Digital Commons Network^™

Description Of Cryptococcosis Following Sars-Cov-2 Infection: A Disease Survey Through The Mycosis Study Group Education And Research Consortium (Msg-19), Jeremey Walker, Todd Mccarty, Gerald Mcgwin, Eloy E Ordaya, Paschalis Vergidis, Luis Ostrosky-Zeichner, Mehriban Mammadova, Andrej Spec, Adriana M Rauseo, John Perfect, Julia Messina, Gabriel Vilchez, Rachel Mcmullen, Carolynn T Jones, Peter G Pappas

Faculty, Staff and Student Publications

BACKGROUND: Invasive fungal infections have been described throughout the COVID-19 pandemic. Cryptococcal disease after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been reported in several isolated case reports and 1 larger case series. We sought to describe cryptococcal infections following SARS-CoV-2 through establishing a database to investigate underlying risk factors, disease manifestations, and outcomes.

METHODS: We created a crowdsourced call for cases solicited through the Mycoses Study Group Education and Research Consortium, the Centers for Disease Control and Prevention Emerging Infectious Diseases Network, and infectious diseases Twitter groups. Data were collected in a web-based and secure REDCap …

Immunity From Nk Cell Subsets Is Important For Vaccine-Mediated Protection In Hpv+ Cancers, Madison P O'Hara, Ananta V Yanamandra, K Jagannadha Sastry

Faculty, Staff and Student Publications

High-risk human papillomaviruses (HPVs) are associated with genital and oral cancers, and the incidence of HPV+ head and neck squamous cell cancers is fast increasing in the USA and worldwide. Survival rates for patients with locally advanced disease are poor after standard-of-care chemoradiation treatment. Identifying the antitumor host immune mediators important for treatment response and designing strategies to promote them are essential. We reported earlier that in a syngeneic immunocompetent preclinical HPV tumor mouse model, intranasal immunization with an HPV peptide therapeutic vaccine containing the combination of aGalCer and CpG-ODN adjuvants (TVAC) promoted clearance of HPV vaginal tumors via induction …

Long Trimer-Immunization Interval And Appropriate Adjuvant Reduce Immune Responses To The Soluble Hiv-1-Envelope Trimer Base, Hongying Duan, Angela R Corrigan, Cheng Cheng, Andrea Biju, Christopher A Gonelli, Adam S Olia, I-Ting Teng, Kai Xu, Sijy O'Dell, Sandeep Narpala, Mike Castro, Leonid Serebryannyy, Jennifer Wang, Danealle K Parchment, Edward K Sarfo, Jelle Van Schooten, John-Paul Todd, Shuishu Wang, Darcy R Harris, Hui Geng, Alexander J Jafari, Vrc Production Program, Ruth A Woodward, Nicole A Doria-Rose, Kathryn E Foulds, Adrian B Mcdermott, Marit J Van Gils, Richard A Koup, Theodore C Pierson, Peter D Kwong, John R Mascola

Faculty, Staff and Student Publications

Soluble 'SOSIP'-stabilized HIV-1 envelope glycoprotein (Env) trimers elicit dominant antibody responses targeting their glycan-free base regions, potentially diminishing neutralizing responses. Previously, using a nonhuman primate model, we demonstrated that priming with fusion peptide (FP)-carrier conjugate immunogens followed by boosting with Env trimers reduced the anti-base response. Further, we demonstrated that longer immunization intervals further reduced anti-base responses and increased neutralization breadth. Here, we demonstrate that long trimer-boosting intervals, but not long FP immunization intervals, reduce the anti-base response. Additionally, we identify that FP priming before trimer immunization enhances antibody avidity to the Env trimer. We also establish that adjuvants Matrix …

Strategies To Combine 3d Vasculature And Brain Cta With Deep Neural Networks: Application To Lvo, Uma M Lal-Trehan Estrada, Arnau Oliver, Sunil A Sheth, Xavier Lladó, Luca Giancardo

