Chemicals and Drugs Commons^™

Determination Of Structural Factors Contributing To Protection Of Zinc Fingers In Estrogen Receptor Α Through Molecular Dynamic Simulations, Patricia B. Lutz, Wesley R. Coombs, Craig A. Bayse

Chemistry & Biochemistry Faculty Publications

The ERα transcription factor that induces tumor growth is a potential target for breast cancer treatment. Each monomer of the ERα DNA-binding domain (ERαDBD) homodimer has two conserved (Cys)₄-type zinc fingers, ZF1 (N-terminal) and ZF2 (C-terminal). Electrophilic agents release Zn²⁺ by oxidizing the coordinating Cys of the more labile ZF2 to inhibit dimerization and DNA binding. Microsecond-length molecular dynamics (MD) simulations show that greater flexibility of ZF2 in the ERαDBD monomer leaves its Cys more solvent accessible and less shielded from electrophilic attack by sulfur-centered hydrogen bonds than ZF1 which is buried in the protein. In the …

A Comparison Of Microcrystal Electron Diffraction And X-Ray Powder Diffraction For The Structural Analysis Of Metal-Organic Frameworks, Erik Biehler, Silvana Pagola, Daniel Stam, Johannes Merkelbach, Christian Jandl, Tarek M. Abdel-Fattah

Chemistry & Biochemistry Faculty Publications

This study successfully implemented microcrystal electron diffraction (microED) and X-ray powder diffraction (XRPD) for the crystal structure determination of a new phase, TAF-CNU-1, Ni(C₈H₄O₄)·3H₂O, solved by microED from single microcrystals in the powder and refined at the kinematic and dynamic electron diffraction theory levels. This nickel metal–organic framework (MOF), together with its cobalt and manganese analogues with formula M (C₈H₄O₄)·2H₂O with M = Mn ^II or Co^II, were synthesized in aqueous media as one-pot preparations from the corresponding hydrated metal chlorides and sodium terephthalate, as a promising `green' synthetic route to moisture-stable MOFs. The crystal structures of the …

Deciphering The Chemistry Of Condensed Aromatic "Black" Carbon And Nitrogen In Amazonian Anthrosols, João Vitor Dos Santos, Aleksandar I. Goranov, Laís G. Fregolente, Marcia C. Bisinoti, Zhenhuan Sun, Klaus Schmidt-Rohr, Patrick G. Hatcher

Chemistry & Biochemistry Faculty Publications

Amazonian anthrosols are renowned for their high fertility and dark color, properties primarily attributed to the abundance of condensed aromatic carbon (ConAC) in the soil organic matter. ConAC, commonly referred to as black carbon, play a key role in the stability and nutrient retention of these soils. However, the processes governing the formation of ConAC and its transformation into oxygenated derivatives remain poorly understood. In this study, we used multiple analytical platforms to investigate the chemistry of ConAC-rich humic acids (HA) extracted from Terra Mulata de Indio, a type of Amazonian anthrosol. The results reveal that ConAC are predominantly …

Bacterial Two-Hybrid Systems Evolved: Innovations For Protein-Protein Interaction Research, Rebecca M. Richardson, Steven M. Pascal

Chemistry & Biochemistry Faculty Publications

Bacterial two-hybrid (B2H) systems offer a versatile platform for detecting protein-protein interactions (PPIs) in vivo. Originally developed to study bacterial transcriptional regulators, these systems have evolved to support a wide range of applications, including interaction mapping, domain analysis, and high-throughput screening. This review surveys the development and expansion of B2H systems across diverse biological contexts. We highlight technical considerations, platform-specific innovations, and recent adaptations that extend the utility of B2H systems in both prokaryotic and eukaryotic protein interaction research environments. By comparing different B2H variants and discussing their integration with complementary approaches, we provide a framework for leveraging these …

