Biochemistry, Biophysics, and Structural Biology Commons^™

Cigarette Smoke-Induced Epithelial-To-Mesenchymal Transition: Insights Into Cellular Mechanisms And Signaling Pathways, Sarah Mohammed Alqithami, Amrita Machwe, David K. Orren

Markey Cancer Center Faculty Publications

This review delves into the molecular complexities underpinning the epithelial-to-mesenchymal transition (EMT) induced by cigarette smoke (CS) in human bronchial epithelial cells (HBECs). The complex interplay of pathways, including those related to WNT//β-catenin, TGF-β/SMAD, hypoxia, oxidative stress, PI3K/Akt, and NF-κB, plays a central role in mediating this transition. While these findings significantly broaden our understanding of CS-induced EMT, the research reviewed herein leans heavily on 2D cell cultures, highlighting a research gap. Furthermore, the review identifies a stark omission of genetic and epigenetic factors in recent studies. Despite these shortcomings, the findings furnish a consolidated foundation not only for the …

Cryo-Em Reconstruction Of Oleate Hydratase Bound To A Phospholipid Membrane Bilayer, Michael L. Oldham, M. Zuhaib Qayyum, Ravi C. Kalathur, Charles O. Rock, Christopher D. Radka

Markey Cancer Center Faculty Publications

Oleate hydratase (OhyA) is a bacterial peripheral membrane protein that catalyzes FAD-dependent water addition to membrane bilayer-embedded unsaturated fatty acids. The opportunistic pathogen Staphylococcus aureus uses OhyA to counteract the innate immune system and support colonization. Many Gram-positive and Gram-negative bacteria in the microbiome also encode OhyA. OhyA is a dimeric flavoenzyme whose carboxy terminus is identified as the membrane binding domain; however, understanding how OhyA binds to cellular membranes is not complete until the membrane-bound structure has been elucidated. All available OhyA structures depict the solution state of the protein outside its functional environment. Here, we employ liposomes to …

Nsd3::Nutm1 Fusion Sarcoma Mimicking Malignant Peripheral Nerve Sheath Tumor With Prolonged Survival, Jing Di, Ali M. Alhaidary, Chi Wang, Jinge Liu, Sainan Wei, Joseph Valentino, Therese J. Bocklage

Markey Cancer Center Faculty Publications

Nuclear Protein in Testis (NUT)-rearranged tumors comprise predominantly NUT car- cinoma but also include certain lymphomas, leukemias, skin appendage tumors, and sarcomas. Although histologically diverse, all are genetically identified by oncogenic rearrangement in the NUTM1 gene. Many fusion partners occur, and NSD3 is NUT carcinoma’s third most common partner. Herein, we present a case of a 26-year-old man with an NSD3::NUTM1 fusion sarcoma. The patient presented at the age of 13 months with a scalp nodule. Over the next 24 years, he experienced five local recurrences and ultimately expired of a rapidly progressive recurrence. His treatment included surgical resections, radiation, …

Pragmatism And Feasibility: A Qualitative Study Of Experiences Implementing And Upgrading Care In Geriatric Emergency Departments, Anita Chary, Annika Bhananker, Vivian Ramont, Lauren Southerland, Aanand Naik, Kyler Godwin, Maura Kennedy

Faculty, Staff and Students Publications

OBJECTIVES: Implementation and sustainability of new care processes in emergency departments (EDs) is difficult. We describe experiences of implementing geriatric care processes in EDs that upgraded their accreditation level for the Geriatric Emergency Department Accreditation (GEDA) program. These EDs can provide a model for adopting and sustaining guidelines for evidence-based geriatric care.

METHODS: We performed qualitative interviews with geriatric ED nurse and physician leaders overseeing their ED's geriatric accreditation processes. The interview guide was based on the Consolidated Framework for Implementation Research (CFIR), a framework consisting of a comprehensive set of factors that impact implementation of evidence-based interventions. We used …

Elevating Plk1 Overcomes Beti Resistance In Prostate Cancer Via Triggering Brd4 Phosphorylation-Dependent Degradation In Mitosis, Yanquan Zhang, Ka-Wing Fong, Fengyi Mao, Ruixin Wang, Derek B. Allison, Dana Napier, Daheng He, Jinpeng Liu, Yeqing Zhang, Jing Chen, Yifan Kong, Chaohao Li, Guangbing Li, Jinghui Liu, Zhiguo Li, Haining Zhu, Chi Wang, Xiaoqi Liu