Faculty, Staff and Student Publications

Automated tools to detect large vessel occlusion (LVO) in acute ischemic stroke patients using brain computed tomography angiography (CTA) have been shown to reduce the time for treatment, leading to better clinical outcomes. There is a lot of information in a single CTA and deep learning models do not have an obvious way of being conditioned on areas most relevant for LVO detection, i.e., the vasculature structure. In this work, we compare and contrast strategies to make convolutional neural networks focus on the vasculature without discarding context information of the brain parenchyma and propose an attention-inspired strategy to encourage this. …

Predictive Criterion Validity Of The Parsley Symptom Index Against The Patient-Reported Outcomes Measurement Information System-10 In A Chronic Disease Cohort: Retrospective Cohort Study, Hants Williams, Sarah Steinberg, Kendall Leon, Ryan Vingum, Mengyao Hu, Robin Berzin, Heather Hagg, Patrick Hanaway

Faculty, Staff and Student Publications

BACKGROUND: Approximately 60% of US adults live with chronic disease, imposing a significant burden on patients and the health care system. With the rise of telehealth, patient-reported outcomes measures (PROMs) have emerged as pivotal tools for managing chronic disease. While numerous PROMs exist, few have been designed explicitly for telehealth settings. The Parsley Symptom Index (PSI) is an electronic patient-reported outcome measure (ePROM) developed specifically for telehealth environments.

OBJECTIVE: Our aim is to determine whether the PSI predicts changes in the established Patient-Reported Outcomes Measurement Information System-10 (PROMIS-10) Global Health, a 10-question short form.

METHODS: We conducted a retrospective cohort …

Strategies To Combine 3d Vasculature And Brain Cta With Deep Neural Networks: Application To Lvo, Uma M Lal-Trehan Estrada, Arnau Oliver, Sunil A Sheth, Xavier Lladó, Luca Giancardo

Faculty, Staff and Student Publications

Automated tools to detect large vessel occlusion (LVO) in acute ischemic stroke patients using brain computed tomography angiography (CTA) have been shown to reduce the time for treatment, leading to better clinical outcomes. There is a lot of information in a single CTA and deep learning models do not have an obvious way of being conditioned on areas most relevant for LVO detection, i.e., the vasculature structure. In this work, we compare and contrast strategies to make convolutional neural networks focus on the vasculature without discarding context information of the brain parenchyma and propose an attention-inspired strategy to encourage this. …

A Small Molecule With Big Impact: Mrtx1133 Targets The Krasg12d Mutation In Pancreatic Cancer, Daoyan Wei, Liang Wang, Xiangsheng Zuo, Anirban Maitra, Robert S Bresalier

Faculty, Staff and Student Publications

KRAS mutations drive oncogenic alterations in numerous cancers, particularly in human pancreatic ductal adenocarcinoma (PDAC). About 93% of PDACs have KRAS mutations, with G12D (∼42% of cases) and G12V (∼32% of cases) being the most common. The recent approval of sotorasib (AMG510), a small-molecule, covalent, and selective KRASG12C inhibitor, for treating patients with non-small cell lung cancer represents a breakthrough in KRAS targeted therapy. However, there is a need to develop other much-needed KRAS-mutant inhibitors for PDAC therapy. Notably, Mirati Therapeutics recently developed MRTX1133, a small-molecule, noncovalent, and selective KRASG12D inhibitor through extensive structure-based drug design. MRTX1133 has demonstrated potent …

Sting Licensing Of Type I Dendritic Cells Potentiates Antitumor Immunity, Jian Wang, Suxin Li, Maggie Wang, Xu Wang, Shuqing Chen, Zhichen Sun, Xiubao Ren, Gang Huang, Baran D Sumer, Nan Yan, Yang-Xin Fu, Jinming Gao

Faculty, Staff and Student Publications

Stimulator of interferon genes (STING) is an immune adaptor protein that senses cyclic GMP-AMP (cGAMP) in response to self or microbial cytosolic DNA as a danger signal. STING is ubiquitously expressed in diverse cell populations including cancer cells with distinct cellular functions such as activation of type I interferons, autophagy induction, or triggering apoptosis. It is not well understood whether and which subsets of immune cells, stromal cells, or cancer cells are particularly important for STING-mediated antitumor immunity. Here using a polymeric STING-activating nanoparticle (PolySTING) with a “shock-and-lock” dual activation mechanism, we show type 1 conventional dendritic cell (cDC1) is …

