Medical Specialties Commons^™

Structural Basis For Mtorc1 Activation On The Lysosomal Membrane, Zhicheng Cui, Alessandra Esposito, Gennaro Napolitano, Andrea Ballabio, James H Hurley

Duncan NRI Faculty and Staff Publications

The mechanistic target of rapamycin complex 1 (mTORC1) integrates growth factor (GF) and nutrient signals to stimulate anabolic processes connected to cell growth and inhibit catabolic processes such as autophagy1,2. GF signalling through the tuberous sclerosis complex regulates the lysosomally localized small GTPase RAS homologue enriched in brain (RHEB)3. Direct binding of RHEB-GTP to the mTOR kinase subunit of mTORC1 allosterically activates the kinase by inducing a large-scale conformational change4. Here we reconstituted mTORC1 activation on membranes by RHEB, RAGs and Ragulator. Cryo-electron microscopy showed that RAPTOR and mTOR interact directly with the membrane. Full engagement of the membrane anchors …

Galntl5 Binds Galnac And Is Required For Migration Through The Uterotubal Junction And Sperm-Zona Pellucida Binding, Taichi Noda, Reika Uriu, Daisuke Mashiko, Hina Shinohara, Yongcun Qu, Ayumu Taira, Ryan M Matzuk, Duri Tahala, Motochika Nakano, Kimi Araki, Zhifeng Yu, Ying Zhang, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

More than 20 genes expressed in the male reproductive tract have been identified as essential factors for sperm migration to and through the utero-tubal junction (UTJ), and they are divided into ADAM3-dependent and ADAM3-independent pathways. In parallel, sperm having UTJ migration defects also show impaired binding to the zona pellucida (ZP). Herein, we demonstrate that knockout of Galntl5, encoding a sperm surface protein, causes impaired sperm binding with the UTJ and ZP, and null males have severe infertility. GALNTL5 appreciably disappears in sperm lacking Adam3 or Lypd4, required for ADAM3-dependent and ADAM3-independent pathways, and GALNTL5 binds to N …

Galntl5 Binds Galnac And Is Required For Migration Through The Uterotubal Junction And Sperm-Zona Pellucida Binding, Taichi Noda, Reika Uriu, Daisuke Mashiko, Hina Shinohara, Yongcun Qu, Ayumu Taira, Ryan M Matzuk, Duri Tahala, Motochika Nakano, Kimi Araki, Zhifeng Yu, Ying Zhang, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

Objective: To review the global impact of the COVID-19 pandemic on stroke care-metrics and report data from a health system in Houston.

Methods: We performed a meta-analysis of the published literature reporting stroke admissions, intracerebral hemorrhage (ICH) cases, number of thrombolysis (tPA) and thrombectomy (MT) cases, and time metrics (door to needle, DTN; and door to groin time, DTG) during the pandemic compared to prepandemic period. Within our hospital system, between January-June 2019 and January-June 2020, we compared the proportion of stroke admissions and door to tPA and MT times.

Results: A total of 32,640 stroke admissions from 29 studies …

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 …

Amino Acids And Cart Distinguish A-Β+ Ketosis-Prone Diabetes From Type 1 And Type 2 Diabetes During Hyperglycemic Crises, Farook Jahoor, Jean W Hsu, Kelly R Keene, W Frank Peacock, Xiaofang Huang, Danielle Guffey, Jinyoung Byun, Rasmus Bennet, Ake Lernmark, Mustafa Tosur, Ashok Balasubramanyam

Children’s Nutrition Research Center Staff Publications

Context: When clinically stable, patients with A-β+ ketosis-prone diabetes (KPD) manifest unique markers of amino acid metabolism. Biomarkers differentiating KPD from type 1 (T1D) and type 2 diabetes (T2D) during hyperglycemic crises would accelerate diagnosis and management.

Objective: Compare serum metabolomics of KPD, T1D, and T2D patients during hyperglycemic crises, and utilize classification and regression tree (CART) modeling to distinguish these forms of diabetes.

Methods: At an urban hospital emergency center, adults with KPD, T1D, and T2D during hyperglycemic crises with or without diabetic ketoacidosis (DKA), and healthy controls, underwent comparisons of serum metabolite and hormonal profiles and CART analyses. …

Sorting Nexin 3 Promotes Ischemic Retinopathy Through Rip1- And Rip3-Mediated Myeloid Cell Necroptosis And Mitochondrial Fission, Jiaojiao Wang, Chunhong Zhou, Kai Zhuang, Jiami Zou, Wanlu Qiu, Mei Jin, Weile Ye, Pinglian Yang, Zhihua Zheng, Qing Zhou, Zunnan Huang, Yuanxiang Wang, Peiqing Liu, Jing Lu, Yuqing Huo, Zhiping Liu