An E. Coli Two-Hybrid System To Investigate Human Protein-Protein Interactions, Rebecca M. Richardson, Sarah M. Ho, Lane Tong, Morgan G. Daniels, Steven M. Pascal

Chemistry & Biochemistry Faculty Publications

Abstract

The LexA-E. coli two-hybrid (LexA-E2H) system was initially developed to study interactions between microbial proteins in an Escherichia coli (E. coli) environment. We here demonstrate its utility for studying mammalian protein interactions. Specifically, this study uses LexA-E2H to provide the first direct and quantitative validation of Glucose Regulated Protein 78 (GRP78) binding to the cleaved-Prostate Apoptosis Response 4 (cl-Par-4) tumor suppressor. Furthermore, the results establish that this interaction does not require phosphorylation of either protein. MacConkey agar was used for initial detection of the interaction through colorimetric colony screening, distinguishing pale white-pink colonies (+ interaction) from …

Antihypertensive Potential Of Euphorbia Hirta And Leptadenia Hastata In Adrenaline-Induced Wistar Rats, Fagbohun Oyenike Bushirat, Emmanuel Ogar Ochonung, Messiah Innocent Atapia, Hassan Abdulsalam Adewuyi, Sakariyau Aido Waheed, Adebimpe Oluwatoyin Hameedah, Chizoba Victory Obunadike, Adeleye Adegboyega Edema, Samad Hussein, Abiola Mohammed Usman, Tolulope Olukayode Jaiyeola

Chemistry & Biochemistry Faculty Publications

Background: Hypertension is a major public health concern worldwide, contributing to cardiovascular morbidity and mortality. The use of plant-based therapies, such as Euphorbia hirta and Leptadenia hastata, has gained attention for their potential antioxidant, anti-hyperlipidemic, and organ-protective effects.

Objectives: This study aimed to investigate the phytotherapeutic approach to hypertension using E. hirta and L. hastata extracts in adrenaline-induced hypertensive Wistar rats

Methods: Utilizing an adrenaline-induced hypertensive rat model, we assessed the effects of E. hirta and L. hastata leaf extracts (50, 100, and 200 mg/kg) on systolic blood pressure, renal function, lipid metabolism, and hematological parameters.

Results: Antioxidant activity: …

Corporate ‘Capture Strategies’ Impacting Human And Ecosystem Health, Alex T. Ford, Marlene Ågerstrand, Michael G. Bertram, Miriam L. Diamond, Rainer Lohmann, Andreas Schäffer, Martin Scheringer, Gabriel Sigmund, Anna Soehl, Maria Clara V.M. Starling, Noriyuki Suzuki, Marta Venier, Penny Vlahos

Graduate School of Oceanography Faculty Publications

The concept of regulatory capture has been extensively studied in academic literature, primarily within the social sciences. This phenomenon has been increasingly discussed in the environmental sciences as the impacts of regulatory capture on human and ecosystem health have become increasingly apparent. Regulatory capture is just one tactic employed by vested interests in the strategy of delaying, weakening, or abolishing policies designed to protect the public interest. Here, we define capture strategies as ‘the act of influencing individuals, organizations, or governments to prioritize corporate interests over those of human and ecosystem health’. Similar to the evolution of terms like whitewashing …

Molecular Imprinting And Nanomaterial Synergy For Lactate Detection, Christopher Animashaun, Gymama Slaughter

Center for Bioelectronics Publications

Molecularly imprinted polymer (MIP)-based electrochemical sensors have emerged as promising non-enzymatic platforms for the selective and stable detection of clinically and environmentally relevant biomarkers. This review provides a critical, comprehensive analysis of recent advances in MIP-based lactate sensing, with particular emphasis on hybrid systems that integrate conductive nanomaterials including gold and silver nanoparticles, laser-induced graphene, and reduced graphene oxide. These synergistic combinations leverage enhanced surface area, electrical conductivity, and molecular recognition to improve sensor sensitivity, selectivity, and long-term operational stability. Key fabrication strategies, such as electropolymerization, green nanomaterial synthesis, and surface imprinting, are critically examined for their roles in optimizing …