Mutant P53 Protects Triple-Negative Breast Adenocarcinomas From Ferroptosis In Vivo, Denada Dibra, Shunbin Xiong, Sydney M Moyer, Adel K El-Naggar, Yuan Qi, Xiaoping Su, Elisabeth K Kong, Anil Korkut, Guillermina Lozano

Faculty, Staff and Student Publications

The TP53 tumor suppressor gene is mutated early in most of the patients with triple-negative breast cancer (TNBC). The most frequent TP53 alterations are missense mutations that contribute to tumor aggressiveness. Here, we used an autochthonous somatic TNBC mouse model, in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53 to identify physiological dependencies on mutant p53. In TNBCs that develop in this model, deletion of two different hotspot p53R172H and p53R245W mutants triggers ferroptosis in vivo, a cell death mechanism involving iron-dependent lipid peroxidation. Mutant p53 protects cells …

Inter-Individual Variations In Circadian Misalignment-Induced Nafld Pathophysiology In Mice, Nobuya Koike, Yasuhiro Umemura, Hitoshi Inokawa, Isao Tokuda, Yoshiki Tsuchiya, Yuh Sasawaki, Atsushi Umemura, Naoko Masuzawa, Kazuya Yabumoto, Takashi Seya, Akira Sugimoto, Seung-Hee Yoo, Zheng Chen, Kazuhiro Yagita

Faculty, Staff and Student Publications

Pathological consequences of circadian misalignment, such as shift work, show considerable individual differences, but the lack of mechanistic understanding hinders precision prevention to prevent and mitigate disease symptoms. Here, we employed an integrative approach involving physiological, transcriptional, and histological phenotypes to examine inter-individual differences in pre-symptomatic pathological progression, preceding irreversible disease onset, in wild-type mice exposed to chronic jet-lag (CJL). We observed that CJL markedly increased the prevalence of hepatic steatosis with pronounced inter-individual differences. Stratification of individual mice based on CJL-induced hepatic transcriptomic signature, validated by histopathological analysis, pinpoints dysregulation of lipid metabolism. Moreover, the period and power of …

Backfilling Patients In Phase I Dose-Escalation Trials Using Bayesian Optimal Interval Design (Boin), Yixuan Zhao, Ying Yuan, Edward L Korn, Boris Freidlin

Faculty, Staff and Student Publications

In recent years, there has been increased interest in incorporation of backfilling into dose-escalation clinical trials, which involves concurrently assigning patients to doses that have been previously cleared for safety by the dose-escalation design. Backfilling generates additional information on safety, tolerability, and preliminary activity on a range of doses below the maximum tolerated dose (MTD), which is relevant for selection of the recommended phase II dose and dose optimization. However, in practice, backfilling may not be rigorously defined in trial protocols and implemented consistently. Furthermore, backfilling designs require careful planning to minimize the probability of treating additional patients with potentially …

Neoadjuvant Trebananib Plus Paclitaxel-Based Chemotherapy For Stage Ii/Iii Breast Cancer In The Adaptively Randomized I-Spy2 Trial-Efficacy And Biomarker Discovery, Kathy S Albain, Christina Yau, Emanuel F Petricoin, Denise M Wolf, Julie E Lang, A Jo Chien, Tufia Haddad, Andres Forero-Torres, Anne M Wallace, Henry Kaplan, Lajos Pusztai, David Euhus, Rita Nanda, Anthony D Elias, Amy S Clark, Constantine Godellas, Judy C Boughey, Claudine Isaacs, Debu Tripathy, Janice Lu, Rachel L Yung, Rosa I Gallagher, Julia D Wulfkuhle, Lamorna Brown-Swigart, Gregor Krings, Yunn Yi Chen, David A Potter, Erica Stringer-Reasor, Sarah Blair, Smita M Asare, Amy Wilson, Gillian L Hirst, Ruby Singhrao, Meredith Buxton, Julia L Clennell, Ashish Sanil, Scott Berry, Adam L Asare, Jeffrey B Matthews, Angela M Demichele, Nola M Hylton, Michelle Melisko, Jane Perlmutter, Hope S Rugo, W Fraser Symmans, Laura J Van't Veer, Douglas Yee, Donald A Berry, Laura J Esserman