Faculty, Staff and Students Publications

Proliferative retinopathy is a leading cause of irreversible blindness in humans; however, the molecular mechanisms behind the immune cell–mediated retinal angiogenesis remain poorly elucidated. Here, using single-cell RNA sequencing in an oxygen-induced retinopathy (OIR) model, we identified an enrichment of sorting nexin (SNX)-related pathways, with SNX3, a member of the SNX family that is involved in endosomal sorting and trafficking, being significantly upregulated in the myeloid cell subpopulations of OIR retinas. Immunostaining showed that SNX3 expression is markedly increased in the retinal microglia/macrophages of mice with OIR, which is mainly located within and around the neovascular tufts. Myeloid cell-specific deficiency …

Artificial Intelligence In Head And Neck Cancer: Towards Precision Medicine, Jacob Hagen, Logan Hornung, William Barham, Supratik Mukhopadhyay, Adam Bess, Kevin Contrera, Devraj Basu, Vlad Sandulache, Guillaume Spielmann, Sagar Kansara

Faculty, Staff and Students Publications

Over the past 20 years, the capabilities of artificial intelligence (AI) have gained significant interest. While AI has been implemented to various degrees in several disciplines, its unique applications in head and neck cancer (HNC) remain underdeveloped. This narrative review examines the existing body of literature regarding the use of AI in HNC. Studies to date have demonstrated AI’s utility across multiple phases of the HNC treatment continuum. Despite its promise, integrating AI into clinical practice faces several challenges, including concerns about system integrity, generalizability, privacy, and bias. In this review, we address these challenges and offer insights into future …

Developmental Transformations Of Purkinje Cells Tracked By Dna Electrokinetic Mobility, Cheryl Brandenburg, Garrett W Crutcher, Andrea J Romanowski, Sarah G Donofrio, Lita R Duraine, Richard N A Owusu-Mensah, Benjamin H Cooper, Izumi Sugihara, Gene J Blatt, Roy V Sillitoe, Alexandros Poulopoulos

Duncan NRI Faculty and Staff Publications

Brain development begins with neurogenesis in progenitor zones and ends with expansive, intricately-patterned cellular diversity in the adult brain. We took advantage of bioelectric interactions between DNA and embryonic tissue to perform "stereo-tracking," a developmental targeting strategy that differentially labels cells at different depths within progenitor zones. This 3D labeling was achieved by delivery of plasmids with distinct electrokinetic mobilities in utero. We applied stereo-tracking with light sheet imaging in the cerebellum and identified that Purkinje cells follow embryonically committed developmental trajectories, linking distinct progenitor zone subfields to the mature topography of the cerebellar cortex. We additionally identified an unexpected …

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 …

Regional Citrate Anticoagulation And Infectious Complications In Critically Ill Children And Young Adults Receiving Continuous Renal Replacement Therapy, Katja M Gist, Sai Prasad N Iyer, H David Humes, Stuart L Goldstein, Mihaela Damian, Andrea Cappoli, Catherine Joseph, Danielle E Soranno, Michelle Starr, Ashita Tolwani, Kevin K Chung, Theresa Mottes, Huaiyu Zang, Jangdong Seo, Nicholas J Ollberding, Shina Menon

Faculty, Staff and Students Publications

Introduction: Recent studies have identified an association between regional citrate anticoagulation (RCA) and subsequent infectious complications during continuous renal replacement therapy (CRRT). We aimed to determine if RCA was associated with infectious complications in children and young adults receiving CRRT.

Methods: A secondary analysis of the multinational Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease (WE-ROCK) registry (34 centers, 9 countries), was performed, including patients from 2015 to 2018. Patients were excluded if they (1) died within 72 h of CRRT initiation, had minor trauma or were postsurgical (analysis 1), or (2) met an exclusion in analysis 1 …

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 …

Pediatric Epilepsy Surgery: The Noninvasive Presurgical Evaluation, Deepankar Mohanty, Michael Quach

Faculty, Staff and Students Publications

Background: Drug-resistant epilepsy is a debilitating condition that afflicts individuals across all demographics, including children. The only recourse for many of these individuals is neurosurgery to reduce seizure burden, by either resecting or ablating the cerebral source or modulating it with a stimulator device. In either case, a thorough presurgical evaluation is required to identify brain regions of interest and construct an appropriate surgical plan. The scope of this evaluation has grown rapidly over the years as new and refined techniques have emerged. The aim of this article was to condense the most salient points regarding investigational tools used commonly …

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 …

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

Faculty, Staff and Student Publications

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.

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

Faculty, Staff and Student Publications

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.

Human Toxocariasis, Susana Lopez-Alamillo, Pravallika Padyala, Megan Carey, Megan M Duffey, Jill E Weatherhead

Faculty, Staff and Students Publications

Human toxocariasis is a globally prevalent zoonotic parasitic infection caused by larvae of Toxocara species, primarily Toxocara canis and Toxocara cati. Toxocariasis is commonly transmitted to humans through the ingestion of embryonated Toxocara eggs found in contaminated soil, water, or on surfaces contaminated with animal feces. Unlike in dogs and cats, humans are not definitive hosts for Toxocara spp., and, as a result, Toxocara larvae do not complete their life cycle in humans. Instead, following accidental oral ingestion of embryonated eggs, Toxocara larvae undergo an aberrant larval migratory cycle to various organs including the lungs, liver, muscles, and central …

