Amino Acids, Peptides, and Proteins Commons^™

Phenotype Specific Nuclear Lamina Remodeling In Hipsc Derived Cardiomyocytes Bearing Tnnt2 Sarcomeric Variants, Isabella Leite Coscarella, Olalekan H. Usman, Lili Wang, Maicon Landim-Vieira, Lillian Wirstiuk, Amber N. Brown, Diego A. R. Zorio, Brian K. Washburn, Cynthia Vied, Bjorn C. Knollmann, Christopher Solís, Vitold E. Galkin, P. Bryant Chase, J. Travis Hinson, Jerome Irianto, Jose Renato Pinto

Department of Biomedical and Translational Sciences Faculty Publications

[Summary] Cardiomyocytes endure physical stress from the myocardium environment while generating their own mechanical strains. The force generated by sarcomeres is transmitted both longitudinally to adjacent sarcomeres and laterally to the cytoskeleton via intermediate filaments. This mechanical stimulus impacts other organelles, including the nucleus, thus playing a vital role in sensing and signaling nuclear adaptations. However, there is limited understanding of how changes in cardiac contractility affect nuclear mechanics. Here, we sought to investigate the effects of hyper- and hypo-contractility in nuclei of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) bearing TNNT2 pathogenic variants associated with hypertrophic (HCM) or dilated …

Caveolin-Mediated Endocytosis: Bacterial Pathogen Exploitation And Host-Pathogen Interaction, Dibyasri Barman, Rishi Drolia

Biological Sciences Faculty Publications

Within mammalian cells, diverse endocytic mechanisms, including phagocytosis, pinocytosis, and receptor-mediated endocytosis, serve as gateways exploited by many bacterial pathogens and toxins. Among these, caveolae-mediated endocytosis is characterized by lipid-rich caveolae and dimeric caveolin proteins. Caveolae are specialized microdomains on cell surfaces that impact cell signaling. Caveolin proteins facilitate the creation of caveolae and have three members in vertebrates: caveolin-1, caveolin-2, and caveolin-3. Many bacterial pathogens hijack caveolin machinery to invade host cells. For example, the Gram-positive facultative model intracellular bacterial pathogen Listeria monocytogenes exploits caveolin-mediated endocytosis for efficient cellular entry, translocation across the intestinal barrier, and cell–cell spread. Caveolin …

Multimodal Imaging Of Protein-Based Biomaterials For Delivering Chemo-Agent Cargo For Glioblastoma Treatment In A Murine Model, Orin Mishkit

Dissertations and Theses

Protein-based self-assembling biomaterials, known as Thermo-Responsive Assembled Proteins (TRAP), present meaningful potential as drug delivery carriers. These materials enable the controlled, slow release of poorly soluble chemotherapeutic agents, such as doxorubicin (Dox), while potentially reducing systemic off-target effects. In collaboration with multiple NYU labs, this study evaluated the efficacy of two TRAP variants—TRAP and F-TRAP—as drug delivery carriers in a xenograft mouse model of glioblastoma multiforme (GBM).

The primary objective was to compare the effectiveness of TRAP-loaded Dox (TRAP-DOX) to free Dox in achieving tumor extravasation and accumulation, facilitating sustained drug release. We hypothesized that the leaky vasculature of GBM …

Redox Control In A Fused Electron Transfer Flavoprotein From A Thermophilic Archaeon And Expanded Significance Of A Hydrogen Bond From A Conserved Histidine Residue That Contributes To Flavin Redox Tuning And Activation For Covalent Modification, Debarati Das

Theses and Dissertations--Chemistry

In absence of O₂ as terminal electron acceptors in anaerobic bacteria and archaea, carbohydrate metabolism is 15 times less efficient compared to aerobic energy metabolism resulting in energy deficit conditions. Despite their meager resources these anaerobes were able to generate H₂ and a chemiosmotic potential able to drive energy demanding reactions such as CO₂ or N₂ fixation. These observations raised concerns as production of high energy reductants (H₂) from mediocre fuels (NADH) defied the laws of thermodynamics.