Faculty, Staff and Student Publications

Purpose: The neutralizing peptibody trebananib prevents angiopoietin-1 and angiopoietin-2 from binding with Tie2 receptors, inhibiting angiogenesis and proliferation. Trebananib was combined with paclitaxel±trastuzumab in the I-SPY2 breast cancer trial.

Patients and methods: I-SPY2, a phase II neoadjuvant trial, adaptively randomizes patients with high-risk, early-stage breast cancer to one of several experimental therapies or control based on receptor subtypes as defined by hormone receptor (HR) and HER2 status and MammaPrint risk (MP1, MP2). The primary endpoint is pathologic complete response (pCR). A therapy "graduates" if/when it achieves 85% Bayesian probability of success in a phase III trial within a given subtype. …

Circulating Microrna Panel For Prediction Of Recurrence And Survival In Early-Stage Lung Adenocarcinoma, Mei-Chee Tai, Leonidas E Bantis, Gargy Parhy, Taketo Kato, Ichidai Tanaka, Chi-Wan Chow, Junya Fujimoto, Carmen Behrens, Tetsunari Hase, Koji Kawaguchi, Johannes F Fahrmann, Edwin J Ostrin, Kohei Yokoi, Toyofumi F Chen-Yoshikawa, Yoshinori Hasegawa, Samir M Hanash, Ignacio I Wistuba, Ayumu Taguchi

Faculty, Staff and Student Publications

Early-stage lung adenocarcinoma (LUAD) patients remain at substantial risk for recurrence and disease-related death, highlighting the unmet need of biomarkers for the assessment and identification of those in an early stage who would likely benefit from adjuvant chemotherapy. To identify circulating miRNAs useful for predicting recurrence in early-stage LUAD, we performed miRNA microarray analysis with pools of pretreatment plasma samples from patients with stage I LUAD who developed recurrence or remained recurrence-free during the follow-up period. Subsequent validation in 85 patients with stage I LUAD resulted in the development of a circulating miRNA panel comprising miR-23a-3p, miR-320c, and miR-125b-5p and …

Development Of A Practical Nomogram For Personalized Anemia Management In Patients Treated With Ataxia Telangiectasia And Rad3-Related Inhibitor Camonsertib, Ezra Rosen, Timothy A Yap, Elizabeth K Lee, Martin Højgaard, Niharika B Mettu, Stephanie Lheureux, Benedito A Carneiro, Ruth Plummer, Adrian J Fretland, Danielle Ulanet, Yi Xu, Robin Mcdougall, Maria Koehler, Elisa Fontana

Faculty, Staff and Student Publications

PURPOSE: Camonsertib is a highly selective and potent inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase. Dose-dependent anemia is a class-related on-target adverse event often requiring dose modifications. Individual patient risk factors for the development of significant anemia complicate the selection of a "one-size-fits-all" ATR inhibitor (ATRi) dose and schedule, possibly leading to suboptimal therapeutic doses in patients at low risk of anemia. We evaluated whether early predictors of anemia could be identified to ultimately inform a personalized dose-modification approach.

PATIENTS AND METHODS: On the basis of preclinical observations and a mechanistic understanding of ATRi-related anemia, we identified several potential …

Serum Biomarker Signature Is Predictive Of The Risk Of Hepatocellular Cancer In Patients With Cirrhosis, Hashem El-Serag, Fasiha Kanwal, Jing Ning, Hannah Powell, Saira Khaderi, Amit G Singal, Sumeet Asrani, Jorge A Marrero, Christopher I Amos, Aaron P Thrift, Michelle Luster, Abeer Alsarraj, Luis Olivares, Darlene Skapura, Jenny Deng, Emad Salem, Omar Najjar, Xian Yu, Hao Duong, Michael E Scheurer, Christie M Ballantyne, Salma Kaochar

Faculty, Staff and Student Publications

BACKGROUND: Inflammatory and metabolic biomarkers have been associated with hepatocellular cancer (HCC) risk in phases I and II biomarker studies. We developed and internally validated a robust metabolic biomarker panel predictive of HCC in a longitudinal phase III study.

