Digital Commons Network^™

Bispecific Antibodies And Autologous Chimeric Antigen Receptor T Cell Therapies For Treatment Of Hematological Malignancies, Samer Al Hadidi, Helen E Heslop, Malcolm K Brenner, Masataka Suzuki

Faculty, Staff and Students Publications

In recent years, the therapeutic landscape for hematological malignancies has markedly advanced, particularly since the inaugural approval of autologous chimeric antigen receptor T cell (CAR-T) therapy in 2017 for relapsed/refractory acute lymphoblastic leukemia (ALL). Autologous CAR-T therapy involves the genetic modification of a patient's T cells to specifically identify and attack cancer cells, while bispecific antibodies (BsAbs) function by binding to both cancer cells and immune cells simultaneously, thereby triggering an immune response against the tumor. The subsequent approval of various CAR-T therapies and BsAbs have revolutionized the treatment of multiple hematological malignancies, highlighting high response rates and a subset …

A Machine Learning Model For Risk Stratification Of Postdiagnosis Diabetic Ketoacidosis Hospitalization In Pediatric Type 1 Diabetes: Retrospective Study, Devika Subramanian, Rona Sonabend, Ila Singh

Faculty, Staff and Students Publications

BACKGROUND: Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in pediatric type 1 diabetes (T1D), occurring in approximately 20% of patients, with an economic cost of $5.1 billion/year in the United States. Despite multiple risk factors for postdiagnosis DKA, there is still a need for explainable, clinic-ready models that accurately predict DKA hospitalization in established patients with pediatric T1D.

OBJECTIVE: We aimed to develop an interpretable machine learning model to predict the risk of postdiagnosis DKA hospitalization in children with T1D using routinely collected time-series of electronic health record (EHR) data.

METHODS: We conducted a retrospective case-control …

Whole Genome Sequencing Based Analysis Of Inflammation Biomarkers In The Trans-Omics For Precision Medicine (Topmed) Consortium, Min-Zhi Jiang, Sheila M Gaynor, Xihao Li, Eric Van Buren, Adrienne Stilp, Erin Buth, Fei Fei Wang, Regina Manansala, Stephanie M Gogarten, Zilin Li, Linda M Polfus, Shabnam Salimi, Joshua C Bis, Nathan Pankratz, Lisa R Yanek, Peter Durda, Russell P Tracy, Stephen S Rich, Jerome I Rotter, Braxton D Mitchell, Joshua P Lewis, Bruce M Psaty, Katherine A Pratte, Edwin K Silverman, Robert C Kaplan, Christy Avery, Kari E North, Rasika A Mathias, Nauder Faraday, Honghuang Lin, Biqi Wang, April P Carson, Arnita F Norwood, Richard A Gibbs, Charles Kooperberg, Jessica Lundin, Ulrike Peters, Josée Dupuis, Lifang Hou, Myriam Fornage, Emelia J Benjamin, Alexander P Reiner, Russell P Bowler, Xihong Lin, Paul L Auer, Laura M Raffield, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Topmed Inflammation Working Group

Faculty, Staff and Student Publications

Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38 465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program (with varying sample size by trait, where the minimum sample size was n = 737 for MMP-1). We identified 22 distinct single-variant …

Poly(Adp-Ribose) Polymerase-1 Regulates Pyroptosis Independent Function Of Nlrp3 Inflammasome In Neutrophil Extracellular Trap Formation, Louis J Delinois, Atul Sharma, Ashwin K Ramesh, Laurel D Boatright, Qun Li, Rong Xu, Hongbo R Luo, Bibhuti B Mishra, Jyotika Sharma

Faculty, Staff and Student Publications

Neutrophil extracellular traps (NETs) function to control infectious agents as well as to propagate inflammatory response in a variety of disease conditions. DNA damage associated with chromatin decondensation and NACHT domain-leucine-rich repeat-and pyrin domain-containing protein 3 (NLRP3) inflammasome activation have emerged as crucial events in NET formation, but the link between the two processes is unknown. In this study, we demonstrate that poly(ADP-ribose) polymerase-1 (PARP-1), a key DNA repair enzyme, regulates NET formation triggered by NLRP3 inflammasome activation in neutrophils. Activation of mouse neutrophils with canonical NLRP3 stimulants LPS and nigericin induced NET formation, which was significantly abrogated by pharmacological …

