Anatomy Commons^™

Glial Cytokine Modulation Improves Sleep And Circadian Disruption In Female Saa Knock-In Mice Of Alzheimer’S-Related Pathology, Teresa Macheda, Margaret R. Hawkins, Carrie E. Johnson, Madison G. Lapid, Haleigh R. Whitlock, Savannah M. Shepard, Makayla F. Cox, Kelly N. Roberts, Leke Bytyqi, Heather M. Hash, Omar A. Abou El-Ezz, Mohammed Abou El-Ezz, Katharina Kohler, Sridhar Sunderam, Bruce F. O'Hara, Linda J. Van Eldik, Michael Paul Murphy, Marilyn J. Duncan, Adam D. Bachstetter

Neuroscience Faculty Publications

Introduction: Sleep and circadian disturbances are early Alzheimer's disease (AD) features, yet mechanisms linking amyloid pathology, neuroinflammation, and sex differences remain unclear.

Methods: We longitudinally assessed sleep, circadian rhythms, and cognition in female and male hAPP^SAA knock-in and control mice from 2 to 19 months using piezoelectric monitoring. Aged mice (15 months) received MW151, a glial cytokine inhibitor (2.5 mg/kg, every other day, 6 weeks).

Results: Only females exhibited midlife reductions in light-phase sleep, increased rhythm fragmentation, and reduced rhythm stability, coinciding with selective reversal learning deficits, effects independent of amyloid or cytokine burden. MW151 increased light-phase sleep and …

Engineering Plga Nanoparticle Size To Modulate Immune Responses After Spinal Cord Injury, Daniel J. Kolpek

University of Kentucky Doctoral Dissertations

Spinal cord injury is a severe and debilitating condition that often results in lifelong complications, including paralysis. Many of these chronic outcomes are driven by a sustained inflammatory response at the injury site, which limits tissue regeneration and functional recovery. As a result, therapeutic strategies that modulate this immune response have gained significant interest. Polymer based nanoparticle therapies have emerged as a promising approach due to their ability to interact with and influence immune cell behavior. Importantly, the physicochemical properties of nanoparticles can be precisely tuned to optimize these effects. Among these properties, size has been shown to influence key …

Temporal Evolution Of Brain Inflammation In The Bilateral Common Carotid Artery Stenosis Model Of Chronic Cerebral Hypoperfusion, Makayla F. Cox, Jill M. Roberts, Ryan K. Shahidehpour, David L. Dornbos Iii, Adam D. Bachstetter

Neuroscience Faculty Publications

Chronic cerebral hypoperfusion is a major contributor to vascular cognitive impairment and dementia, primarily through its disruption of white matter integrity and promotion of neuroinflammatory cascades. The bilateral common carotid artery stenosis (BCAS) model has emerged as the predominant experimental approach for studying the effects of chronic cerebral hypoperfusion, particularly in aging-relevant contexts. This review synthesizes current knowledge of inflammatory responses in the BCAS model, with an emphasis on their temporal progression and functional consequences. We begin by outlining the clinical burden of hypoperfusion, the rationale for BCAS, and the hemodynamic phases it produces. We then examine early neurovascular unit …

Dim Light At Night Impacts Circadian Rhythms And Alzheimer’S Disease-Like Neuroinf Lammation And Neuropathology In Humanized App Saa Knock-In Mice, Marilyn J. Duncan, Margaret R. Hawkins, Leke Bytyqi, Haleigh R. Whitlock, Savannah M. Shepard, Makayla F. Cox, Esther G. Drinkard, Teresa Macheda, Kelly N. Roberts, Katharina Kohler, Mary-Claire Schmidt, Carrie E. Johnson, Sridhar Sunderam, Bruce F. O'Hara, Michael Paul Murphy, Adam D. Bachstetter

