Bamd Essentiality By Mutations In A Non-Essential Substrate, Santosh Kumar, Anna Konovalova

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The β-barrel assembly machinery (Bam) is essential for assembling all transmembrane β-barrel outer membrane proteins in gram-negative bacteria. The Bam complex consists of the central β-barrel protein BamA and accessory Bam lipoproteins, including the widely conserved and essential BamD. BamD is assumed to be an essential regulator of OMP assembly, as its absence causes a global defect in OMP biogenesis. Here, we challenge this view by demonstrating that BamD essentiality is both conditional and substrate specific. In Escherichia coli, its function can be bypassed by preventing BamA jamming by a single, non-essential substrate RcsF. Our findings suggest that BamD …

Infectious Prions In Brains And Muscles Of Domestic Pigs Experimentally Challenged With The Bse, Scrapie, And Cwd Agents, Francisca Bravo-Risi, Fraser Brydon, Angela Chong, Kane Spicker, Justin J Greenlee, Glenn Telling, Claudio Soto, Sandra Pritzkow, Marcelo A Barria, Rodrigo Morales

Faculty, Staff and Student Publications

Experimental studies suggest that animal species not previously described as naturally infected by prions are susceptible to prion diseases affecting sheep, cattle, and deer. These interspecies transmissions may generate prions with unknown host ranges. Pigs are susceptible to prions from different origins, including deer chronic wasting disease (CWD), sheep scrapie, and bovine spongiform encephalopathy (BSE). Here, we studied prions in brains and muscles from pigs previously infected with these different prion sources. Specifically, we measured the total prion protein (PrP) and PK-resistant PrP by western blot. Seeding activity in these tissues was evaluated using the protein misfolding cyclic amplification (PMCA) …

Inhibition Of The Ufd-1-Npl-4 Complex Triggers An Aberrant Immune Response In Caenorhabditis Elegans, Rajneesh Rao, Alejandro Aballay, Jogender Singh

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The UFD-1 (ubiquitin fusion degradation 1)-NPL-4 (nuclear protein localization homolog 4) heterodimer is involved in extracting ubiquitinated proteins from several plasma membrane locations, including the endoplasmic reticulum. This heterodimer complex helps in the degradation of ubiquitinated proteins via the proteasome with the help of the AAA+ATPase CDC-48. While the ubiquitin-proteasome system is known to have important roles in maintaining innate immune responses, the role of the UFD-1-NPL-4 complex in regulating immunity remains elusive. In this study, we investigate the role of the UFD-1-NPL-4 complex in maintaining

Sleep Architecture And Dementia Risk In Adults: An Analysis Of 5 Cohorts From The Sleep And Dementia Consortium, Stephanie Yiallourou, Andree-Ann Baril, Crystal Wiedner, Jeffrey R Misialek, Christopher E Kline, Stephanie Harrison, Ethan Cannon, Qiong Yang, Rebecca Bernal, Alycia Bisson, Dibya Himali, Marina Cavuoto, Antoine Weihs, Alexa Beiser, Rebecca F Gottesman, Yue Leng, Oscar Lopez, Pamela L Lutsey, Shaun M Purcell, Susan Redline, Sudha Seshadri, Katie L Stone, Kristine Yaffe, Sonia Ancoli-Israel, Qian Xiao, Eleni Okeanis Vaou, Jayandra J Himali, Matthew P Pase

Faculty, Staff and Student Publications

Study objectives: Poor sleep may play a role in the risk of dementia. However, few studies have investigated the association between polysomnography (PSG)-derived sleep architecture and dementia incidence. We examined the relationship between sleep architecture and dementia incidence across five US-based cohort studies from the Sleep and Dementia Consortium.

Methods: Percent of time spent in stages of sleep (N1, N2, N3, rapid eye movement sleep), wake after sleep onset, sleep maintenance efficiency, apnea-hypopnea index, and relative delta power were derived from a single night home-based PSG. Dementia was ascertained in each cohort using its cohort-specific criteria. Each cohort performed Cox …

Therapeutic Restoration Of Mitochondria-Endoplasmic Reticulum Cross Talk For Osteoarthritis, Mingzhuang Hou, Yifan Ma, Yaoge Deng, Yubin Wu, Yanrun Zhu, Yang Liu, Xiaoping Li, Lili Yu, Zirui He, Yifan Wang, Shiyan Dong, Xiaowei Xia, Jianfeng Yu, Chenqi Yu, Kang Kang, Yingjie Lu, Lili Sun, Betty Y S Kim, Yuan Yuan, Yijian Zhang, Wen Jiang, Xuesong Zhu