Autophagic Signaling Promotes Systems-Wide Remodeling In Skeletal Muscle Upon Oncometabolic Stress By D2-Hg, Yaqi Gao, Kyoungmin Kim, Heidi Vitrac, Rebecca L Salazar, Benjamin D Gould, Daniel Soedkamp, Weston Spivia, Koen Raedschelders, An Q Dinh, Anna G Guzman, Lin Tan, Stavros Azinas, David J R Taylor, Walter Schiffer, Daniel Mcnavish, Helen B Burks, Roberta A Gottlieb, Philip L Lorenzi, Blake M Hanson, Jennifer E Van Eyk, Heinrich Taegtmeyer, Anja Karlstaedt

Faculty, Staff and Student Publications

OBJECTIVES: Cachexia is a metabolic disorder and comorbidity with cancer and heart failure. The syndrome impacts more than thirty million people worldwide, accounting for 20% of all cancer deaths. In acute myeloid leukemia, somatic mutations of the metabolic enzyme isocitrate dehydrogenase 1 and 2 cause the production of the oncometabolite D2-hydroxyglutarate (D2-HG). Increased production of D2-HG is associated with heart and skeletal muscle atrophy, but the mechanistic links between metabolic and proteomic remodeling remain poorly understood. Therefore, we assessed how oncometabolic stress by D2-HG activates autophagy and drives skeletal muscle loss.

METHODS: We quantified genomic, metabolomic, and proteomic changes in …

Addendum: A Small Molecule Produced By Lactobacillus Species Blocks Candida Albicans Filamentation By Inhibiting A Dyrk1-Family Kinase, Jessie Macalpine, Martin Daniel-Ivad, Zhongle Liu, Junko Yano, Nicole M. Revie, Robert T. Todd, Peter J. Stogios, Hiram Sanchez, Teresa R. O'Meara, Thomas A. Tompkins, Alexei Savchenko, Anna Selmecki, Amanda O. Veri, David R. Andes, Paul L. Fidel, Nicole Robbins, Justin Nodwell, Luke Whitesell, Leah E. Cowen

School of Dentistry Faculty Publications

No abstract provided.

Detection Of Soil-Transmitted Helminths And Schistosoma Spp By Nucleic Acid Amplification Test: Results Of The First 5 Years Of The Only International External Quality Assessment Scheme, Annemiek H J Schutte, Rob Koelewijn, Sitara S R Ajjampur, Bruno Levecke, James S Mccarthy, Rojelio Mejia, Steven A Williams, Jaco J Verweij, Lisette Van Lieshout, Jaap J Van Hellemond

Faculty, Staff and Students Publications

BACKGROUND: Infections with soil-transmitted helminths (STH) and schistosomiasis (SCH) result in a significant global health burden, particularly in rural communities in low and middle-income countries. While microscopy remains the primary diagnostic method for STH and SCH in resource-limited settings, nucleic acid amplification tests (NAATs) are gaining prominence as tools for evaluation of public health control programs in endemic countries, and individual diagnosis in high-income countries. Despite the high sensitivity and specificity of NAATs, previous research has highlighted inter-laboratory variations, both in technical and clinical performance, justifying the need for continuous proficiency testing.

METHODOLOGY: Results from 5 rounds over a 5-year …

Treatments And The Perspectives Of Developing A Vaccine For Chagas Disease, Priscila Silva Grijó Farani, Kathryn Marie Jones, Cristina Poveda

Faculty, Staff and Students Publications

Chagas disease (CD) treatment and vaccine development are critical due to the significant health burden caused by the disease, especially in Latin America. Current treatments include benznidazole and nifurtimox, which are most effective in the acute phase of the disease but less so in the chronic phase, often with significant side effects. Here, using the available literature, we summarize the progress in vaccine development and new treatments that promise to reduce CD incidence and improve the quality of life for those at risk, particularly in endemic regions. New treatment options, such as posaconazole and fexinidazole, are being explored to improve …

Herpes Vegetans In A Patient With Acquired Immunodeficiency Syndrome (Aids) In The Setting Of Immune Reconstitution Inflammatory Syndrome, Angelique Ruml, Ibeth Caceres, Anna Catinis, Theodore Rosen