Neuroscience Faculty Publications

Artificial light at night (light pollution) is widespread but understudied in the context of Alzheimer’s disease (AD). Sleep and circadian disruption have been linked to amyloid-β (Aβ) accumulation and neuroinflammation, but whether dim light at night (dLAN) modifies these processes remains unclear. We tested whether chronic dLAN exposure (8 lux during the dark phase, 8 weeks) alters circadian rhythms, amyloid pathology, and neuroinflammation in 12–13 month-old humanized APP knock-in (KI) mice. hAPP^SAA KI mice, which develop plaques, were compared with hAPP^WT KI controls carrying only a humanized APP sequence. dLAN reduced circadian rhythm amplitude and stability while increasing …

Introducing Neuro Sscial Work: A Brief Reflection On Neuroscience And The Profession, Priscila Llamosa

Social Work Faculty Publications

This reflection introduces and contextualizes the term Neuro Social Work, which I coin to name a specialized practice area at the intersection of social work, neuroscience, and neurodiversity. Drawing on my experience as a social work educator and practitioner, I discuss social work’s uneasy relationship with neuroscience, marked both by the opportunity to deepen our understanding of trauma, development, and healing, and by the risks of using brain‑based evidence to individualize structural harms or justify surveillance of marginalized communities. I outline, in broad strokes, what distinguishes Neuro Social Work from general neuroscience‑informed practice. The note is intended as a concept …

Alzheimer’S Disease And The Immune System: The Emerging Role Of Temra Cells, Edric D. Winford, Adam D. Bachstetter

Neuroscience Faculty Publications

No abstract provided.

You’Re Too Slow! Self-Selected Volitional Efforts Reveal Unexploited Neuromuscular Reserve Capacity Compared To Maximal Efforts During Fatiguing, Load Equated Resistance Exercise, Brian Benitez

Theses and Dissertations--Kinesiology and Health Promotion

This investigation examined how movement intent influences neuromuscular excitation strategies during fatiguing resistance exercise, comparing maximal intended concentric efforts versus self-selected volitional efforts during load-equated Smith machine back squat exercise to quantify reserve capacity and characterize underlying neuromuscular mechanisms. Twenty-three resistance-trained participants (12 males, 11 females) completed a repeated-measures design, with replication, across six visits, performing smith machine back squat repetitions-to-failure at 70% 1RM under maximal intent (accelerate rapidly) and volitional intent (self-selected effort) conditions. Maximal voluntary isometric contractions used rapid (instantaneous 10-second effort) and ramp (5-second build-up, 5-second maximal) protocols. Surface electromyography (sEMG) was recorded from vastus lateralis and …

Cellular And Behavioral Consequences Of Psychedelic Drug Action In The Claustrum, Tanner L. Anderson

Theses and Dissertations--Neuroscience

Psychedelics are rapidly garnering research attention for their ability to successfully treat a variety of psychiatric diseases after one or a handful of treatments in recent clinical research. Among the conditions treated is substance use disorder (SUD), which afflicted 48.5 million (16.7%) Americans aged 12 and older in 2023 (NSDUH). As clinical trial results continue to show lasting positive effects of psychedelic psychotherapy, there remains an enormous gap in knowledge regarding how these drugs cause lasting changes in the brain to achieve these therapeutic effects. It has been suggested that psychedelics must induce rapid and long-lasting neuronal plasticity in order …

Neural Mechanisms Of Respiratory Interoception, Pei-Ying Sarah Chan, Lu-Yuan Lee, Paul W. Davenport

UK CARES Faculty Publications

Respiratory interoception is one of the internal bodily systems that is comprised of different types of somatic and visceral sensations elicited by different patterns of afferent input and respiratory motor drive mediating multiple respiratory modalities. Respiratory interoception is a complex system, having multiple afferents grouped into afferent clusters and projecting into both discriminative and affective centers that are directly related to the behavioral assessment of breathing. The multi-afferent system provides a spectrum of input that result in the ability to interpret the different types of respiratory interceptive sensations. This can result in a response, commonly reported as breathlessness or dyspnea. …