METHODS: We used data and banked serum from a prospective cohort of 2266 adult patients with cirrhosis who were followed until the development of HCC (n=126). We custom designed a FirePlex immunoassay to measure baseline serum levels of 39 biomarkers and established a set of biomarkers with the highest discriminatory ability for HCC. We performed bootstrapping to evaluate the predictive performance …

Generalizable Pipeline For Constructing Hiv Risk Prediction Models Across Electronic Health Record Systems, Sarah B May, Thomas P Giordano, Assaf Gottlieb

Faculty, Staff and Student Publications

OBJECTIVE: The HIV epidemic remains a significant public health issue in the United States. HIV risk prediction models could be beneficial for reducing HIV transmission by helping clinicians identify patients at high risk for infection and refer them for testing. This would facilitate initiation on treatment for those unaware of their status and pre-exposure prophylaxis for those uninfected but at high risk. Existing HIV risk prediction algorithms rely on manual construction of features and are limited in their application across diverse electronic health record systems. Furthermore, the accuracy of these models in predicting HIV in females has thus far been …

Cyp2a6 Activity And Cigarette Consumption Interact In Smoking-Related Lung Cancer Susceptibility, Mulong Du, Junyi Xin, Rui Zheng, Qianyu Yuan, Zhihui Wang, Hongliang Liu, Hanting Liu, Guoshuai Cai, Demetrius Albanes, Stephen Lam, Adonina Tardon, Chu Chen, Stig E Bojesen, Maria Teresa Landi, Mattias Johansson, Angela Risch, Heike Bickeböller, H-Erich Wichmann, Gad Rennert, Susanne Arnold, Paul Brennan, John K Field, Sanjay S Shete, Loïc Le Marchand, Geoffrey Liu, Angeline S Andrew, Lambertus A Kiemeney, Shan Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil E Caporaso, Angela Cox, Yun-Chul Hong, Jian-Min Yuan, Matthew B Schabath, Melinda C Aldrich, Meilin Wang, Hongbing Shen, Feng Chen, Zhengdong Zhang, Rayjean J Hung, Christopher I Amos, Qingyi Wei, Philip Lazarus, David C Christiani

Faculty, Staff and Student Publications

Cigarette smoke, containing both nicotine and carcinogens, causes lung cancer. However, not all smokers develop lung cancer, highlighting the importance of the interaction between host susceptibility and environmental exposure in tumorigenesis. Here, we aimed to delineate the interaction between metabolizing ability of tobacco carcinogens and smoking intensity in mediating genetic susceptibility to smoking-related lung tumorigenesis. Single-variant and gene-based associations of 43 tobacco carcinogen-metabolizing genes with lung cancer were analyzed using summary statistics and individual-level genetic data, followed by causal inference of Mendelian randomization, mediation analysis, and structural equation modeling. Cigarette smoke-exposed cell models were used to detect gene expression patterns …

Risk Of Chronic Health Conditions In Lesbian, Gay, And Bisexual Survivors Of Adolescent And Young Adult Cancers, Amy M Berkman, Eunju Choi, Christabel K Cheung, John M Salsman, Susan K Peterson, Clark R Andersen, Qian Lu, J Andrew Livingston, Michelle A T Hildebrandt, Susan K Parsons, Michael E Roth

Faculty, Staff and Student Publications

BACKGROUND: In the general population, individuals with minoritized sexual orientation and gender identity have a higher burden of chronic health conditions than heterosexual individuals. However, the extent to which sexual orientation is associated with excess burden of chronic conditions in adolescent and young adult cancer survivors (AYACS) is unknown.

