Medical Molecular Biology Commons^™

Multimodal Approach In Distinguishing And Managing Uterine Arteriovenous Malformation: A Case Report, Sajeev Sridhar, Roman Sukhovershin, John A Hancock

The Brown Foundation: Institute of Molecular Medicine

Arteriovenous malformations (AVMs) are abnormal vascular connections bypassing the capillary system, categorized as acquired or congenital. Acquired uterine AVMs, often resulting from uterine trauma due to procedures like dilatation and curettage, can be life threatening, necessitating prompt diagnosis and management. Here we present a 34-year-old woman with a history of missed abortion and dilatation and curettage presenting with abnormal uterine bleeding 2 months postprocedure. Although initial transvaginal ultrasound suggested retained products of conception, several modalities were required to accurately diagnose uterine AVM with invasive angiography revealing the culprit vessel. Multimodal imaging approaches are crucial for accurate diagnosis and treatment. This …

Type 2 Diabetes Polygenic Risk Score Interactions With Lifestyle Risk Factors In Black Americans, Ashley W Scadden, Aastha Kakar, Elizabeth M Litkowski, Mariah C Meyer, Nicole D Armstrong, Steven Buyske, Yanwei Cai, Iona Cheng, Burcu F Darst, Myriam Fornage, Mariaelisa Graff, Boya Guo, Christopher A Haiman, Heather M Highland, Charles Kooperberg, Loïc Le Marchand, Kari North, Ulrike Peters, Stephen S Rich, Jerome I Rotter, Vinodh Srinivasasainagendra, Hemant K Tiwari, Stephanie Waldrop, Kristin Young, Sridharan Raghavan, Ethan M Lange, Leslie A Lange, Marguerite R Irvin, Maggie A Stanislawski

The Brown Foundation: Institute of Molecular Medicine

Introduction: Prior work in predominantly European ancestry populations has explained how the risk associated with demographic, lifestyle, and health factors differs with underlying genetic susceptibility to type 2 diabetes (T2D), but less is known about these relationships in Black Americans.

Methods: We used covariate-adjusted logistic regression models of T2D to examine interactions between a published trans-ancestry derived T2D polygenic risk score (PRS) and various demographic, lifestyle, and health-related factors among 28,251 self-identified Black Americans from six cohort studies.

Results: The results are generally consistent with prior work in White populations. The PRS showed a significant interaction with body mass index, …

Mechanisms And Environmental Factors Shaping The Ecosystem Of Brain Macrophages, Silvia Penati, Simone Brioschi, Zhangying Cai, Claudia Z Han, Marco Colonna

The Brown Foundation: Institute of Molecular Medicine

Brain macrophages encompass two major populations: microglia in the parenchyma and border-associated macrophages (BAMs) in the extra-parenchymal compartments. These cells play crucial roles in maintaining brain homeostasis and immune surveillance. Microglia and BAMs are phenotypically and epigenetically distinct and exhibit highly specialized functions tailored to their environmental niches. Intriguingly, recent studies have shown that both microglia and BAMs originate from the same myeloid progenitor during yolk sac hematopoiesis, but their developmental fates diverge within the brain. Several works have partially unveiled the mechanisms orchestrating the development of microglia and BAMs in both mice and humans; however, many questions remain unanswered. …

A Systematic Review And Evaluation Of Mobile Health Apps Designed For Parents Who Are Preparing Or Caring For Medically Complex Infants, Anne Chevalier Mckechnie, Nellie Munn Swanson, Ratchada Jantraporn, Kristin M Elgersma, Taylor Iwaszko Wagner, Suhyun Park, Anna Trebilcock

The Brown Foundation: Institute of Molecular Medicine

Background: Parents learning about their children with medical complexity often use numerous health-related resources, including mobile health applications (mHealth apps). mHealth apps could provide broad access to key information and support, lower healthcare costs, and improve care. The quality of mHealth apps for this population has been a concern, but is currently unknown. The objective of this systematic review was to identify and evaluate the quality of publicly available mHealth apps designed for parents who are preparing or caring for medically complex infants.

Methods: A systematic search strategy was applied to identify mHealth apps in the Apple and Google Play …

The Importance Of Atomic Charges For Predicting Site-Selective Ir-, Ru-, And Rh-Catalyzed C-H Borylations, Shannon M. Stephens, Kyle M. Lambert

Chemistry & Biochemistry Faculty Publications

A supervised machine learning model has been developed that allows for the prediction of site selectivity in late-stage C-H borylations. Model development was accomplished using literature data for the site-selective (≥95%) C-H borylation of 189 unique arene, heteroarene, and aliphatic substrates that feature a total of 971 possible sp² or sp³ C-H borylation sites. The reported experimental data was supplemented with additional chemoinformatic descriptors, computed atomic charges at the C-H borylation sites, and data from parameterization of catalytically active tris-boryl complexes resulting from the combination of seven different Ir-, Ru-, and Rh-based precatalysts with eight different ligands. Of the over …

Astrocyte Specific Enhancers In The Cortex And Striatum Of Mice, Mikaela Kottelich

Williams Honors College, Honors Research Projects

Among glial cells, astrocytes have a prevalent influence on supporting neuronal function and overall brain health. Specifically targeting this cell type for disease treatment is an existing issue. Other cell types tend to express the desired treatment, which is not always wanted and can lead to unintended, negative consequences. Astrocytes contribute largely to maintaining the blood brain barrier, which is disrupted in Parkinson’s disease. Certain genes are thought to be the reason for this disruption, so if they can be specifically targeted in astrocytes with a specific enhancer, the disruption of the disease could be reversed. In our experiment, we …