Markey Cancer Center Faculty Publications

Bromodomain-containing protein 4 (BRD4) has emerged as a promising therapeutic target in prostate cancer (PCa). Understanding the mechanisms of BRD4 stability could enhance the clinical response to BRD4-tar- geted therapy. In this study, we report that BRD4 protein levels are significantly decreased during mitosis in a PLK1-dependent manner. Mechanistically, we show that BRD4 is primarily phosphorylated at T1186 by the CDK1/cyclin B complex, recruiting PLK1 to phosphorylate BRD4 at S24/S1100, which are recognized by the APC/CCdh1 complex for proteasome pathway degradation. We find that PLK1 overexpression lowers SPOP mutation-stabilized BRD4, consequently rendering PCa cells re-sensitized to BRD4 inhibitors. Intrigu-ingly, we …

Genetic Diversity Of 1,845 Rhesus Macaques Improves Genetic Variation Interpretation And Identifies Disease Models, Jun Wang, Meng Wang, Ala Moshiri, R Alan Harris, Muthuswamy Raveendran, Tracy Nguyen, Soohyun Kim, Laura Young, Keqing Wang, Roger Wiseman, David H O'Connor, Zach Johnson, Melween Martinez, Michael J Montague, Ken Sayers, Martha Lyke, Eric Vallender, Tim Stout, Yumei Li, Sara M Thomasy, Jeffrey Rogers, Rui Chen

Faculty, Staff and Students Publications

Understanding and treating human diseases require valid animal models. Leveraging the genetic diversity in rhesus macaque populations across eight primate centers in the United States, we conduct targeted-sequencing on 1845 individuals for 374 genes linked to inherited human retinal and neurodevelopmental diseases. We identify over 47,000 single nucleotide variants, a substantial proportion of which are shared with human populations. By combining rhesus and human allele frequencies with established variant prediction methods, we develop a machine learning-based score that outperforms established methods in predicting missense variant pathogenicity. Remarkably, we find a marked number of loss-of-function variants and putative deleterious variants, which …

Soxb1 Transcription Factors Are Essential For Initiating And Maintaining Neural Plate Border Gene Expression, Elizabeth Schock, Joshua R. York, Austin P. Li, Ashlyn Y. Tu, Carole Labonne

Markey Cancer Center Faculty Publications

SoxB1 transcription factors (Sox2/3) are well known for their role in early neural fate specification in the embryo, but little is known about functional roles for SoxB1 factors in non-neural ectodermal cell types, such as the neural plate border (NPB). Using Xenopus laevis, we set out to determine whether SoxB1 transcription factors have a regulatory function in NPB formation. Here, we show that SoxB1 factors are necessary for NPB formation, and that prolonged SoxB1 factor activity blocks the transition from a NPB to a neural crest state. Using ChIP-seq, we demonstrate that Sox3 is enriched upstream of NPB genes in …

Response To Replication Stress And Maintenance Of Genome Stability By Wrn, The Werner Syndrome Protein, David K. Orren, Amrita Machwe

Markey Cancer Center Faculty Publications

Werner syndrome (WS) is an autosomal recessive disease caused by loss of function of WRN. WS is a segmental progeroid disease and shows early onset or increased frequency of many characteristics of normal aging. WRN possesses helicase, annealing, strand exchange, and exonuclease activities and acts on a variety of DNA substrates, even complex replication and re- combination intermediates. Here, we review the genetics, biochemistry, and probably physiological functions of the WRN protein. Although its precise role is unclear, evidence suggests WRN plays a role in pathways that respond to replication stress and maintain genome stability particularly in telomeric regions.

An Electronic Health Record Model For Predicting Risk Of Hepatic Fibrosis In Primary Care Patients, Aaron P Thrift, Theresa H Nguyen Wenker, Kyler Godwin, Maya Balakrishnan, Hao T Duong, Rohit Loomba, Fasiha Kanwal, Hashem B El-Serag

Faculty, Staff and Students Publications

BACKGROUND: One challenge for primary care providers caring for patients with nonalcoholic fatty liver disease is to identify those at the highest risk for clinically significant liver disease.