METHODS: Lesbian, gay, and bisexual (LGB) AYACSs, LGB individuals without a history of cancer, and heterosexual AYACSs were identified by self-reported data from the cross-sectional National Health Interview Survey (2013-2020). Socioeconomic factors and the prevalence of chronic health conditions were compared between groups using χ

RESULTS: One hundred seventy LGB cancer …

Aloe Vera Assisted Green Synthesis Of Ag And Cu Co-Doped Zno Nanoparticles And A Comprehensive Analysis Of Their Structural, Morphological, Optical, Electrical And Antibacterial Properties, Md Hasnat Rashid, Saiful Islam Sujoy, Md Saifur Rahman, Md Jahidul Haque

Faculty, Staff and Student Publications

This study investigates the potential of utilizing Aloe vera-assisted green synthesis with transition metal dopants of Ag and Cu for greater efficiency and sustainability in advanced scientific applications utilizing ZnO nanoparticles. Samples were prepared using the co-precipitation method, maintaining a basic pH media of 10. Aloe vera gel extract was chosen for its acclaimed role as a stabilizing and reducing agent and its proven antioxidant, antibacterial, and anticancer properties. The XRD report revealed the hexagonal Wurtzite crystal structure of nanoparticles, exhibiting a crystallite size range of 17-23 nm with substantial alterations in lattice parameters, dislocation density, and bond lengths when …

Effect Of Multiple Quantum Well Periods On Structural Properties And Performance Of Extended Short-Wavelength Infrared Leds, Phuc Dinh Nguyen, Minkyeong Kim, Yeongho Kim, Jiyeon Jeon, Suho Park, Chang Soo Kim, Quang Liem Nguyen, Byong Sun Chun, Sang Jun Lee

Faculty, Staff and Student Publications

We present research on the role of multiple quantum well periods in extended short-wavelength infrared InGaAs/InAsPSb type-I LEDs. The fabricated LEDs consisted of 6, 15, and 30 quantum well periods, and we evaluated the structural properties and device performance through a combination of theoretical simulations and experimental characterization. The strain and energy band offset was precisely controlled by carefully adjusting the composition of the InAsPSb quaternary material, achieving high valence and conduction band offsets of 350 meV and 94 meV, respectively. Our LEDs demonstrated a high degree of relaxation of 94-96 %. Additionally, we discovered that the temperature-dependent dark current …

Small Airways In Non-Cystic Fibrosis Bronchiectasis, John D Dickinson, Christopher M Evans, Burton F Dickey

Faculty, Staff and Student Publications

No abstract provided.

A Mutation In F-Actin Polymerization Factor Suppresses The Distal Arthrogryposis Type 5 Piezo2 Pathogenic Variant In Caenorhabditis Elegans, Xiaofei Bai, Harold E Smith, Luis O Romero, Briar Bell, Valeria Vásquez, Andy Golden

Faculty, Staff and Student Publications

The mechanosensitive PIEZO channel family has been linked to over 26 disorders and diseases. Although progress has been made in understanding these channels at the structural and functional levels, the underlying mechanisms of PIEZO-associated diseases remain elusive. In this study, we engineered four PIEZO-based disease models using CRISPR/Cas9 gene editing. We performed an unbiased chemical mutagen-based genetic suppressor screen to identify putative suppressors of a conserved gain-of-function variant pezo-1[R2405P] that in human PIEZO2 causes distal arthrogryposis type 5 (DA5; p. R2718P). Electrophysiological analyses indicate that pezo-1(R2405P) is a gain-of-function allele. Using genomic mapping and whole-genome sequencing approaches, we identified a …

Slc25a39 Links Mitochondrial Gsh Sensing With Iron Metabolism, Xiong Chen, Boyi Gan

Faculty, Staff and Student Publications

Two recent studies by Liu et al.1 in Science and Shi et al.2 in this issue of Molecular Cell identify a mitochondrial GSH-sensing mechanism that couples SLC25A39-mediated GSH import to iron metabolism, advancing our understanding of nutrient sensing within organelles.