Age-Related Brain Atrophy And The Positive Effects Of Behavioral Enrichment In Middle-Aged Beagles., Jessica A Noche, Hamsanandini Radhakrishnan, Margo F. Ubele, Kathy Boaz, Jennifer L Mefford, Erin D Jones, Hollie Y Van Rooyen, Jessica A Perpich, Katie Mccarty, Beverly Meacham, Jeffrey R. Smiley, Stasia A Bembenek Bailey, László G Puskás, David K. Powell, Lorena Sordo, Michael J Phelan, Christopher M. Norris, Elizabeth Head, Craig E L Stark

Neuroscience Faculty Publications

Aging dogs serve as a valuable preclinical model for Alzheimer's disease (AD) due to their natural age-related development of β-amyloid (Aβ) plaques, human-like metabolism, and large brains that are ideal for studying structural brain aging trajectories from serial neuroimaging. Here we examined the effects of chronic treatment with the calcineurin inhibitor (CNI) tacrolimus or the nuclear factor of activated T cells (NFAT)-inhibiting compound Q134R on age-related canine brain atrophy from a longitudinal study in middle-aged beagles (36 females, 7 males) undergoing behavioral enrichment. Annual MRI was analyzed using modern, automated techniques for region-of-interest-based and voxel-based volumetric assessments. We found that …

Overexpression Of Fatty Acid Synthase Upregulates Glutamine–Fructose-6-Phosphate Transaminase 1 And O-Linked N-Acetylglucosamine Transferase To Increase O-Glcnac Protein Glycosylation And Promote Colorectal Cancer Growth, James Drury, Mariah E. Geisen, Josiane Weber Tessmann, Piotr G. Rychahou, Courtney O. Kelson

Markey Cancer Center Faculty Publications

Fatty acid synthesis has been extensively investigated as a therapeutic target in cancers, including colorectal cancer (CRC). Fatty acid synthase (FASN), a key enzyme of de novo lipid synthesis, is significantly upregulated in CRC, and therapeutic approaches of targeting this enzyme are currently being tested in multiple clinical trials. However, the mechanisms behind the pro- oncogenic action of FASN are still not completely understood. Here, for the first time, we show that overexpression of FASN increases the expression of glutamine–fructose-6-phosphate transaminase 1 (GFPT1) and O-linked N-acetylglucosamine transferase (OGT), enzymes involved in hexosamine metabolism, and the level of O-GlcNAcylation in vitro …

An Efficient And High-Throughput Method For The Evaluation Of Mitochondrial Dysfunction In Frozen Brain Samples After Traumatic Brain Injury., Hemendra J Vekaria, Olivia J. Kalimon, Paresh Prajapati, Gopal V. Velmurugan, Patrick G Sullivan

Neuroscience Faculty Publications

Mitochondrial function analysis is a well-established method used in preclinical and clinical investigations to assess pathophysiological changes in various disease states, including traumatic brain injury (TBI). Although there are multiple approaches to assess mitochondrial function, one common method involves respirometric assays utilizing either Clark-type oxygen electrodes or fluorescent-based Seahorse analysis (Agilent). However, these functional analysis methods are typically limited to the availability of freshly isolated tissue samples due to the compromise of the electron transport chain (ETC) upon storage, caused by freeze-thaw-mediated breakdown of mitochondrial membranes. In this study, we propose and refine a method for evaluating electron flux through …

Elucidating The Role Of Fatty Acid Synthase In Apc-Driven Colorectal Cancer, Courtney O. Kelson

Theses and Dissertations--Toxicology and Cancer Biology

Globally, colorectal cancer (CRC) is the second leading cause of cancer related deaths. Currently, there is a growing incidence rate for individuals aged 20-49 years. Genetic and environmental factors contribute to the risk of this cancer. Early detection of CRC allows for the most effective treatment option in which surgical resection of the primary tumor occurs along with adjuvant chemotherapy. This therapeutic approach contributes to 5-year survival rate of 91%. However, surgical procedures and chemotherapy struggles against metastatic and relapsed CRC resulting in 5-year survival rate of 14%. Inefficacious treatments for relapsed and metastatic diseases emphasizes the need for more …