Faculty, Staff and Students Publications

Herpes simplex virus (HSV) infections classically present as a vesicular eruption on an erythematous base; however, viral infections may present much differently in the setting of immune deficiency. Herpes vegetans is an atypical presentation of HSV that occurs in immunocompromised patients, typically those with human immunodeficiency virus infection and acquired immunodeficiency syndrome (AIDS). Herpes vegetans is characterized by hyperkeratotic, exophytic, and, sometimes, ulcerated nodules, often with a chronic and persistent course. Herein, we present an interesting example of biopsy-confirmed anogenital herpes vegetans in a 61-year-old male with AIDS in the setting of immune reconstitution inflammatory syndrome, an association that is …

The Role Of An Ultraconserved Long Non-Coding Rna In B-Cell Lymphomagenesis, Swati Mohapatra

Dissertations and Theses (Open Access)

Ultraconserved regions (UCRs) are genomic segments with perfect (100%) conservation between the orthologous regions of human, rat, and mouse genomes. UCRs can be transcribed into mono-exonic long non-coding RNAs (lncRNAs) known as transcribed ultraconserved regions (T-UCRs). These regions, despite lacking protein-coding potential, are increasingly recognized for their regulatory roles in gene expression, including the modulation of non-coding RNA (ncRNA) transcripts. NcRNAs play crucial roles in cellular processes, including oncogenic transformation, with emerging evidence revealing their ability to encode small peptides known as ncRNA-encoded peptides (ncPEPs). These peptides, originating from small open reading frames (smORFs), contribute to diverse cellular functions and …

Accelerated Tumor Progression After Covid-19 Infection In Patients With Glioblastoma: A Retrospective Case-Control Study, Timothy A Gregory, Stephanie R Knight, Ashley E Aaroe, Kaitlin N Highsmith, Zachary C Janatpour, Barbara J O'Brien, Nazanin K Majd, Monica E Loghin, Chirag B Patel, Shiao-Pei Weathers, Vinay K Puduvalli, Carlos Kamiya-Matsuoka

Faculty, Staff and Student Publications

Background: We observed rapid tumor progression following COVID-19 infection among patients with glioblastoma and sought to systematically characterize their disease course in a retrospective case-control study.

Methods: Using an institutional database, we retrospectively identified a series of COVID-19-positive glioblastoma cases and matched them by age and sex 1:2 to glioblastoma controls who had a negative COVID-19 test during their disease course. Demographic and clinical data were analyzed. Hyperprogression was defined using modified response evaluation criteria in solid tumors criteria. Time to progression and overall survival were estimated using the Kaplan-Meier method.

Results: Thirty-two glioblastoma cases with positive COVID-19 testing were …

Candida Albicans Natural Diversity: A Resource To Dissect Fungal Commensalism And Pathogenesis, Elena Lindemann-Perez, J Christian Perez

Faculty, Staff and Student Publications

Candida albicans is a ubiquitous fungus of humans. It is not only a component of the oral and intestinal microbiota of most healthy adults but also a major cause of mucosal disorders and life-threatening disseminated infections. Until recently, research on the biology and pathogenesis of the fungus was largely based on a single clinical isolate. We review investigations that have started to dissect a diverse set of C. albicans strains. Using different approaches to leverage the species' phenotypic and/or genetic diversity, these studies illuminate the wide range of interactions between fungus and host. While connecting genetic variants to phenotypes of …

Central Irf4/5 Signaling Are Critical For Microglial Activation And Impact On Stroke Outcomes, Conelius Ngwa, Abdullah Al Mamun, Shaohua Qi, Romana Sharmeen, Maria P Blasco Conesa, Bhanu P Ganesh, Bharti Manwani, Fudong Liu

Faculty, Staff and Student Publications

Microglia and monocytes play a critical role in immune responses to cerebral ischemia. Previous studies have demonstrated that interferon regulatory factor 4 (IRF4) and IRF5 direct microglial polarization after stroke and impact outcomes. However, IRF4/5 are expressed by both microglia and monocytes, and it is not clear if it is the microglial (central) or monocytic (peripheral) IRF4-IRF5 regulatory axis that functions in stroke. In this work, young (8-12 weeks) male pep boy (PB), IRF4 or IRF5 flox, and IRF4 or IRF5 conditional knockout (CKO) mice were used to generate 8 types of bone marrow chimeras, to differentiate the role of …

The Surgical Infection Society Guidelines On The Management Of Intra-Abdominal Infection: 2024 Update, Jared M Huston, Philip S Barie, E Patchen Dellinger, Joseph D Forrester, Therese M Duane, Jeffrey M Tessier, Robert G Sawyer, Miguel A Cainzos, Kemal Rasa, Jeffrey G Chipman, Lillian S Kao, Frederic M Pieracci, Kristin P Colling, Daithi S Heffernan, Janice Lester

Faculty, Staff and Student Publications

Background: The Surgical Infection Society (SIS) published evidence-based guidelines for the management of intra-abdominal infection (IAI) in 1992, 2002, 2010, and 2017. Here, we present the most recent guideline update based on a systematic review of current literature.