In 2008, a known mechanism “electron bifurcation” but with flavins as redox mediators instead of quinones was …

A Novel D-Peptide Modulates Dclk1 Gelsolin Interactions, Reducing Pdac Tumor Growth, Landon L. Moore, Dongfeng Qu, Parthasarathy Chandrekesan, Kamille Pitts, Randal May, Byron E. Anderson, Milton L. Brown, Courtney W. Houchen

Department of Medicine Faculty Publications

What drives inflammation-associated tumorigenesis and progression in pancreatic ductal adenocarcinoma (PDAC)? Doublecortin-like kinase 1 (DCLK1) is a central driver of inflammation-associated tumorigenesis, with elevated expression linked to worse clinical outcomes. Two isoforms of DCLK1 possess a unique extracellular domain (ECD). DCLK1 isoform 2 contains two microtubule-binding domains, while isoform 4, lacks the microtubule-binding domains but, plays a pivotal role in tumor progression. We identified novel D-peptides that selectively target this ECD, significantly suppressing PDAC cell proliferation in vitro and tumor growth in xenograft models without inducing cell death. In silico modeling and binding assays revealed DCLK1 isoform 4 interacts with …

Fibrinolysis For Apical Thrombus As A Bridge To Emergent Valve-In-Valve Transcatheter Aortic Valve Replacement, Nicholas J. Valle, Omar A. Saleh, Mani C. Akunuri, Parth K. Parikh, Joshua A. Cohen, Deepak R. Talreja, Matthew R. Summers

Department of Medicine Faculty Publications

Background

Left ventricular (LV) thrombus is traditionally a contraindication to transcatheter aortic valve replacement due to embolic risk. Consequently, management of valvular cardiogenic shock complicated by LV thrombus identifies unique challenges that require innovative strategies.

Case Summary

A 58-year-old woman with critical bioprosthetic aortic stenosis, cardiogenic shock, and large LV thrombus (2.8 × 2.6 cm) underwent successful valve-in-valve transcatheter aortic valve replacement after systemic fibrinolysis bridge therapy.

Why Beyond the Guidelines

Current guidelines contraindicate transcatheter aortic valve replacement in patients with LV thrombus. This case demonstrates the novel use of low-dose, slow infusion tissue plasminogen activator as a bridge therapy …

American Heart Association Blood Pressure Classification And Subsequent Risk Of Preeclampsia, Rebecca Horgan, Erkan Kalafat, Elena Sinkovskaya, Alfred Abuhamad, George Saade

Department of Obstetrics & Gynecology Faculty Publications

Background: In 2017, the American Heart Association (AHA) and American College of Cardiology updated their hypertension guidelines for the nonpregnant population, lowering the diagnostic thresholds to systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg. This reclassification has raised important questions regarding whether blood pressure (BP) values previously considered within the normal range in pregnancy may, in fact, confer an increased risk for hypertensive disorders of pregnancy (HDPs).

Objective: To evaluate the association between first-trimester BP classified by AHA thresholds and the subsequent development of HDPs.

Study design: This was a secondary analysis of a prospective, multicenter cohort …

Her2 Alterations Across Solid Tumors: Implications For Comprehensive Testing, Ahmed Ismail, Chimay Jani, Nusrat Jahan, Malla Midhun, Arnab Basu, Garima Gupta, Bassel El-Rayes, Sejong Bae, Tyler Mattox, Cyntanna Hawkins, Rebecca C. Arend, Mehmet Akce, Yanis Boumber, Aakash Desai

Department of Medicine Faculty Publications

Purpose

ERBB2 (HER2) alterations (e.g., overexpression, amplification, and mutations) are known to drive tumor progression. These changes, particularly in non-breast and gastric/gastroesophageal cancers, remain poorly characterized. With pan-tumor approval of HER2-targeted therapies like Trastuzumab deruxetecan (T-DXd), understanding ERBB2 alterations across diverse cancers is crucial.

Methods

HER2 analysis was conducted on 653 solid tumor specimens at the University of Alabama, using immunohistochemistry (IHC), copy number (CN) variation (CNV) assessment, and mutational profiling. The correlation between CN amplification and IHC expression was evaluated using Somers' D ordinal association.

Results

Of the 653 cases, HER2 IHC scores were distributed as 3 + (3.1%), …

Changes In Cardiovascular Risk Factors And Health Care Expenditures Among Patients Prescribed Semaglutide, Yuan Lu, Yuntian Lu, Tedi Totojani, Chungsoo Kim, Rohan Khera, Hua Xu, John E. Brush Jr., Harlan M. Krumholtz, Jason Abaluck

Department of Medicine Faculty Publications

Importance Semaglutide, a glucagon-like peptide-1 receptor agonist, has demonstrated substantial weight reduction and cardiovascular benefits in clinical trials. However, its association with clinical outcomes and health care expenditures remains underexplored.

Objective To evaluate changes in cardiovascular risk factors and health care expenditures among patients prescribed semaglutide across multicenter cohorts.

Design, Setting, and Participants This retrospective cohort study included 23 522 adults (≥18 years) who received an initial semaglutide prescription between January 1, 2018, and January 1, 2025, at Sentara Healthcare and between January 1, 2018, and May 1, 2025, at Yale New Haven Health System.