Phytochemical Analysis, Antioxidant, And Antibacterial Properties Of Partition Fractions Of Adansonia Digitata And Annona Muricata Extracts Using Chloroform, Ethyl Acetate, Ethanol, And Aqueous Solvent Systems, Fagbohun Oyenike Bushirat, Hassan Abdusalam Adewuyi, Sakariyau Adio Waheed, Maryam Nana Musa, Timothy God-Giveth Olusegun, Ayomide Babatunde Ishola, Agumage Idoko, Adeola Victor Kolawole, Adesanmi Adefunmilayo Oluwatuyi, Sarah Ngozi Agwasim

Chemistry & Biochemistry Faculty Publications

Adansonia digitata and Annona muricata are traditionally used medicinal plants with reported pharmacological properties. In this study, we aimed to elucidate the phytochemical composition, antioxidant activity, and antibacterial properties of partition fractions of Adansonia digitata and Annona muricata extracts obtained using chloroform, ethyl acetate, ethanol, and aqueous solvent systems. The plant extracts were successively partitioned using chloroform, ethyl acetate, ethanol, and aqueous solvent systems. Phytochemical analysis was performed using standard methods. Antioxidant activity was evaluated using FRAP and DPPH assays. Antibacterial activity was assessed using agar well diffusion and MIC determination. Phytochemical analysis revealed the presence of alkaloids (10.2-15.6%), flavonoids …

Effects Of Perinatal Exposure To Lipopolysaccharide And Acetaminophen On Learning In Adult Long-Evans Rats, Lucy A. Sivils

College of Graduate Studies: Theses & Dissertations

The present study investigated the individual and combined effects of elevated perinatal inflammation, oxidative stress caused by acetaminophen (APAP) exposure, or elevated inflammation and oxidative stress on adult learning behaviors in Long-Evans rats. While prior studies have examined these factors independently, the combined effects of inflammation and oxidative stress via APAP exposure during early development on learning-related behaviors remain unexplored. The present research aimed to address this gap by the analysis of potential long-term neurodevelopmental consequences of lipopolysaccharide (LPS)-induced inflammation and APAP-induced oxidative stress. LPS, APAP, or LPS + APAP was administered during the perinatal period: postnatal days (PD) 9, …

Synthesis Of Small Molecules As Therapeutic Candidates, Savia Boyer

Electronic Theses & Dissertations (2024 - present)

RNA plays a critical role in many biological functions, such as normal cellular functions or disease-related processes. Regulating biological processes through RNA-based therapeutics can be employed by the reversible photoregulation of oligonucleotides. Azobenzene, a light-responsive compound that changes conformation when exposed to ultraviolet (UV) or visible light, is attached to cytidine phosphoramidite to be incorporated in a series of RNA oligonucleotides. The reversibility of the nucleoside and oligonucleotide is verified through UV melting point experiments. The modified oligonucleotide can change conformation upon light irradiation to stop reverse transcription (RT) in the presence of many different reverse transcriptase enzymes. This technique …

Opioid Usage And Non-Opioid Alternatives In Septorhinoplasty: A Narrative Review, Robert M. Frederick, Eric Dobratz

Department of Otolaryngology (ENT) Faculty Publications

Background and Objective: Opioids are routinely prescribed following septorhinoplasty and oftentimes surgeons prescribe a larger number of tablets than patients require. Considering the high risk of developing opioid dependence and risk of diversion, it is imperative that surgeons practice safer, evidence-based prescribing habits. This review is intended to detail the current state of opioid usage after septorhinoplasty, focusing on articles that show pertinent and practice-altering findings. This will allow surgeons to reflect on their prescribing patterns and make evidence-based decisions to improve them.