AIM: To derive a risk stratification tool using variables from structured electronic health record (EHR) data for use in populations which are disproportionately affected with obesity and diabetes.

METHODS: We used data from 344 participants who underwent Fibroscan examination to measure liver fat and liver stiffness measurement [LSM]. Using two approaches, multivariable logistic regression and random forest classification, we assessed risk factors for any hepatic fibrosis (LSM > 7 kPa) and significant hepatic …

Subspecialty Choices Among Medicine-Pediatrics Graduates: Results From A Four-Year National Program Director Survey, Anoop Agrawal, Daniel Wells, Michael Kisielewski, Savita Misra, Benjamin Doolittle

Faculty, Staff and Students Publications

Background and objectives Dual-trained medicine-pediatrics physicians (med-peds) play an important role in the healthcare ecosystem. Little is known about the subspecialty choices of med-peds residency graduates. This study aims to characterize the subspecialty choices of med-peds residency graduates. Methods The Medicine-Pediatrics Program Directors Association (MPPDA) administers an annual survey to the program directors of all med-peds residency programs accredited by the Accreditation Council for Graduate Medical Education (ACGME). This project represents aggregate survey data from 2020-2023. Results The number of program directors responding to the survey ranged from 80.8% (63/78) to 85.7% (66/77; mean response rate: 82.8%). About 465 of …

Jacc: Advances Expert Panel Perspective: Shared Decision-Making In Multidisciplinary Team-Based Cardiovascular Care, Elizabeth M Perpetua, Roseanne Palmer, Viet T Le, Sana M Al-Khatib, Craig J Beavers, Joshua A Beckman, Biykem Bozkurt, Megan Coylewright, Caroline Lloyd Doherty, Kimberly A Guibone, Marian Hawkey, Patricia A Keegan, James N Kirkpatrick, Jessica Laperle, Sandra B Lauck, Glenn Levine, Brian R Lindman, Michael J Mack, Andrea L Price, Susan Strong, Janet F Wyman, Quentin R Youmans, Martha Gulati

Faculty, Staff and Students Publications

Shared decision-making (SDM) and multidisciplinary team-based care delivery are recommended across several cardiology clinical practice guidelines. However, evidence for benefit and guidance on implementation are limited. Informed consent, the use of patient decision aids, or the documentation of these elements for governmental or societal agencies may be conflated as SDM. SDM is a bidirectional exchange between experts: patients are the experts on their goals, values, and preferences, and clinicians provide their expertise on clinical factors. In this Expert Panel perspective, we review the current state of SDM in team-based cardiovascular care and propose best practice recommendations for multidisciplinary team implementation …

Achieving Equitable Cardiovascular Care For All: Acc Board Of Trustees Health Equity Task Force Action Plan, Paul L Douglass, Dipti Itchhaporia, Biykem Bozkurt, Robert O Roswell, Akshay Khandelwal, Quinn Capers, Kathryn Berlacher, Modele O Ogunniyi, Alison L Bailey, Phillip D Levy, Aubrey J Grant, Jack Tocco, Angela Natcheva, Akua G Asare, Ami B Bhatt, Jennifer H Mieres, Maghee F Disch, Melvin R Echols

Faculty, Staff and Students Publications

Advancements in cardiovascular (CV) disease management are notable, yet health inequities prevail, associated with increased morbidity and mortality noted among non-Hispanic African Americans in the United States. The 2002 Institute of Medicine Report revealed ongoing racial and ethnic health care disparities, spearheading a deeper understanding of the social determinants of health and systemic racism to develop strategies for CV health equity (HE). This article outlines the strategic HE approach of the American College of Cardiology, comprising 6 strategic equity domains: workforce pathway inclusivity, health care, data, science, and tools; education and training; membership, partnership, and collaboration; advocacy and policy; and …

Use Of Cobalt(Iii) And Copper(Ii) Complexes With Thiosemicarbazone Ligands And Berberine Chloride As Anti-Cancer Agents Against Triple Negative Breast Cancer, Duaa Rashad Alajroush