Zebrafish Drug Screening Identifies Erlotinib As An Inhibitor Of Wnt/ Β-Catenin Signaling And Self-Renewal In T-Cell Acute Lymphoblastic Leukemia, Majd A. Al-Hamaly, Anna H. Cox, Meghan G. Haney, Wen Zhang, Emma C. Arvin, Shilpa Sampathi, Mary Wimsett, Chunming Liu, Jessica S. Blackburn

Markey Cancer Center Faculty Publications

The Wnt/β-catenin pathway’s significance in cancer initiation, progression, and stem cell biology underscores its therapeutic potential. However, the clinical application of Wnt inhibitors remains limited due to challenges posed by off-target effects and complex cross-talk of Wnt signaling with other pathways. In this study, we leveraged a zebrafish model to perform a robust and rapid drug screening of 773 FDA-approved compounds to identify Wnt/β-catenin inhibitors with minimal toxicity. Utilizing zebrafish expressing a Wnt reporter, we identified several drugs that suppressed Wnt signaling without compromising zebrafish development. The effi- cacy of the top hit, Erlotinib, extended to human cells, where it …

The Delineation Of Platelet Pathology In Cardiometabolic Disease, Chi Peng

Theses and Dissertations--Pharmacology and Nutritional Sciences

Obesity is a multifactorial disease with many comorbidities leading to multiorgan dysfunction. Current studies point towards dysregulation of platelet signaling as a driver for increased risk of cardiovascular disease and stroke. The exact mechanisms remain elusive due to the complex interplay of factors involved, warranting the need to further understand how platelets are affected. Our preliminary data evaluating changes in platelet and coagulation parameters from bariatric patients showed that obesity did not affect platelet count or clotting time as demonstrated in INR values. However, female patients had increased bleeding events before surgery that were decreased after surgery. Due to limitations …

Characterization Of Bowel Dysfunction After Spinal Cord Injury In Mice, Olivia Wireman

Theses and Dissertations--Physiology

Most individuals who suffer a spinal cord injury (SCI) will experience some form of bowel dysfunction. Trauma to the spinal cord can result in severe constipation and/or incontinence, otherwise known as neurogenic bowel. Constipation requires extensive bowel routines typically involving the help of another person. Still, many living with SCI are hospitalized due to bowel complications such as fecal impaction. While neurogenic bowel has been well characterized in the clinic, pre-clinical models of neurogenic bowel after SCI are still in development. Most pre-clinical studies in bowel dysfunction after SCI are published in rat models. Studies existing in mice, to our …

Association Of Plasma Neurofilament Light Chain With Microstructural White Matter Changes In Down Syndrome, Herminia Diana Rosas, Nathaniel David Mercaldo, Yasemin Hasimoglu, Melissa Petersen, Lydia R. Lewis, Florence Lai, David Powell, Asim Dhungana, Ali Demir, David Keater, Michael Yassa, Adam M. Brickman, Sid O'Bryant

Neuroscience Faculty Publications

INTRODUCTION: Both micro- and macrostructural white matter (WM) abnormalities, particularly those related to axonal degeneration, are associated with cognitive decline in adults with Down syndrome (DS) prior to a diagnosis of Alzheimer disease. Neurofilament light chain (NfL) is a support protein within myelinated axons released into blood following axonal damage. In this study we investigated cross-sectional relationships between WM microstructural changes as measured by diffusion tensor imaging (DTI) and plasma NfL concentration in adults with DS without dementia.