Methods: A literature search was performed in November 20, 2024 via PubMed using keywords such as ‘opioid …

Acute Exacerbations Of Chronic Rhinosinusitis, Robert M. Frederick, Kent Lam, Joseph K. Han

Department of Otolaryngology (ENT) Faculty Publications

Purpose of Review

We aim to highlight recent advancements on the evolving chronic rhinosinusitis (CRS) phenotype: acute exacerbations of chronic rhinosinusitis (AECRS). We focused on studies that expanded the current understanding of its pathophysiology, patient characteristics, and disease burden.

Recent findings

Defining AECRS has been a topic of discussion for many years. A recent regulatory definition of AECRS in the literature incorporates a > 3 day requirement of worsened symptoms and an escalation of treatment. It is important not to rely on patient-reported rescue medication frequency as it was recently demonstrated these are only obtained for 1/3 of reported AECRS episodes. …

January 2025, Swosu Rural Health Center

RURAL ROCKS

This is the January 2025 issue of Rural Rocks from the SWOSU College of Pharmacy.

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 …

Biomedical Mxene-Polymer Nanocomposites: Advancing Photothermal Therapy, Antibacterial Action, And Smart Drug Delivery: A Review, Ali Mohammad Amani, Lobat Tayebi, Ehsan Vafa, Mohammad Javad Azizli, Milad Abbasi, Ahmad Vaez, Hesam Kamyab, Daniel Simancas-Racines, Shreeshivadasan Chelliapan

Electrical & Computer Engineering Faculty Publications

MXenes are hydrophilic, conductive, tunable, and biocompatible two-dimensional ceramic materials prepared by etching the 'A' layer from their precursor MAX phases. Although MXenes show exceptional promise in photothermal therapy, biosensing, and regenerative medicine, they face challenges such as oxidative instability in physiological environments, limited drug-loading capacity, and unpredictable immune responses. To address these limitations, MXene/polymer nanocomposites incorporating both synthetic polymers (e.g., polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), and polylactic-co-glycolic acid (PLGA)) and natural biopolymers (e.g., cellulose nanofiber, gelatin, chitosan, hyaluronic acid, and soybean phospholipids) have been developed. These composites enhance functionality for biomedical applications such as photothermal cancer …

Enhancing Bone Regeneration Using Kaempferol As An Osteoprotective Compound: Signaling Mechanisms, Delivery Strategies, And Potential Applications, Mojdeh Salehi Namini, Sanam Mohandesnezhad, Sadaf Mohandesnezhad, Vahid Mansouri, Lobat Tayebi, Nima Beheshtizadeh

Electrical & Computer Engineering Faculty Publications

Various plants, including fruits, vegetables, and spices, contain kaempferol, a bioflavonoid compound with diverse medicinal effects, such as antioxidant, antibacterial, and anti-inflammatory characteristics. Furthermore, this compound exhibits multiple health-promoting properties, including osteoprotection and osteogenesis, primarily by modulating various cell-signaling pathways. This review aims to illustrate the medical advantages of kaempferol and its role in regulating bone metabolism through cell signaling mechanisms. Numerous studies have demonstrated the bone-protective properties of kaempferol and its encapsulated form. Further research is needed to clarify the optimal dosages, toxicity, safety, and other potential mechanisms of action. This review demonstrates that several signaling pathways, including nuclear …

Synthesis Of Tu100 Analogs And Biological Assays, Feyisope Tonye Oladapo

College of Graduate Studies: Theses & Dissertations

TU100 (14-methyl-5H-5,12-epiminobenzo[4,5]cyclohepta[1,2-b]naphthalene-6,11,13(12H)-trione) exhibits exceptional chemotherapeutic properties. It operates via a distinct mechanism that triggers cell death to create cytotoxic effects while concurrently inhibiting topoisomerase I and II. Its efficacy rivals that of well-known chemotherapeutic drugs like Daunorubicin. The distinctive characteristics of TU100 have led to initiatives aimed at creating structurally similar compounds to discover even more effective bioactive alternatives.