Chemistry & Biochemistry Theses & Dissertations

It is a worrying fact that chemotherapeutic options for treating triple negative breast cancer are limited in nature, including the use of inorganic pharmaceuticals such as cisplatin and its analogues. It has been reported that cisplatin has undesirable side effects when used as a chemotherapeutic drug. As such, there is a need to use non-platinum-containing complexes as chemotherapeutic agents. Based on that issue, it has been reported by our research group and others that cobalt- and copper-containing complexes have shown great potential in anti-cancer properties when compared to cisplatin. In this research project, the cytotoxic effects of the following complexes: …

Effect Of Plumbagin On Chemo-Resistant Metastatic Retinoblastoma, John J. Soto

Theses and Dissertations

Retinoblastoma, which is an ocular malignancy, usually results in poor prognoses in pediatric patients worldwide. Retinoblastoma in some events, can develop metastatic phenotypes which can lead to secondary tumor formation, furthering deleterious patient outcomes. It is of paramount importance to identify and research potent novel compounds that can be used to increase the likelihood of remission. Plumbagin (PLB) is a plant-derived, neuroprotective agent, which exhibits significant anticancer activities during in vitro study. PLB has been shown to have a high therapeutic efficacy against chemoresistant sublines as well as their normal counterparts. We attempted to show that the chemoresistant ABCC1 could …

Scanless Two-Photon Voltage Imaging, Ruth R Sims, Imane Bendifallah, Christiane Grimm, Aysha S Mohamed Lafirdeen, Soledad Domínguez, Chung Yuen Chan, Xiaoyu Lu, Benoît C Forget, François St-Pierre, Eirini Papagiakoumou, Valentina Emiliani

Faculty, Staff and Students Publications

Two-photon voltage imaging has long been heralded as a transformative approach capable of answering many long-standing questions in modern neuroscience. However, exploiting its full potential requires the development of novel imaging approaches well suited to the photophysical properties of genetically encoded voltage indicators. We demonstrate that parallel excitation approaches developed for scanless two-photon photostimulation enable high-SNR two-photon voltage imaging. We use whole-cell patch-clamp electrophysiology to perform a thorough characterization of scanless two-photon voltage imaging using three parallel illumination approaches and lasers with different repetition rates and wavelengths. We demonstrate voltage recordings of high-frequency spike trains and sub-threshold depolarizations from neurons …

Folate As A Potential Treatment For Lethal Ventricular Arrhythmias In Tango2-Deficiency Disorder, Weiyi Xu, Yingqiong Cao, Sara B Stephens, Maria Jose Arredondo, Yifan Chen, William Perez, Liang Sun, Andy C Yu, Jean J Kim, Seema R Lalani, Na Li, Frank T Horrigan, Francisco Altamirano, Xander Ht Wehrens, Christina Y Miyake, Lilei Zhang

Faculty, Staff and Students Publications

TANGO2-deficiency disorder (TDD) is an autosomal-recessive genetic disease caused by biallelic loss-of-function variants in the TANGO2 gene. TDD-associated cardiac arrhythmias are recalcitrant to standard antiarrhythmic medications and constitute the leading cause of death. Disease modeling for TDD has been primarily carried out using human dermal fibroblast and, more recently, in Drosophila by multiple research groups. No human cardiomyocyte system has been reported, which greatly hinders the investigation and understanding of TDD-associated arrhythmias. Here, we established potentially novel patient-derived induced pluripotent stem cell differentiated cardiomyocyte (iPSC-CM) models that recapitulate key electrophysiological abnormalities in TDD. These electrophysiological abnormalities were rescued in iPSC-CMs …

Echocardiogram By Apical-Subcostal Protocol In Prone Position During Invasive Mechanical Ventilation In Cardiovascular Intensive Care Unit, César Del Castillo, Fernando Verdugo, Franco Appiani, Francisca Yáñez, Camila Bontá, Carlos Torres-Herrera, Angela Garcia, Zorba Blázquez-Bermejo, Javier Castrodeza, Daniel Requena, Andreina Rodríguez, Arquimedes Silvio, Agustín Gatica, Arnulfo Begazo, Mario Alfaro

Faculty, Staff and Students Publications

AIMS: To evaluate the feasibility of a transthoracic echocardiogram using an apical-subcostal protocol in invasive mechanical ventilation (IMV) and prone position.