METHODS: Thirty cognitively stable (CS) adults with DS underwent diffusion-weighted MRI scanning and plasma NfL measurement. DTI measures of select WM tracts …

The Impact Of Lung Cancer Screening Education On Knowledge And Screening Rates In A Kentucky Cancer Survivorship Clinic, Alexandra Isler

DNP Projects

Background: Lung cancer is a significant problem in Kentucky, which ranks fourth in the nation in adults who currently smoke. Early detection, through lung cancer screening, can prevent untimely deaths. Several barriers to screening exist including lack of knowledge and awareness among patients regarding lung cancer screening. By increasing knowledge, at risk patients can take the necessary steps to decrease incidence of late stage diagnoses.

Purpose: The purpose of this project was to evaluate patients’ knowledge of lung cancer screening and referral and screening rates before and after one-on-one patient education.

Methods: This was a quality improvement project that used …

The Last Of Us In Therapy: How Mind-Controlling Fungi And Gut Bacteria Affect Your Mental Health, Anastasia Lyon

Journal of Pharmacology & Nutritional Sciences

The "psilocybiome" represents the mutually beneficial relationship between ourselves, our bacteria, and psychedelic drugs. This short review briefly discusses the benefits and limitations surrounding the potential for psychedelic therapy to synergize with gut bacteria to help regulate and maintain proper balance in the immune system, diet, and stress levels. Psychedelic therapy is a novel treatment strategy that has the potential to improve patient mental health, and, by identifying the types of gut bacteria present in patients, it can aid in personalizing medicine by determining how well their "psilocybiome" may respond.

Microglia Proliferation Underlies Synaptic Dysfunction In The Prefrontal Cortex: Implications For The Pathogenesis Of Hiv-1- Associated Neurocognitive And Affective Alterations, Hailong Li, Kristen A. Mclaurin, Charles F. Mactutus, Rosemarie M. Booze

Neuroscience Faculty Publications

Microglia, which are productively infected by HIV-1, are critical for brain development and maturation, as well as synaptic plasticity. The pathophysiology of HIV-infected microglia and their role in the pathogenesis of HIV-1-associated neurocognitive and affective alterations, however, remains understudied. Three complementary aims were undertaken to critically address this knowledge gap. First, the expression of HIV-1 mRNA in the dorsolateral prefrontal cortex of postmortem HIV-1 seropositive individuals with HAND was investigated. Utilization of a combined RNAscope multiplex fluorescent and immunostaining assay revealed prominent HIV-1 mRNA in microglia of postmortem HIV-1 seropositive individuals with HAND. Second, measures of microglia proliferation and neuronal …

Mitochondria As Causes Of And Therapeutic Targets In Chronic Post-Sepsis Skeletal Muscle Weakness, Meagan Scott Kingren

Theses and Dissertations--Pharmacology and Nutritional Sciences

Sepsis, or the organ damage that ensues after the body fails to properly contain a local infection, is the leading cause of in-patient hospitalization in the United States. Advances in critical care medicine over the last 20 years have enabled most sepsis patients to survive the life-threatening dysregulated immune response. However, a majority of survivors report chronic weakness and fatigue years after sepsis, and the cause of this weakness remains largely unknown. This dissertation work focused first on elucidating the major causes of post-sepsis muscle weakness (Aim 1). This aim involved a time-course study to determine when muscle weakness was …

Exploring The Efficacy Of Mir-33 Antagonism In Promoting Regression Of Intracranial Atherosclerosis In A Nonhuman Primate Model, Peter Hecker

Theses and Dissertations--Pharmacology and Nutritional Sciences

Atherosclerosis, characterized by lipid accumulation and arterial inflammation, is a major contributor to global morbidity and mortality. Despite significant progress in understanding atherosclerosis in extracranial arteries, the study of intracranial atherosclerosis (ICAS) has been relatively neglected, despite its crucial role in stroke and vascular cognitive impairment. Challenges related to ICAS, including its location within the cranium and limited availability of suitable animal models, have hindered research progress in this area. Although nonhuman primates (NHPs) are commonly used for studying extracranial atherosclerosis, a comprehensive understanding of ICAS pathophysiology in these animals is lacking. By subjecting NHPs to a high-fat/cholesterol diet, we …