Methods: The writing group, including current and former members of the SIS Therapeutics and Guidelines Committee and other individuals with content or guideline expertise within the SIS, working with a professional librarian, performed a systematic review using PubMed/Medline, the Cochrane Library, Embase, and Web of Science from 2016 until February 2024. Keyword descriptors combined "surgical site infections" or "intra-abdominal infections" in adults …

Vertebrate And Invertebrate Animal Infection Models Of Candida Auris Pathogenicity, Melissa Martinez, Danielle A Garsin, Michael C Lorenz

Faculty, Staff and Student Publications

Candida auris is an emerging fungal pathogen with several concerning qualities. First recognized in 2009, it has arisen in multiple geographically distinct genomic clades nearly simultaneously. C. auris strains are typically multidrug resistant and colonize the skin much better than most other pathogenic fungi; it also persists on abiotic surfaces, enabling outbreaks due to transmission in health care facilities. All these suggest a biology substantially different from the 'model' fungal pathogen, Candida albicans and support intensive investigation of C. auris biology directly. To uncover novel virulence mechanisms in this species requires the development of appropriate animal infection models. Various studies …

Myeloablation Followed By Hematopoietic Stem Cell Transplantation And Long-Term Normalization Of Systemic Sclerosis Molecular Signatures, Nancy Wareing, Xuan Wang, Lynette Keyes-Elstein, Ellen A Goldmuntz, Marka A Lyons, Peter Mcsweeney, Daniel E Furst, Richard A Nash, Leslie J Crofford, Beverly Welch, Ashley Pinckney, Maureen D Mayes, Keith M Sullivan, Shervin Assassi

Faculty, Staff and Student Publications

Objective: In the randomized Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial, myeloablation, followed by hematopoietic stem cell transplantation (HSCT), led to the normalization of systemic sclerosis (SSc) peripheral blood cell (PBC) gene expression signature at the 26-month visit. Herein, we examined long-term molecular changes ensuing 54 months after randomization for individuals receiving an HSCT or 12 months of intravenous cyclophosphamide (CYC).

Methods: Global PBC transcript studies were performed in study participants at pretreatment baseline and at 38 months and 54 months after randomization, as well as in healthy controls using Illumina HT-12 arrays.

Results: Thirty (HSCT = 19 and CYC = …

Enolase Inhibitors As Therapeutic Leads For Naegleria Fowleri Infection, Jillian E Milanes, Victoria C Yan, Cong-Dat Pham, Florian Muller, Samuel Kwain, Kerrick C Rees, Brian N Dominy, Daniel C Whitehead, Steven W Millward, Madison Bolejack, Roger Shek, Logan Tillery, Isabelle Q Phan, Bart Staker, E Ashley Moseman, Xiang Zhang, Xipeng Ma, Audriy Jebet, Xinmin Yin, James C Morris

Faculty, Staff and Student Publications

Infections with the pathogenic free-living amoebae Naegleria fowleri can lead to life-threatening illnesses including catastrophic primary amoebic meningoencephalitis (PAM). Efficacious treatment options for these infections are lacking and the mortality rate remains >95% in the US. Glycolysis is very important for the infectious trophozoite lifecycle stage and inhibitors of glucose metabolism have been found to be toxic to the pathogen. Recently, human enolase 2 (ENO2) phosphonate inhibitors have been developed as lead agents to treat glioblastoma multiforme (GBM). These compounds, which cure GBM in a rodent model, are well-tolerated in mammals because enolase 1 (ENO1) is the predominant isoform used …

Outcome Of Corynebacterial Bloodstream Infection In Patients With Cardiac Implantable Electronic Devices: A Brief Report And Systematic Review, Supavit Chesdachai, Larry M Baddour, M Rizwan Sohail, Bharath Raj Palraj, Malini Madhavan, Hussam Tabaja, Michele T Mcginnis, Madiha Fida, Douglas W Challener, Daniel C Desimone

Faculty, Staff and Students Publications

Cardiac implantable electronic device infection in the context of corynebacterial bloodstream infection (BSI) remains poorly understood. From 2012 to 2023 at Mayo Clinic, 4 of 12 patients with corynebacterial BSI had cardiac implantable electronic device infection: 1 patient was diagnosed during a relapsing BSI episode. Undefined source, persistent BSI, and the presence of a prosthetic cardiac valve were common characteristics.