Structural Insights Into The Molecular Mechanism Of High-Level Ceftazidime-Avibactam Resistance Conferred By Cmy-185, Akito Kawai, William C Shropshire, Masahiro Suzuki, Jovan Borjan, Samuel L Aitken, William C Bachman, Christi L Mcelheny, Micah M Bhatti, Ryan K Shields, Samuel A Shelburne, Yohei Doi

Faculty, Staff and Student Publications

β-Lactamases can accumulate stepwise mutations that increase their resistance profiles to the latest β-lactam agents. CMY-185 is a CMY-2-like β-lactamase and was identified in an Escherichia coli clinical strain isolated from a patient who underwent treatment with ceftazidime-avibactam. CMY-185, possessing four amino acid substitutions of A114E, Q120K, V211S, and N346Y relative to CMY-2, confers high-level ceftazidime-avibactam resistance, and accumulation of the substitutions incrementally enhances the level of resistance to this agent. However, the functional role of each substitution and their interplay in enabling ceftazidime-avibactam resistance remains unknown. Through biochemical and structural analysis, we present the molecular basis for the enhanced …

Frequency Specific Optogenetic Stimulation Of The Locus Coeruleus Induces Task-Relevant Plasticity In The Motor Cortex, Ching-Tzu Tseng, Hailey F Welch, Ashley L Gi, Erica Mina Kang, Tanushree Mamidi, Sahiti Pydimarri, Kritika Ramesh, Alfredo Sandoval, Jonathan E Ploski, Catherine A Thorn

Faculty, Staff and Student Publications

The locus ceruleus (LC) is the primary source of neocortical noradrenaline, which is known to be involved in diverse brain functions including sensory perception, attention, and learning. Previous studies have shown that LC stimulation paired with sensory experience can induce task-dependent plasticity in the sensory neocortex and in the hippocampus. However, it remains unknown whether LC activation similarly impacts neural representations in the agranular motor cortical regions that are responsible for movement planning and production. In this study, we test whether optogenetic stimulation of the LC paired with motor performance is sufficient to induce task-relevant plasticity in the somatotopic cortical …

Drug Resistance Assessed In A Phase 3 Clinical Trial Of Maribavir Therapy For Refractory Or Resistant Cytomegalovirus Infection In Transplant Recipients, Sunwen Chou, Sophie Alain, Carlos Cervera, Roy F Chemaly, Camille N Kotton, Jens Lundgren, Genovefa A Papanicolaou, Marcus R Pereira, Jingyang J Wu, Rose Ann Murray, Neil E Buss, Martha Fournier

Faculty, Staff and Student Publications

Background: This drug resistance analysis of a randomized trial includes 234 patients receiving maribavir and 116 receiving investigator-assigned standard therapy (IAT), where 56% and 24%, respectively, cleared cytomegalovirus DNA at week 8 (treatment responders).

Methods: Baseline and posttreatment plasma samples were tested for mutations conferring drug resistance in viral genes UL97, UL54, and UL27.

Results: At baseline, genotypic testing revealed resistance to ganciclovir, foscarnet, or cidofovir in 56% of patients receiving maribavir and 68% receiving IAT, including 9 newly phenotyped mutations. Among them, 63% (maribavir) and 21% (IAT) were treatment responders. Detected baseline maribavir resistance mutations were UL27 L193F (n …

Multifaceted Roles For Stat3 In Gammaherpesvirus Latency Revealed Through In Vivo B Cell Knockout Models, Chad H Hogan, Shana M Owens, Glennys V Reynoso, Yifei Liao, Thomas J Meyer, Monika A Zelazowska, Bin Liu, Xiaofan Li, Anna K Grosskopf, Camille Khairallah, Varvara Kirillov, Nancy C Reich, Brian S Sheridan, Kevin M Mcbride, Benjamin E Gewurz, Heather D Hickman, J Craig Forrest, Laurie T Krug