METHODS: Prospective study of adults who required a prone position during IMV. A pillow was placed only under the left hemithorax in the prone position to elevate and ease the apical and subcostal windows. A critical care cardiologist (prone group) acquired and evaluated the images using the apical-subcostal protocol. Besides, we used ambulatory echocardiograms performed as a comparative group (supine group).

RESULTS: 86 patients were included, 43 in the prone and 43 in the supine. In the prone group, …

Molecular Therapy Nucleic Acids, Jasmin Morandell, Alan Monziani, Martina Lazioli, Deborah Donzel, Jessica Döring, Claudio Oss Pegorar, Angela D'Anzi, Miguel Pellegrini, Andrea Mattiello, Dalia Bortolotti, Guendalina Bergonzoni, Takshashila Tripathi, Virginia B Mattis, Marina Kovalenko, Jessica Rosati, Christoph Dieterich, Erik Dassi, Vanessa C Wheeler, Zdenka Ellederová, Jeremy E Wilusz, Gabriella Viero, Marta Biagioli

Faculty, Staff and Students Publications

Circular RNA (circRNA) molecules have critical functions during brain development and in brain-related disorders. Here, we identified and validated a circRNA, circHTT(2,3,4,5,6), stemming from the Huntington’s disease (HD) gene locus that is most abundant in the central nervous system (CNS). We uncovered its evolutionary conservation in diverse mammalian species, and a correlation between circHTT(2,3,4,5,6) levels and the length of the CAG-repeat tract in exon-1 of HTT in human and mouse HD model systems. The mouse orthologue, circHtt(2,3,4,5,6), is expressed during embryogenesis, increases during nervous system development, and is aberrantly upregulated in the presence of the expanded CAG tract. …

Cyp3a Mediates An Unusual C(Sp2)-C(Sp3) Bond Cleavage Via Ipso-Addition Of Oxygen In Drug Metabolism, Xuan Qin, Yong Wang, Qiuji Ye, John M Hakenjos, Jin Wang, Mingxing Teng, Lei Guo, Zhi Tan, Damian W Young, Kevin R Mackenzie, Feng Li

Faculty, Staff and Students Publications

Mammalian cytochrome P450 drug-metabolizing enzymes rarely cleave carbon–carbon (C-C) bonds and the mechanisms of such cleavages are largely unknown. We identified two unusual cleavages of non-polar, unstrained C(sp2)-C(sp3) bonds in the FDA-approved tyrosine kinase inhibitor pexidartinib that are mediated by CYP3A4/5, the major human phase I drug metabolizing enzymes. Using a synthetic ketone, we rule out the Baeyer-Villiger oxidation mechanism that is commonly invoked to address P450-mediated C-C bond cleavages. Our studies in 18O2 and H218O enriched systems reveal two unusual distinct mechanisms of C-C bond cleavage: one bond is cleaved by CYP3A-mediated ipso-addition of oxygen to a C(sp2) …

Single-Cell Analysis Identifies Plk1 As A Driver Of Immunosuppressive Tumor Microenvironment In Luad, Yifan Kong, Chaohao Li, Jinpeng Liu, Sai Wu

Markey Cancer Center Faculty Publications

PLK1 (Polo-like kinase 1) plays a critical role in the progression of lung adenocarcinoma (LUAD). Recent studies have unveiled that targeting PLK1 improves the efficacy of immuno- therapy, highlighting its important role in the regulation of tumor immunity. Nevertheless, our understanding of the intricate interplay between PLK1 and the tumor microenvironment (TME) remains incomplete. Here, using genetically engineered mouse model and single- cell RNA-seq analysis, we report that PLK1 promotes an immunosuppressive TME in LUAD, characterized with enhanced M2 polarization of tumor associated macrophages (TAM) and dampened antigen presentation process. Mechanistically, elevated PLK1 coin- cides with increased secretion of CXCL2 …

Intravascular Imaging-Guided Versus Coronary Angiography-Guided Complex Pci: A Meta-Analysis Of Randomized Controlled Trials, Mohamed Hamed, Sheref Mohamed, Mohamed Mahmoud, Jonathan Kahan, Amr Mohsen, Faisal Rahman, Waleed Kayani, Fernando Alfonso, Emmanuel S Brilakis, Islam Y Elgendy, Mamas A Mamas, Ayman Elbadawi

Faculty, Staff and Students Publications

INTRODUCTION: Trials evaluating the role of intravascular imaging in percutaneous coronary intervention (PCI) for complex coronary artery disease have yielded mixed results. This study aimed to compare the outcomes of intravascular imaging specifically intravascular ultrasound (IVUS) with those from conventional coronary angiography in complex PCI.