Cognitive Behavioral Therapy Factors Related To Outcomes In Depression Among Youth With Hiv, Betsy D Kennard, Larry K Brown, Kristin Baltrusaitis, Miriam Chernoff, Graham J Emslie, Jessica Jones, Sarah Buisson, Jaime Deville, Megan Wilkins, Amber Bunch, Chivon Mcmullen Jackson, Christy Beneri, David E Shapiro

Faculty, Staff and Students Publications

PURPOSE: This is a secondary analysis of a multi-site, cluster (site) randomized trial of the efficacy of a combined Health and Wellness Cognitive Behavior Therapy (H&W CBT) and medication management approach for depression in youth with HIV (YWH) compared to standard care. In this study, we explored the association between H&W CBT factors and depression outcomes after 24 weeks of treatment to discover treatment elements associated with symptom reduction.

METHODS: Participants (12-24 years of age) were YWH in the United States (US) diagnosed with moderate to severe depression [Quick Inventory of Depressive Symptomatology (QIDS), Clinician-Rated score ≥ 11]. Thirteen US …

Something Seems Fishy: Hepatic Abscess Due To Foreign Body Ingestion In A Pediatric Patient, James Rhodes, Amanda Macias, Emma Cooke, Joel Jacob, Ashley Devoll, Chelsea Young, Bradford Nguyen

Faculty, Staff and Students Publications

Pediatric hepatic abscesses are uncommon in children. They are usually preceded by intra-abdominal infections or caused by acute or chronic biliary disease. Cases of hepatic abscesses secondary to foreign body ingestion are even rarer but are most reported in countries such as China, where ingestion of fish and chicken bones is common. We report a rare case of an adolescent patient who developed a hepatic abscess after ingestion of a fishbone foreign body. He presented to the emergency department with emesis, abdominal pain, and subjective fevers of unknown etiology. Initial imaging of the abdomen was pertinent for a heterogeneous hepatic …

Promoting Resilience In Stress Management For Adolescents With Type 1 Diabetes: A Randomized Clinical Trial, Joyce P Yi-Frazier, Marisa E Hilliard, Maeve B O'Donnell, Chuan Zhou, Britney M Ellisor, Samantha Garcia Perez, Brenda Duran, Yuliana Rojas, Faisal S Malik, Daniel J Desalvo, Catherine Pihoker, Miranda C Bradford, Samantha Scott, Sridevi Devaraj, Abby R Rosenberg

Faculty, Staff and Students Publications

IMPORTANCE: Type 1 diabetes (T1D) requires demanding self-management health behaviors, and adolescents with T1D are at risk for poor psychosocial and medical outcomes. Developing resilience skills may help adolescents with T1D and elevated distress navigate common stressors and achieve positive outcomes.

OBJECTIVE: To test the efficacy of the Promoting Resilience in Stress Management (PRISM) intervention on levels of hemoglobin A1c (HbA1c), diabetes distress, self-management behaviors, resilience, and quality of life among adolescents.

DESIGN, SETTING, AND PARTICIPANTS: This phase 3, parallel, 1:1 randomized clinical trial that followed up 172 participants for 12 months was conducted from January 1, 2020, to November …

Crohn's Disease-Associated Granulomatous Pancreatitis With Exocrine Pancreatic Insufficiency, Anthony A Xu, Sara Vincent, Samuel Ma, Vanessa Catania, Neda Zarrin-Khameh

Faculty, Staff and Students Publications

Extraintestinal manifestations of inflammatory bowel disease occur commonly and can lead to considerable morbidity. Pancreatic manifestations of inflammatory bowel disease have been reported to be more common in Crohn's disease (CD) than ulcerative colitis. We report a case of granulomatous inflammation in the body of the pancreas with exocrine pancreatic insufficiency, which prompted a diagnosis switch from ulcerative colitis to CD. This is of interest to readers to remind them that pancreatic manifestations can occur and are more common in CD.