Faculty, Staff and Student Publications

Osteoarthritis is a prevalent joint disease in the aging population. The hallmark of osteoarthritis is the degeneration of the joint cartilage, characterized by changes in chondrocytes including mitochondrial dysfunction. However, the precise mechanisms of how this affects chondrocyte homeostasis and whether such processes can be explored as therapeutic targets for osteoarthritis remain unclear. Here, we show that impaired mitochondrial function and disrupted cartilage matrix metabolism due to loss of mitofusin-2 (MFN2) expression in chondrocytes leads to the development of osteoarthritis. Sirtuin-3 (SIRT3), a key regulator of mitochondrial function, plays a critical role in modulating MFN2 to restore mitochondrial dynamics, reduce …

A Phase 2 Study Of Obinutuzumab Combined With Lenalidomide In Previously Untreated High Tumor Burden Follicular Lymphoma, Neha Akkad, Lei Feng, Jason R Westin, Fredrick B Hagemeister, Hun Ju Lee, Luis Fayad, Sairah Ahmed, Ranjit Nair, Maria Alma Rodriguez, Paolo Strati, Dai Chihara, Christopher R Flowers, Linda Claret, Karina Ibanez, Michael Wang, Nathan H Fowler, Jared Henderson, R Eric Davis, Sattva S Neelapu, Michael Green, Loretta J Nastoupil

Faculty, Staff and Student Publications

Follicular lymphoma (FL) has a clinical course that is often characterized by high response rates to first-line therapy, followed by multiple relapses over a prolonged natural history. Currently, there are multiple possible approaches to frontline therapy for untreated advanced-stage FL, but there is an ongoing debate around what is the preferred approach. Based on the benefits seen with combining lenalidomide, an immunomodulatory agent, with rituximab, an anti-CD20 antibody, we aimed to evaluate the safety and efficacy of lenalidomide in combination with obinuzutumab, an anti-CD20 antibody with enhanced antibody-dependent cellular cytotoxicity. The eligibility criteria included a diagnosis of FL, grade 1 …

Fruquintinib In Less Pretreated Patients: Multivariate Profile-Matching Analysis Of Fresco-2 To Fresco, Arvind Dasari, Cathy Eng, Sara Lonardi, Rocio Garcia-Carbonero, Toshiki Masuishi, Chiara Cremolini, François Ghiringhelli, Joleen Hubbard, Tanios Bekaii-Saab, Jeremy Jones, Rui-Hua Xu, Lin Shen, Jianming Xu, Yuxian Bai, Yanhong Deng, Ying Yuan, Wei Wei, Jianchang Lin, Lucy Chen, Zhao Yang, William R Schelman, Shukui Qin, Jin Li

Faculty, Staff and Student Publications

Background: In the phase 3 FRESCO (NCT02314819) and FRESCO-2 (NCT04322539) studies, fruquintinib vs placebo, plus best supportive care, significantly improved overall survival (OS) in patients with metastatic colorectal cancer (mCRC). These studies were conducted in temporally and geographically diverse populations that received distinct prior therapies; FRESCO patients were less pretreated than FRESCO-2 patients. This analysis assessed the efficacy and safety of fruquintinib in a less pretreated global population than the FRESCO-2 intention-to-treat (ITT) population.

Methods: In FRESCO and FRESCO-2, patients were randomized 2:1 to receive oral fruquintinib 5 mg or matched placebo. Profile matching was undertaken …

Defining Breast Epithelial Cell Types In The Single-Cell Era, G Kenneth Gray, Eric G Carlson, Tatyana Lev, Bailey Marshall, Austin D Reed, Alex P Sánchez-Covarrubias, Alecia-Jane Twigger, Aleix Puig-Barbe, Aatish Thennavan, Ayodele Omotoso, Lyndsay M Murrow, Deeptiman Chatterjee, Siyuan He, Sara Pensa, Brian Aevermann, Norbert K Tavares, Natalie Chen, Jason A Hilton, Kerrigan Blake, Yunlong Liu, Kiet Phong, Zev J Gartner, Devon A Lawson, Alexander Swarbrick, Camila O Dos Santos, Sophia H L George, Joan S Brugge, Mark A Labarge, Harikrishna Nakshatri, Nicholas Navin, Kai Kessenbrock, Walid T Khaled

Faculty, Staff and Student Publications

Single-cell studies on breast tissue have contributed to a change in our understanding of breast epithelial diversity that has, in turn, precipitated a lack of consensus on breast cell types. The confusion surrounding this issue highlights a possible challenge for advancing breast atlas efforts. In this perspective, we present our consensus on the identities, properties, and naming conventions for breast epithelial cell types and propose goals for future atlas endeavors. Our proposals and their underlying thought processes aim to catalyze the adoption of a shared model for this tissue and to serve as guidance for other investigators facing similar challenges.