Key Factors For Improving Rigor And Reproducibility: Guidelines, Peer Reviews, And Journal Technical Reviews, Hong S. Lu, Alan Daugherty

Saha Cardiovascular Research Center Faculty Publications

To respond to the NIH's policy for rigor and reproducibility in preclinical research, many journals have implemented guidelines and checklists to guide authors in improving the rigor and reproducibility of their research. Transparency in developing detailed prospective experimental designs and providing raw data are essential premises of rigor and reproducibility. Standard peer reviews and journal-specific technical and statistical reviews are critical factors for enhancing rigor and reproducibility. This brief review also shares some experience from Arteriosclerosis, Thrombosis, and Vascular Biology, an American Heart Association journal, that has implemented several mechanisms to enhance rigor and reproducibility for preclinical research.

Β-Aminopropionitrile-Induced Aortic Aneurysm And Dissection In Mice, Hisashi Sawada, Zachary A. Beckner, Sohei Ito, Alan Daugherty, Hong S. Lu

Saha Cardiovascular Research Center Faculty Publications

The mechanistic basis for the formation of aortic aneurysms and dissection needs to be elucidated to facilitate the development of effective medications. β-Aminopropionitrile administration in mice has been used frequently to study the pathologic features and mechanisms of aortic aneurysm and dissection. This mouse model mimics several facets of the pathology of human aortic aneurysms and dissection, although many variables exist in the experimental design and protocols that must be resolved to determine its application to the human disease. In the present brief review, we have introduced the development of this mouse model and provided insights into understanding its pathologic …

Patient And Therapist Perceptions Of Respiratory Functioning Due To Spinal Cord Injury: Implications For Music Therapists, A'Marie Dotson

Theses and Dissertations--Music

Decreased respiratory functioning is a common symptom of spinal cord injury (SCI) and can impact individuals’ personal, professional, and social lives. In spite of this, researchers have not explored the use of music in the lives of individuals with SCIs or music’s role in their healthcare professionals’ treatment plans to improve respiratory functioning. The purpose of this qualitative study was to better understand how decreased respiratory functioning affects individuals with SCIs and healthcare professionals through a multiple case study design. Participants were two individuals with SCIs and three healthcare professionals (physical therapist, recreational therapist, and music therapist) who worked with …

Single-Cell Analysis Of Aneurysmal Aortic Tissue In Patients With Marfan Syndrome Reveals Dysfunctional Tgf-Β Signaling, Ashley Dawson, Yanming Li, Yang Li, Pingping Ren, Hernan G. Vasquez, Chen Zhang, Kimberly R. Rebello, Waleed Ageedi, Alon R. Azares, Aladdein Burchett Mattar, Mary Burchett Sheppard, Hong S. Lu, Joseph S. Coselli, Lisa A. Cassis, Alan Daugherty, Ying H. Shen, Scott A. Lemaire

Saha Cardiovascular Research Center Faculty Publications

The molecular and cellular processes leading to aortic aneurysm development in Marfan syndrome (MFS) remain poorly understood. In this study, we examined the changes of aortic cell populations and gene expression in MFS by performing single-cell RNA sequencing (scRNA seq) on ascending aortic aneurysm tissues from patients with MFS (n = 3) and age-matched non-aneurysmal control tissues from cardiac donors and recipients (n = 4). The expression of key molecules was confirmed by immunostaining. We detected diverse populations of smooth muscle cells (SMCs), fibroblasts, and endothelial cells (ECs) in the aortic wall. Aortic tissues from MFS showed alterations …