Amoxicillin And Penicillin G Dosing In Pediatric Community-Acquired Pneumococcal Pneumonia In The Era Of Conjugate Pneumococcal Vaccines, Dustin Huynh, Norint Tung, Quang Dam, Tri Tran, Kristina G Hulten, Christopher J Harrison, Sheldon L Kaplan, Allison Nguyen, Tyler H Do, Amartya Setty, Jennifer Le

Faculty, Staff and Students Publications

Background: Parenteral penicillin G (PENG) and oral amoxicillin (AMOX) are recommended as treatment for pediatric community-acquired pneumonia (CAP). With recent epidemiologic penicillin susceptibility data for Streptococcus pneumoniae, the most common etiology of CAP, the objective of this study was to evaluate optimal dosing regimens of PENG and AMOX based on population pharmacokinetics linked to current susceptibility data.

Methods: Using NONMEM v7.3, Monte Carlo simulations (N = 10,000) were conducted for AMOX 15 mg/kg/dose PO every 8 h (standard-dose), AMOX 45 mg/kg/dose PO every 12 h (high-dose), and PENG 62,500 units/kg/day IV every 6 h using six virtual subjects with ages …

Preeclampsia In The Context Of Covid-19: Mechanisms, Pathophysiology, And Clinical Outcomes, Guilherme M Nobrega, Brittany R Jones, Indira U Mysorekar, Maria Laura Costa

Center on Aging Staff Publications

The emergence of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to the global COVID-19 pandemic, significantly impacting the health of pregnant women. Obstetric populations, already vulnerable, face increased morbidity and mortality related to COVID-19, aggravated by preexisting comorbidities. Recent studies have shed light on the potential correlation between COVID-19 and preeclampsia (PE), a leading cause of maternal and perinatal morbidity worldwide, emphasizing the significance of exploring the relationship between these two conditions. Here, we review the pathophysiological similarities that PE shares with COVID-19, with a particular focus on severe COVID-19 cases and in PE-like syndrome cases related with …

Clinical Features And Outcomes Of Pediatric And Adult Patients Hospitalized For Coronavirus Disease 2019: A Comparison Across Age Strata, Grace X Li, Komal Gopchandani, Noah Brazer, Ashley Tippett, Chris Choi, Hui-Mien Hsiao, Miriam Oseguera, Abiodun Foresythe, Sanchita Bhattacharya, Venice Servellita, Alicia Sotomayor Gonzalez, Jennifer K Spinler, Mark D Gonzalez, Dalia Gulick, Colleen Kraft, Vyjayanti Kasinathan, Yun F Wayne Wang, Jennifer Dien Bard, Pei Ying Chen, Jessica Flores-Vazquez, Audrey R Odom John, Paul J Planet, Sridevi Devaraj, Ananth V Annapragada, Ruth Ann Luna, Charles Y Chiu, Christina A Rostad

Faculty, Staff and Students Publications

BACKGROUND: Coronavirus disease 2019 (COVID-19) continues to cause hospitalizations and severe disease in children and adults.

METHODS: This study compared the risk factors, symptoms, and outcomes of children and adults hospitalized for COVID-19 from March 2020 to May 2023 across age strata at 5 US sites participating in the Predicting Viral-Associated Inflammatory Disease Severity in Children with Laboratory Diagnostics and Artificial Intelligence consortium. Eligible patients had an upper respiratory swab that tested positive for severe acute respiratory syndrome coronavirus 2 by nucleic acid amplification. Adjusted odds ratios (aOR) of clinical outcomes were determined for children versus adults, for pediatric age …

Adaptative Survival Of Aspergillus Fumigatus To Echinocandins Arises From Cell Wall Remodeling Beyond Β−1,3-Glucan Synthesis Inhibition, Malitha C. Dickwella Widanage, Isha Gautam, Daipayan Sarkar, Frederic Mentink-Vigier, Josh V. Vermaas, Shi You Ding, Andrew S. Lipton, Thierry Fontaine, Jean Paul Latgé, Ping Wang, Tuo Wang