The analog synthesis incorporated quinoxaline or its derivatives (diphenyl quinoxaline, dipyridinyl quinoxaline, and dibenzophenazine-10,13-dione) that have been shown to have promising chemotherapeutic effects. Synthesizing the hetero naphthoquinones required a multi-step synthetic process, so quinoxaline/ derivatives intermediates are first prepared, then the …

Molecular Screening And Dynamics Simulation Reveal Potential Phytocompounds In Swertia Chirayita Targeting The Uspa1 Protein Of Moraxella Catarrhalis For Copd Therapy, Md. Moin Uddin, Md. Shydhur Rahman Chowdhury, Md. Arju Hossain, Asif Ahsan, Md. Tanvir Hossain, Abdul Barik, Md. Arif Hossen, Md. Faisal Amin, Rafsan Abir, Mohammad Shah Alam

School of Integrative Biological & Chemical Sciences Faculty Publications

Chronic obstructive pulmonary disease (COPD) is a global health burden, with Moraxella catarrhalis significantly contributing to acute exacerbations and increased healthcare challenges. This study aimed to identify potential drug candidates in Swertia chirayita, a traditional Himalayan medicinal plant, demonstrating efficacy against the ubiquitous surface protein A1 (UspA1) of M. catarrhalis through an in-silico computational approach. The three-dimensional structures of 46 phytocompounds of S. chirayita were retrieved from the IMPPAT 2.0 database. The structures underwent thorough analysis and screening, emphasizing key factors such as binding energy, molecular docking performance, drug-likeness, and toxicity prediction to assess their therapeutic potential. Considering the …

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 …

Psychedelic Minimalism: The Case Against Music In Psychedelic Therapy Settings, Samir A. Nader

Department of Medicine Faculty Publications

[Introduction: reframing the role of setting] In recent years, renewed attention has been given to the centrality of set and setting in psychedelic-assisted therapy. The Reporting of Setting in Psychedelic Clinical Trials (ReSPCT) guidelines reflect an evolving consensus: therapeutic outcomes are not solely pharmacologically determined but are heavily shaped by both the environment and the psychological state of the participant (2). Within this evolving paradigm, music has assumed a privileged role, framed as a therapeutic constant, typically curated to be emotionally supportive or evocative, and especially emphasized during peak psychedelic states (3). The prevailing assumption is that music facilitates safety, …

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%), …

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 …

Discordance Between Profound Hyperprolactinemia And Hormone Immunostaining In A Pit1-Positive Pituitary Neuroendocrine Tumor. A Rare Case Report, Aneela Arif, Radwa Osman

Department of Medicine Faculty Publications

We present a rare case of a functioning macroprolactinoma with negative hormone immunohistochemistry (IHC) but positive PIT1 transcription factor staining. This case highlights the diagnostic value of transcription factor IHC when clinical and biochemical findings are discordant with hormone staining. An 18-year-old female with unremarkable medical history presented with high prolactin levels, galactorrhea, and amenorrhea for 6 months. She was not on any medications, and was not sexually active, or trying to conceive. Prolactin levels were markedly elevated (462, 1,067, and 1,282 ng/mL). MRI showed a 13×12×14 mm T2-hyperintense, slightly cystic pituitary macroadenoma with suprasellar extension and optic chiasm compression, …

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 …

Diverticulitis—New Evidence To Share With Patients, Nicholas B. D'Alessandro, Tarun Vippa, Edward C. Oldfield Iv, David A. Johnson

Department of Medicine Faculty Publications

Diverticulitis is one of the most common gastrointestinal causes of hospitalization in Western society. While previously characterized as a disease of older patients, new literature highlights an increasing incidence among the younger population. Over the past few decades, the understanding of etiology and management of diverticulitis has changed drastically. New data refute past beliefs while promoting other novel recommendations to mitigate incidence and subsequent complications. Data now confirms the safety and possible protective benefit of particulate food, while highlighting evidence-based approaches for the use of diagnostic imaging and antibiotics. We recognize modifiable and non-modifiable risk factors that are commonly seen …