Exposure The first prescription of …

Inflammatory Mediators And The Rage Pathway In Placental Tissues Of Pregnancies Complicated By Severe Preeclampsia, Neelima Chandra, Thomas D. Kimble, Kathleen R. Heim, Sharon M. Anderson, Andrew P. Wong, Andrea R. Thurman, Gustavo F. Doncel

CONRAD Publications

Introduction: Preeclampsia (PE) is a complex multisystem disorder of pregnancy associated with abnormal placentation, vascular anomalies, and systemic inflammation and hypertension. Previous research assessing inflammatory triggers of the condition used plasma, amniotic fluid, or explant samples. Studies using placental tissue from either vaginal or cesarean deliveries are confined to semiquantitative analysis using subjective scoring methods and generally involve a small sample size.

Methods: In this study, we have quantified the expression of inflammatory mediators by immunohistochemical image analysis of archived placental tissues obtained from cesarean delivery of preeclamptic, chorioamnionitic, and normal pregnancies.

Results: Among the inflammatory mediators, we found a …

Cath-Ddg: Towards Robust Mutation Effect Prediction On Protein-Protein Interactions Out Of Cath Homologous Superfamily, Guanglei Yu, Xuehua Bi, Teng Ma, Yaohang Li, Jianxin Wang

Computer Science Faculty Publications

Motivation: Protein-protein interactions (PPIs) are fundamental aspects in understanding biological processes. Accurately predicting the effects of mutations on PPIs remains a critical requirement for drug design and disease mechanistic studies. Recently, deep learning models using protein 3D structures have become predominant for predicting mutation effects. However, significant challenges remain in practical applications, in part due to the considerable disparity in generalization capabilities between easy and hard mutations. Specifically, a hard mutation is defined as one with its maximum TM-score < 0.6 when compared to the training set. Additionally, compared to physics-based approaches, deep learning models may overestimate performance due to potential data leakage.

Results: We propose new training/test splits that mitigate data leakage according to the CATH homologous superfamily. Under the constraints of physical …

A Survey On Deep Learning For Drug-Target Binding Prediction: Models, Benchmarks, Evaluation, And Case Studies, Kusal Debnath, Pratip Rana, Preetam Ghosh

Computer Science Faculty Publications

Conventional drug discovery is expensive, time-consuming, and prone to failure. Artificial intelligence has become a potent substitute over the last decade, providing strong answers to challenging biological issues in this field. Among these difficulties, drug-target binding (DTB) is a key component of drug discovery techniques. In this context, drug-target affinity and drug–target interaction are complementary and essential frameworks that work together to improve our comprehension of DTB dynamics. In this work, we thoroughly analyze the most recent deep learning models, popular benchmark datasets, and assessment metrics for DTB prediction. We look at the paradigm shift in the development of drug …

Deepssetracer 2.0: Improved Deep Learning Model Performance For Protein Secondary Structure Segmentation From Cryo-Em Maps, Bryan Hawickhorst, Thu Nguyen, Willy Wriggers, Jiangwen Sun, Jing He

Computer Science Faculty Publications

DeepSSETracer is a method for segmenting protein secondary structure from medium-resolution (5-10Å) cryogenic electron microscopy (cryo-EM) density maps. We conducted experiments and ablation studies to examine the effects of normalization methods, max-pooling, activation functions, and loss calculation region on DeepSSETracer. By combining multiple technical improvements, the performance of the new version, DeepSSETracer 2.0, was significantly enhanced compared to DeepSSETracer 1.1. On a set of 77 test cases, the weighted average per-voxel F1 score increased from 62.1% to 70.3% for helix detection, and from 47.8% to 62.5% for β-sheet detection. While each of the five modifications in the network enhanced the …

Automating The Amino Acid Identification In Elliptical Dichroism Spectrometer With Machine Learning, Ridhanya Sree Balamurugan, Yusuf Asad, Tommy Gao, Dharmakeerthi Nawarathna, Umamaheswara Rao Tida, Dali Sun

Electrical & Computer Engineering Faculty Publications

Amino acid identification is crucial across various scientific disciplines, including biochemistry, pharmaceutical research, and medical diagnostics. However, traditional methods such as mass spectrometry require extensive sample preparation and are time-consuming, complex and costly. Therefore, this study presents a pioneering Machine Learning (ML) approach for automatic amino acid identification by utilizing the unique absorption profiles from an Elliptical Dichroism (ED) spectrometer. Advanced data preprocessing techniques and ML algorithms to learn patterns from the absorption profiles that distinguish different amino acids were investigated to prove the feasibility of this approach. The results show that ML can potentially revolutionize the amino acid analysis …

Asymmetric Synthesis Of The Hiv Protease Inhibitor Tmc-126 And An Anti-Malarial Agent Via A Titanium Tetrachloride Mediated Asymmetric Glycolate Aldol Addition Reaction. Redefining The Curtius Rearrangement Reaction Via Dehomologation Of Carboxylic Acids Bearing Alpha-Leaving Groups, Kweku Amaning Affram