Adult Spiny Mice (Acomys) Exhibit Endogenous Cardiac Recovery In Response To Myocardial Infarction, Hsuan Peng, Kazuhiro Shindo, Renée R. Donahue, Erhe Gao, Brooke M. Ahern, Bryana M. Levitan, Himi Tripathi, David Powell, Ahmed Noor, Garrett A. Elmore, Jonathan Satin, Ashley W. Seifert, Ahmed K. Abdel-Latif

Physiology Faculty Publications

Complex tissue regeneration is extremely rare among adult mammals. An exception, however, is the superior tissue healing of multiple organs in spiny mice (Acomys). While Acomys species exhibit the remarkable ability to heal complex tissue with minimal scarring, little is known about their cardiac structure and response to cardiac injury. In this study, we first examined baseline Acomys cardiac anatomy and function in comparison with commonly used inbred and outbred laboratory Mus strains (C57BL6 and CFW). While our results demonstrated comparable cardiac anatomy and function between Acomys and Mus, Acomys exhibited a higher percentage of cardiomyocytes displaying …

Dietary And Pharmacologic Manipulations Of Host Lipids And Their Interaction With The Gut Microbiome In Non-Human Primates, Jennifer M. Lang, Leslie R. Sedgeman, Lei Cai, Joseph D. Layne, Zhen Wang, Calvin Pan, Richard Lee, Ryan E. Temel, Aldons J. Lusis

Physiology Faculty Publications

The gut microbiome influences nutrient processing as well as host physiology. Plasma lipid levels have been associated with the microbiome, although the underlying mechanisms are largely unknown, and the effects of dietary lipids on the gut microbiome in humans are not well-studied. We used a compilation of four studies utilizing non-human primates (Chlorocebus aethiops and Macaca fascicularis) with treatments that manipulated plasma lipid levels using dietary and pharmacological techniques, and characterized the microbiome using 16S rDNA. High-fat diets significantly reduced alpha diversity (Shannon) and the Firmicutes/Bacteroidetes ratio compared to chow diets, even when the diets had different compositions …

Mechanisms Of Smoothened Regulation In Hedgehog Signaling, Jie Zhang, Zulong Liu, Jianhang Jia

Markey Cancer Center Faculty Publications

The seven-transmembrane protein, Smoothened (SMO), has shown to be critical for the hedgehog (HH) signal transduction on the cell membrane (and the cilium in vertebrates). SMO is subjected to multiple types of post-translational regulations, including phosphorylation, ubiquitination, and sumoylation, which alter SMO intracellular trafficking and cell surface accumulation. Recently, SMO is also shown to be regulated by small molecules, such as oxysterol, cholesterol, and phospholipid. The activity of SMO must be very well balanced by these different mechanisms in vivo because the malfunction of SMO will not only cause developmental defects in early stages, but also induce cancers in late …

Hypertrophic Cardiomyopathy Β-Cardiac Myosin Mutation (P710r) Leads To Hypercontractility By Disrupting Super Relaxed State, Alison Schroer Vander Roest, Chao Liu, Makenna M. Morck, Kristina Bezold Kooiker, Gwanghyun Jung, Dan Song, Aminah Dawood, Arnav Jhingran, Gaspard Pardon, Sara Ranjbarvaziri, Giovanni Fajardo, Mingming Zhao, Kenneth S. Campbell, Beth L. Pruitt, James A. Spudich, Kathleen M. Ruppel, Daniel Bernstein

Physiology Faculty Publications

Hypertrophic cardiomyopathy (HCM) is the most common inherited form of heart disease, associated with over 1,000 mutations, many in β-cardiac myosin (MYH7). Molecular studies of myosin with different HCM mutations have revealed a diversity of effects on ATPase and load-sensitive rate of detachment from actin. It has been difficult to predict how such diverse molecular effects combine to influence forces at the cellular level and further influence cellular phenotypes. This study focused on the P710R mutation that dramatically decreased in vitro motility velocity and actin-activated ATPase, in contrast to other MYH7 mutations. Optical trap measurements of single myosin molecules revealed …