METHODS: Comprehensive electronic search of MEDLINE, EMBASE, and Cochrane databases was performed until March 2023 for randomized clinical trials (RCTs) comparing intravascular imaging with coronary angiography in patients undergoing complex PCI. Complex PCI was defined per each study, and included PCI for American College of Cardiology/American Heart Association (ACC/AHA) type B2/C lesions, unprotected left main …

Bacillary Angiomatosis In A Patient With Hiv And Disseminated Mycobacterium Avium Complex Infection, Ibeth P Caceres, Angelique Ruml, Rubi Montejano, Omid Jalali, Theodore Rosen

Faculty, Staff and Students Publications

Bartonella is a genus of arthropod-borne bacterial pathogens that typically cause persistent infections of erythrocytes and endothelial cells in mammalian hosts. The species that primarily infect humans are Bartonella henselae and Bartonella quintana. Depending on immune status, the clinical presentation of B. henselae may differ, manifesting as cat-scratch disease in immunocompetent individuals or bacillary angiomatosis (BA) and peliosis in immunocompromised patients. The cutaneous manifestations of BA are typically characterized by occasionally painful, angiomatous papules and nodules, often with a chronic, persistent course. Herein, we present a case of biopsy-confirmed B. henselae infection in a 32-year-old HIV-positive female with acquired immunodeficiency …

Myocardial Infarction Suppresses Protein Synthesis And Causes Decoupling Of Transcription And Translation, Shijie Liu, Vaibhav Deshmukh, Fangfei Wang, Jie Liang, Jenna Cusick, Xiao Li, James F Martin

Faculty, Staff and Students Publications

Gene expression involves transcription, translation, and mRNA and protein degradation. Advanced RNA sequencing measures mRNA levels for cell state assessment, but mRNA level does not fully reflect protein level. Identifying heart cell proteomes and their stress response is crucial. Using a cardiomyocyte-specific mouse model, we tracked protein synthesis after myocardial infarction. Our results showed that myocardial infarction suppresses protein synthesis and unveils a decoupling of translation and transcription regulation in cardiomyocytes.

Humanism Rounds: A Multifaceted "Back To Bedside" Initiative To Improve Meaning At Work For Internal Medicine Residents, Jennifer M Kaplan, Suchi Agrawal, Disha Kumar, Ann Xu, Kristen A Staggers, Anna G Symmes, Reina U Styskel, Brett Styskel, Anoop Agrawal, Stacey R Rose

Faculty, Staff and Students Publications

INTRODUCTION: Burnout is an increasingly prevalent problem among resident physicians. To address this problem, the Accreditation Council on Graduate Medical Education (ACGME) created the Back to Bedside initiative, supporting resident-driven projects focused on increasing direct interactions with patients. In 2017, Baylor College of Medicine (BCM) Internal Medicine Residency received a Back to Bedside grant to develop and implement “Humanism Rounds,” a multifaceted program which sought to promote personal connections between residents and patients and foster reflection about patients’ non-clinical stories, with the hopes of reducing burnout and increasing residents’ sense of meaning at work.

MATERIALS AND METHODS: Between 2018 and …

Using Rapid Protein Degradation To Determine The Effect Of Runx1 Loss-Of- Function On Dna Damage Accumulation And Repair., Jackriel Pina Morales

Theses and Dissertations

Germline mutations in RUNX1 are associated with familial platelet disorder with a predisposition to myeloid malignancy (RUNX1-FPDMM), in which patients present with low platelet counts,excessive bleeding and bruising, and an increased risk of Acute Myeloid Leukemia (AML)/Myelodysplastic Syndrome (MDS) development throughout their lifetime. To understand how these loss-of-function mutations in RUNX1 drive predispose to malignancy, it is important to develop a detailed understanding of the molecular basis of RUNX1 function. While RUNX1 is a transcription factor, preliminary data from our group and work from others suggests that RUNX1 also interacts with proteins that are critical for DNA damage …