Theses and Dissertations

Acquired Immune Deficiency Syndrome (AIDS) and malaria are two devastating infectious diseases caused by HIV and Plasmodium parasites. AIDS is caused by HIV-1 and HIV-2, transmitted through sexual contact, blood transfusions, needle sharing, and perinatal routes. Malaria, caused by plasmodium parasites through mosquito bites. Today, millions of people around the world have been infected with HIV and malaria and much research has been done to treat it. However, despite advancements in therapeutic options, these diseases remain a significant global health threat, particularly in developing countries due to the emergence of drug-resistant strains for both HIV and malaria complicating eradication efforts. …

Structural Optimization And Stability Enhancement Of Uba(2) And Ntl9 Using The Computational Tool: Emcast, Bahar Ghazi Esfahani

Graduate Student Theses, Dissertations, & Professional Papers

This study enhances protein stability prediction by refining EmCAST (Empirical C-Alpha Stability Tool), a computational tool used to identify stabilizing mutations in protein domains. We applied EmCAST to two model proteins: the α-helical ubiquitin-associated domain 2 (UBA(2)) and the α/β N-terminal domain of ribosomal protein L9 (NTL9). Protein stability is critical for proper function, and mutations can lead to misfolding and disease. To validate EmCAST’s predictions, guanidine hydrochloride-induced denaturation was monitored using circular dichroism (CD) spectroscopy for both wild-type and mutant variants. Results guided refinements to EmCAST’s algorithm, incorporating new experimental datasets to improve accuracy. Additionally, we examined the assumption …

Reversible Degradation Of Peptidoglycan By Lytic Transglycosylases, Aaron Devereaux

Theses and Dissertations (Comprehensive)

Antimicrobial resistance continues to be a burden on the global healthcare system with an estimated cost of billions of dollars and millions of deaths each year. Recently, there has been little to no development on new antibiotics to treat bacterial infection, and any that are developed become resisted to within a few years. Both Gram-positive and Gram-negative bacteria contain a mesh-like layer called peptidoglycan (PG) that surrounds their cells providing strength, cell shape, and protection from their environments. This layer is a polymer of N-acetylmuramic acid (MurNAc) and N-acetylglucosamine (GlcNAc) connected via a b-1,4-glycosidic bond, with each strand being cross-linked …

Alpha-Synuclein Interaction With Gedunin, Tony Matundura Nyabayo

Graduate Theses/Dissertations

Parkinson’s disease (PD) and other Proteinopathies develop when α-synuclein misfolds and aggregates into toxic amyloids. While existing treatments for PD are primarily focused on managing its symptoms, a viable solution for slowing down the progress of Parkinson’s disease involves targeting the toxic α-synuclein amyloids. Gedunin, a natural inhibitor of heat shock protein 90, has been extensively used to treat malaria. Also, recent research investigations have shed light on its potential beyond malaria therapy, indicating that Gedunin may offer a possible solution for treating a variety of neurodegenerative diseases. Using plate-based assays, we examined how Gedunin influences α-synuclein fibrillation and its …

Ribosome Hibernation In Mycobacterium Abscessus And Its Effect On Antibiotic Resistance, Ryan Treen

Electronic Theses & Dissertations (2024 - present)

Non-tuberculosis mycobacteria (NTM) represent a diverse repertoire of species, most of which are ubiquitous in the environment. Some NTM species, such as Mycobacterium abscessus, can cause life-threatening infections in people with underlying medical conditions. The clinical incidence of such infections is on the rise, posing an emerging threat to public health. M. abscessus is characterized by intrinsic and acquired antibiotic resistance, complicating treatment strategies. Most chemotherapeutic approaches for M. abscessus infection target the bacterial ribosome, necessitating a better understanding of the physiological processes which confer this resistance. Multiple mycobacterial species respond to zinc-limiting conditions by inducing remodeling and hibernation …

The Complexity And Significance Of Fibroblast Growth Factor (Fgf) Signaling For Fgf-Targeted Cancer Therapies, Anh Nguyen, Caroline Facey, Bruce Boman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Fibroblast growth factors (FGFs) have diverse functions in the regulation of cell proliferation and differentiation in development, tissue maintenance, wound repair, and angiogenesis. The goal of this review paper is to (i) deliberate on the role of FGFs and FGF receptors (FGFRs) in different cancers, (ii) present advances in FGF-targeted cancer therapies, and (iii) explore cell signaling mechanisms that explain how FGF expression becomes dysregulated during cancer development. FGF is often mutated and overexpressed in cancer and the different FGF and FGFR isoforms have unique expression patterns and distinct roles in different cancers. Among the FGF members, the FGF 15/19 …