Irritable Bowel Syndrome Risk In Acne Patients: Implications For Dermatologic Care, Alex Y. Liu, Ana Ormaza Vera, Clinton W. Enos

Department Dermatology Faculty Publications

[Practice points]

• Clinicians should consider monitoring for early signs of irritable bowel syndrome (IBS) in adult patients with acne to facilitate prompt diagnosis and intervention.
• Clinicians should remain judicious when prescribing antibiotics for acne management to minimize potential disruptions to the gut microbiota and the risk for IBS.
• Isotretinoin may serve as a safer alternative to antibiotics in patients with acne, particularly those with gastrointestinal concerns.

Interaction Of Cardiac Leiomodin With The Native Cardiac Thin Filament, Madison Little, Cristina M. Risi, Tania M. Larrinaga, Mason D. Summers, Tyler Nguyen, Garry E. Smith Jr., Jennifer Atherton, Carol C. Gregorio, Alla S. Kostyukova, Vitold E. Galkin

Department of Biomedical and Translational Sciences Faculty Publications

Every heartbeat depends on cyclical contraction-relaxation produced by the interactions between myosin-containing thick and actin-based thin filaments (TFs) arranged into a crystalline-like lattice in the cardiac sarcomere. Therefore, the maintenance of thin filament length is crucial for myocardium function. The thin filament is comprised of an actin backbone, the regulatory troponin complex and tropomyosin that controls interactions between thick and thin filaments. Thin filament length is controlled by the tropomodulin family of proteins; tropomodulin caps pointed ends of thin filaments, and leiomodin (Lmod) promotes elongation of thin filaments by a “leaky-cap” mechanism. The broader distribution of Lmod on the thin …

Swinging Lever Mechanism Of Myosin Directly Shown By Time-Resolved Cryo-Em, David P. Klebl, Sean N. Mcmillan, Cristina Risi, Eva Forgacs, Betty Virok, Jennifer L. Atherton, Sarah A. Harris, Michele Stofella, Donald A. Winkelmann, Frank Sobott, Vitold E. Galkin, Peter J. Knight, Stephen P. Muench, Charlotte A. Scarfi, Howard D. White

Department of Biomedical and Translational Sciences Faculty Publications

Myosins produce force and movement in cells through interactions with F-actin¹. Generation of movement is thought to arise through actin-catalysed conversion of myosin from an ATP-generated primed (pre-powerstroke) state to a post-powerstroke state, accompanied by myosin lever swing²,³. However, the initial, primed actomyosin state has never been observed, and the mechanism by which actin catalyses myosin ATPase activity is unclear. Here, to address these issues, we performed time-resolved cryogenic electron microscopy (cryo-EM)⁴ of a myosin-5 mutant having slow hydrolysis product release⁵,⁶. Primed actomyosin was predominantly captured 10 ms after …

Deletion Of Chop In Beta Cell Protects Mice From Cardiovascular Complications In Type 2 Diabetes: Evidence From A Pre-Clinical Mouse Model, Balaji Srinivas, Kiran Alluri, Nour-Eddine Rhaleb, Khalid Matrougui

Department of Biomedical and Translational Sciences Faculty Publications

Introduction

Cardiovascular complications are the leading cause of morbidity and mortality in patients with type 2 diabetes (T2D), which is recognized as a major independent risk factor for coronary artery disease, stroke, peripheral vascular disease, and heart failure. The interrelationship between metabolic dysfunction and cardiovascular disease is complex and multifactorial, involving hyperglycemia, insulin resistance, inflammation, and oxidative stress. Evidence indicates that endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR) contribute to metabolic dysregulation and vascular dysfunction. However, the specific role of beta cell-derived UPR mediators, particularly C/EBP homologous protein (CHOP), in coordinating this interorgan axis between …