School of Graduate Studies Faculty Publications

Antifungal echinocandins inhibit the biosynthesis of β−1,3-glucan, a major and essential polysaccharide component of the fungal cell wall. However, the efficacy of echinocandins against the pathogen Aspergillus fumigatus is limited. Here, we use solid-state nuclear magnetic resonance (ssNMR) and other techniques to show that echinocandins induce dynamic changes in the assembly of mobile and rigid polymers within the A. fumigatus cell wall. The reduction of β−1,3-glucan induced by echinocandins is accompanied by a concurrent increase in levels of chitin, chitosan, and highly polymorphic α−1,3-glucans, whose physical association with chitin maintains cell wall integrity and modulates water permeability. The rearrangement of …

Adaptation Of The Protein Misfolding Cyclic Amplification (Pmca) Technique For The Screening Of Anti-Prion Compounds, Katherine Do, Rebeca Benavente, Celso S G Catumbela, Uffaf Khan, Carlos Kramm, Claudio Soto, Rodrigo Morales

Faculty, Staff and Student Publications

Prion diseases result from the misfolding of the physiological prion protein (PrPC) to a pathogenic conformation (PrPSc). Compelling evidence indicates that prevention and/or reduction of PrPSc replication are promising therapeutic strategies against prion diseases. However, the existence of different PrPSc conformations (or strains) associated with disease represents a major problem when identifying anti-prion compounds. Efforts to identify strain-specific anti-prion molecules are limited by the lack of biologically relevant high-throughput screening platforms to interrogate compound libraries. Here, we describe adaptations to the protein misfolding cyclic amplification (PMCA) technology (able to faithfully replicate PrPSc strains) that increase its throughput to facilitate the …

In Silico Analysis Of The Rop29 Protein As A Vaccine Candidate Against Toxoplasma Gondii, Amir Karimipour-Saryazdi, Fatemeh Ghaffarifar, Abdolhossein Dalimi, Masoud Foroutan, John Horton, Javid Sadraei

Faculty, Staff and Student Publications

The progression of Toxoplasma gondii (T. gondii) invasion is aided by rhoptry proteins (ROPs), which are also crucial for the parasite's survival in host cells. In this study, in silico analysis was performed to examine the various aspects of the ROP29 protein, such as physicochemical properties, potential T- and B-cell epitopes, and other significant features. The research revealed that there were 55 possible sites for posttranslational modification in the ROP29 protein. The secondary structure of the ROP29 protein consists of a random coil, an alpha-helix, and an extended strand, which account for 49.69%, 36.81%, and 13.50%, respectively. Moreover, …

Selection For Robust Metabolism In Domesticated Yeasts Is Driven By Adaptation To Hsp90 Stress, Natalia Condic, Hatim Amiji, Dipak Patel, William Charles Shropshire, Nejla Ozirmak Lermi, Youssef Sabha, Beryl John, Blake Hanson, Georgios Ioannis Karras

Faculty, Staff and Student Publications

Protein folding both promotes and constrains adaptive evolution. We uncover this surprising duality in the role of the protein-folding chaperone heat shock protein 90 (Hsp90) in maintaining the integrity of yeast metabolism amid proteotoxic stressors within industrial domestication niches. Ethanol disrupts critical Hsp90-dependent metabolic pathways and exerts strong selective pressure for redundant duplications of key genes within these pathways, yielding the classical genomic signatures of beer and bread domestication. This work demonstrates a mechanism of adaptive canalization in an ecology of major economic importance and highlights Hsp90-dependent variation as an important source of phantom heritability in complex traits.

Trends Of Methicillin-Resistant Staphylococcus Aureus Infections Among Thai Pediatric Patients, Pintip Suchartlikitwong, Nopphon Wuthinantiwong, Watsamon Jantarabenjakul, Noppadol Wacharachaisurapol, Jiratchaya Sophonphan, Tanittha Chatsuwan, Thanyawee Puthanakit

Chulalongkorn Medical Journal

Background While reductions in methicillin-resistant Staphylococcus aureus (MRSA) infections have been reported, vancomycin prescription rates have remained high.

Objectives We aimed to update trends in pediatric prevalence and antibiotic susceptibilities of MRSA infections.

Methods We conducted a retrospective study in patients aged S. aureus infections during 2016-2022 at a Thai tertiary-care hospital. MRSA was defined when resistant to cefoxitin or oxacillin MIC of >4 µg/mL. Patients with MRSA infections and their first isolates were classified into HA-MRSA or CA-MRSA based on surveillance definitions. Antibiotic susceptibilities were tested using the VITEK 2XL automated system and disk diffusion. The annual prevalence of …