Ciliary Tip Actin Dynamics Regulate Photoreceptor Outer Segment Integrity, Roly Megaw, Abigail Moye, Zhixian Zhang, Fay Newton, Fraser Mcphie, Laura C Murphy, Lisa Mckie, Feng He, Melissa K Jungnickel, Alex Von Kriegsheim, Peter A Tennant, Chloe Brotherton, Christine Gurniak, Alecia K Gross, Laura M Machesky, Theodore G Wensel, Pleasantine Mill

Faculty, Staff and Students Publications

As signalling organelles, cilia regulate their G protein-coupled receptor content by ectocytosis, a process requiring localised actin dynamics to alter membrane shape. Photoreceptor outer segments comprise an expanse of folded membranes (discs) at the tip of highly-specialised connecting cilia, into which photosensitive GPCRs are concentrated. Discs are shed and remade daily. Defects in this process, due to mutations, cause retinitis pigmentosa (RP). Whilst fundamental for vision, the mechanism of photoreceptor disc generation is poorly understood. Here, we show membrane deformation required for disc genesis is driven by dynamic actin changes in a process akin to ectocytosis. We show RPGR, a …

An Unexpected Path For Malat1 In Neurons: Trafficking Out Of The Nucleus For Translation, Bradley W Wright, Jeremy E Wilusz

Faculty, Staff and Students Publications

The Malat1 (metastasis-associated lung adenocarcinoma transcript 1) long noncoding RNA is highly and broadly expressed in mammalian tissues, accumulating in the nucleus where it modulates expression and pre-mRNA processing of many protein-coding genes. In this issue of Genes & Development, Xiao and colleagues (doi:10.1101/gad.351557.124) report that a significant fraction of Malat1 transcripts in cultured mouse neurons are surprisingly exported from the nucleus. These transcripts are packaged with Staufen proteins in RNA granules and traffic down the lengths of neurites. They then can be released in a stimulus-dependent manner to be locally translated into a microprotein that alters neuronal gene …

Unveiling The Nexus Of Cellular Quality Control: Exploring The Interplay Between Ribosome-Associated Protein Quality Control And Mitochondrial Quality Control Pathways, Foozhan Tahmasebinia

Biological Sciences Theses and Dissertations

In eukaryotic cells, the intricate interplay between cellular quality control mechanisms is crucial for maintaining homeostasis and safeguarding the integrity of vital processes, spanning from macromolecule synthesis to the renewal of entire cellular organelles.

Disruption of these networks can lead to severe diseases such as metabolic disorders, underscoring the interconnected nature and feedback control mechanisms inherent in biological systems, including cellular quality control systems. This interconnectedness extends to the intricate communication between organelles, enabling coordinated functioning and adaptation to changing cellular conditions, particularly in response to stressors.

While the exact mechanisms governing these communications within cellular quality control systems remain …

Protein Oxidation In Aging And Alzheimer’S Disease Brain, Rukhsana Sultana, D. Allan Butterfield

Markey Cancer Center Faculty Publications

Proteins are essential molecules that play crucial roles in maintaining cellular homeostasis and carrying out biological functions such as catalyzing biochemical reactions, structural proteins, immune response, etc. However, proteins also are highly susceptible to damage by reactive oxygen species (ROS) and reactive nitrogen species (RNS). In this review, we summarize the role of protein oxidation in normal aging and Alzheimer’s disease (AD). The major emphasis of this review article is on the carbonylation and nitration of proteins in AD and mild cognitive impairment (MCI). The oxidatively modified proteins showed a strong correlation with the reported changes in brain structure, carbohydrate …

Predicting The Pathway Involvement Of Metabolites Based On Combined Metabolite And Pathway Features, Erik D. Huckvale, Hunter N. B. Moseley

Markey Cancer Center Faculty Publications

A major limitation of most metabolomics datasets is the sparsity of pathway annotations for detected metabolites. It is common for less than half of the identified metabolites in these datasets to have a known metabolic pathway involvement. Trying to address this limitation, machine learning models have been developed to predict the association of a metabolite with a “pathway category”, as defined by a metabolic knowledge base like KEGG. Past models were implemented as a single binary classifier specific to a single pathway category, requiring a set of binary classifiers for generating the predictions for multiple pathway categories. This past approach …