Assessing Reliable Change, Mcid, Treatment Response, And Remission Using The Pediatric Anxiety Rating Scale (Pars) In Youth With Anxiety Disorders, Matti Cervin, Philip C Kendall, John C Piacentini, Elizabeth A Gosch, Jeffrey J Wood, Sophie C Schneider, Alison Salloum, Boris Birmaher, Andrew G Guzick, David Mataix-Cols, Eric A Storch

Faculty, Staff and Students Publications

Youth anxiety disorders are common and heterogeneous. The Pediatric Anxiety Rating Scale (PARS) is a clinician-administered tool designed to assess overall anxiety severity, independent of specific symptoms. The thresholds on PARS for the reliable change index (RCI), the minimal clinically important difference (MCID), treatment response, and full and partial remission remain unclear. Using the Clinical Global Impression (CGI) scales and diagnostic interviews as benchmark measures, several thresholds for the 6-item PARS were estimated using data from 904 youth with anxiety disorders, of which 36 % had an autism diagnosis. Data were drawn from 9 clinical trials conducted in the United …

Barriers And Timely Postoperative Radiation Therapy In Head And Neck Cancer, Megan T Nguyen, Emily Kistner-Griffin, Reid Demass, Bhisham S Chera, Chanita Hughes Halbert, Katherine R Sterba, Elizabeth G Hill, Brian Nussenbaum, Anthony J Alberg, Vlad C Sandulache, David J Hernandez, Ryan S Jackson, Sidharth V Puram, Russel Kahmke, Nosayaba Osazuwa-Peters, Gail Jackson, Sue S Yom, Evan M Graboyes

Faculty, Staff and Students Publications

Importance: Initiation of postoperative radiation therapy (PORT) within 6 weeks of surgery is associated with improved outcomes among patients with head and neck squamous cell carcinoma. However, the relationship of barriers to care with timely PORT is unknown.

Objective: To categorize barriers to timely PORT, evaluate the association of barriers to care with initiation of timely PORT, and describe the primary reason for delay among patients without timely PORT.

Design, setting, and participants: This prospective cohort study at a US academic medical center included adults with head and neck squamous cell carcinoma undergoing curative-intent surgery with an indication for PORT. …

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

Faculty, Staff and Student Publications

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

Faculty, Staff and Student Publications

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

High Beta Power In The Ventrolateral Prefrontal Cortex Indexes Human Approach Behavior: A Case Study, Nicole R Provenza, Sameer V Rajesh, Gabriel Reyes, Kalman A Katlowitz, Lokesha S Pugalenthi, Raphael A Bechtold, Nabeel Diab, Sandesh Reddy, Anthony K Allam, Ajay D Gandhi, Katherine E Kabotyanski, Kasra A Mansourian, Jonathan H Bentley, Jordan R Altman, Saurabh Hinduja, Nisha Giridharan, Garrett P Banks, Mohammed Hasen, Ben Shofty, Sarah R Heilbronner, Jeffrey F Cohn, David A Borton, Eric A Storch, Jeffrey A Herron, Benjamin Y Hayden, Mary L Phillips, Wayne K Goodman, Sameer A Sheth

Faculty, Staff and Students Publications

Deep brain stimulation (DBS) of the ventral capsule and ventral striatum (VC/VS) is an effective therapy for treatment-resistant obsessive–compulsive disorder (trOCD). DBS initiation often produces acute improvements in mood and energy. These acute behavioral changes, which we refer to as “approach behaviors,” include increased social engagement and talkativeness. We investigated the relationship between stimulation amplitude, spectral power in the ventrolateral prefrontal cortex (vlPFC), and speech rate in one male patient with trOCD implanted with bilateral VC/VS DBS leads and subdural electrodes adjacent to the orbitofrontal cortex and vlPFC. Several times over the first 24 weeks of therapy, we conducted experiments …

Development Of A Patient-Centered Outcome Tool For Blepharospasm: A Stepwise Modified Delphi Study, Brian D Berman, Fares Qeadan, Amanda D Henderson, Andrew R Harrison, Giovanni Defazio, Mark Hallett, Gamze Kilic-Berkmen, Laura Wright, Samantha Pentecost, Paul Reyes, Anna Tingin, Joseph Jankovic, Jane Boyd, Charlene Hudgins, Janet Hieshetter, Joel S Perlmutter, Hyder A Jinnah, Sarah Pirio Richardson

Faculty, Staff and Students Publications

Blepharospasm (BSP) is characterized by excessive orbicularis oculi muscle activity leading to abnormal blinking and involuntary eyelid closure. Botulinum neurotoxin (BoNT) injections are the main treatment for BSP, but they only partially and transiently relieve symptoms, leading to a waxing and waning therapeutic response. A patient-centered outcome (PCO) tool that measures BSP symptoms in a simple and efficient way could inform the development of better treatments. Using a stepwise modified Delphi approach, potential PCO items were first identified using the Dystonia Coalition Database with data from over 200 individuals with BSP who had provided responses to existing clinical assessment scales. …