Faculty, Staff and Student Publications

Cancers associated with the oncogenic gammaherpesviruses, Epstein-Barr virus and Kaposi sarcoma herpesvirus, are notable for their constitutive activation of the transcription factor signal transducer and activator of transcription 3 (STAT3). To better understand the role of STAT3 during gammaherpesvirus latency and the B cell response to infection, we used the model pathogen murine gammaherpesvirus 68 (MHV68). Genetic deletion of STAT3 in B cells of CD19cre/+Stat3f/f mice reduced peak MHV68 latency approximately sevenfold. However, infected CD19cre/+Stat3f/f mice exhibited disordered germinal centers and heightened virus-specific CD8 T cell responses compared to wild-type (WT) littermates. To circumvent the systemic immune alterations observed in …

Synergic Effect Of Cai2 And Lii On Ionic Conductivity Of Solution-Based Synthesized Li7p3s11 Solid Electrolyte†, Tran Anh Tu, Tran Viet Toan, Luu Tuan Anh, Le Van Thang, Nguyen Huu Huy Phuc

Faculty, Staff and Student Publications

Li7P3S11 doped with CaX2 (X = Cl, Br, I) and LiI solid electrolytes were successfully prepared by liquid-phase synthesis using acetonitrile as the reaction medium. Their structure was investigated using XRD, Raman spectroscopy and SEM-EDS. The data obtained from complex impedance spectroscopy was analyzed to study the ionic conductivity and relaxation dynamics in the prepared samples. The XRD results suggested that a part of CaX2 and LiI incorporated into the structure of Li7P3S11, while the remaining part existed at the grain boundary of the Li7P3S11 particle. The Raman peak positions of PS43- and P2S74- ions in samples 90Li7P3S11-5CaI2 and 90Li7P3S11-5CaI2-5LiI …

Sugar-Binding And Split Domain Combinations In Repeats-In-Toxin Adhesins From Vibrio Cholerae And Aeromonas Veronii Mediate Cell-Surface Recognition And Hemolytic Activities, Mustafa Sherik, Robert Eves, Shuaiqi Guo, Cameron J Lloyd, Karl E Klose, Peter L Davies

Faculty, Staff and Student Publications

Many pathogenic Gram-negative bacteria use repeats-in-toxin adhesins for colonization and biofilm formation. In the cholera agent Vibrio cholerae, flagellar-regulated hemagglutinin A (FrhA) enables these functions. Using bioinformatic analysis, a sugar-binding domain was identified in FrhA adjacent to a domain of unknown function. AlphaFold2 indicated the boundaries of both domains to be slightly shorter than previously predicted and assisted in the recognition of the unknown domain as a split immunoglobulin-like fold that can assist in projecting the sugar-binding domain toward its target. The AlphaFold2-predicted structure is in excellent agreement with the molecular envelope obtained from small-angle X-ray scattering analysis of …

The Il6/Jak/Stat3 Signaling Axis Is A Therapeutic Vulnerability In Smarcb1-Deficient Bladder Cancer, Chandra Sekhar Amara, Karthik Reddy Kami Reddy, Yang Yuntao, Yuen San Chan, Danthasinghe Waduge Badrajee Piyarathna, Lacey Elizabeth Dobrolecki, David J H Shih, Zhongcheng Shi, Jun Xu, Shixia Huang, Matthew J Ellis, Andrea B Apolo, Leomar Y Ballester, Jianjun Gao, Donna E Hansel, Yair Lotan, H Courtney Hodges, Seth P Lerner, Chad J Creighton, Arun Sreekumar, W Jim Zheng, Pavlos Msaouel, Shyam M Kavuri, Nagireddy Putluri

Faculty, Staff and Student Publications

SMARCB1 loss has long been observed in many solid tumors. However, there is a need to elucidate targetable pathways driving growth and metastasis in SMARCB1-deficient tumors. Here, we demonstrate that SMARCB1 deficiency, defined as genomic SMARCB1 copy number loss associated with reduced mRNA, drives disease progression in patients with bladder cancer by engaging STAT3. SMARCB1 loss increases the chromatin accessibility of the STAT3 locus in vitro. Orthotopically implanted SMARCB1 knockout (KO) cell lines exhibit increased tumor growth and metastasis. SMARCB1-deficient tumors show an increased IL6/JAK/STAT3 signaling axis in in vivo models and patients. Furthermore, a pSTAT3 selective inhibitor, TTI-101, reduces …