Characterization Of The Overexpression Of Reca Homologs Rad51 And Dmc1 In Tetrahymena Thermophila, Jianna M. Cox

Graduate Theses/Dissertations

RecA homologs, Dmc1 and Rad51, work to repair DNA double-strand breaks (DSBs) within the cell through the recombination of homologous sections of DNA. Dmc1 works to repair programmed DSBs through meiotic recombination, while Rad51 functions to repair both meiotic and non-meiotic DSBs, the latter repaired through the process of homologous recombination repair (HHR). Chemotherapeutics, exogenous agents, work to form DSBs in cancer cells, attempting to inhibit the cell’s growth. A hyper recombinant phenotype is often seen in cancer cells due to the overexpression of RAD51, leading to drug resistance, the persistence of cancers, and an overall poor patient outcome. …

Limiting H1n1 Replication Via The Dsrnai Pathway Using Sequence-Specific Ldsrna, Shawn Marie Sharon Carr, Stephanie Dewitte-Orr

Theses and Dissertations (Comprehensive)

The seasonal influenza virus causes a common respiratory illness that can be life threatening to the immunocompromised, the very young, and the elderly. The current strategies for avoiding a serious influenza virus infection are good hygiene practices and the annual influenza vaccine. Unfortunately, last year’s influenza virus vaccine effectiveness ranged between 32-60% for children and adolescents and 46-54% for adults. These low efficacy rates are due to the vaccine often targeting hemagglutinin, a highly variable surface protein. This thesis seeks to create a prophylactic treatment via the RNA interference (RNAi) response that targets the virus’s conserved genes that are integral …

Advanced Method For The In Vivo Measurements Of Lysophospholipid Translocation Across The Inner (Cytoplasmic) Membrane Of Escherichia Coli

Faculty, Staff and Student Publications

Phospholipid translocation occurs ubiquitously in biological membranes and primarily is protein catalyzed. Lipid flippases mediate the net translocation of specific phospholipids from one leaflet of a membrane to the other. In the inner (cytoplasmic) membrane (IM) of Gram-negative bacteria, lysophospholipid translocase (LplT) and cytosolic bifunctional acyl-acyl carrier protein (ACP) synthetase/2-acylglycerolphosphoethanolamine acyltransferase (Aas) form a glycerophospholipid regeneration system, which is capable of facilitating rapid retrograde translocation of lyso forms of phosphatidylethanolamine (PE), phosphatidylglycerol (PG), and cardiolipin (CL) but not exogenous (host-derived) phosphatidylcholine (PC) across the IM of Gram-negative diderm (two-membraned) bacteria in consequential order lyso-PE = lyso-PG > > lysophosphatidic acid (lyso-PA) >> lyso-PC. …

Additional Evidence From A Case Report Supports A Novel Hypothesis On The Association Between Complex Regional Pain Syndrome And Lymphedema, M Mark Melin, John C Rasmussen, Melissa B Aldrich, Ron J Karni, Caroline E Fife, Kristen A Eckert

The Brown Foundation: Institute of Molecular Medicine

A previous report of 4 heterogeneous cases demonstrated that automated manual lymphatic drainage therapy (AMLDT), administered by a novel, pneumatic mat of 16 pressurized air channels that inflate and deflate sequentially to mimic the stretch and release action of manual lymphatic drainage therapy (MLD), altered lymphatic contractility and relieved pain. Near-infrared fluorescence imaging (NIRF-LI) was used 1 h before AMLDT, during 1 h of AMDLT, and 30-60 min after treatment to obtain images that could be used to determine lymphatic contractility, as measured by pulsing frequency over a given timeframe. Herein, a case of type 2 complex regional pain syndrome …

Enhanced Anticancer Activity Of Novel Pyrimidine Nucleoside Analog In Pancreatic Cancer, Raviteja Bulusu, Joy Okoro, Esther Frimpong, Sunil Krishnan, Saunjoo Yoon, Bo Han, Xue Zhu, Edward Agyare

The Brown Foundation: Institute of Molecular Medicine

This study explores the synthesis, characterization, and therapeutic efficacy of AGY1, AGY2, AGY3, AGY4, and AGY5, which are novel 5-FU analogs designed to improve metabolic stability, prolong half-life, and anti-tumor activity against pancreatic cancer. The 5-FU molecule was chemically modified to bypass dihydropyrimidine dehydrogenase (DPD)-mediated inactivation, enhancing drug retention and increasing lipophilicity for improved cellular uptake. The analog cytotoxic activity was evaluated in 2D monolayer cultures and 3D pancreatic cancer spheroids and organoid models derived from MiaPaCa-2 and PANC-1 cells to simulate a more complex tumor environment. In the 2D model, AGY1, AGY2, AGY3, AGY4, and AGY5 displayed significantly higher …

Rezafungin For Suppressive Therapy Of Candida Auris In A Patient With A Left Ventricular Assist Device (Lvad), Matthew A Stack, Luis Ostrosky-Zeichner, Rodrigo Hasbun, Sun O Park, Jessica Babic, Mona Kapadia

The Brown Foundation: Institute of Molecular Medicine

Introduction: Invasive candidiasis is a common healthcare-associated infection with significant morbidity and mortality. Candida auris in particular has emerged as a problematic and challenging healthcare-associated infection, especially with regards to infections involving left ventricular assist devices (LVADs). There is a paucity of evidence on the best management of these particular types of infections. Rezafungin is a newly-approved echinocandin and an important new tool in the management of invasive candidiasis. We report the novel use of rezafungin for suppressive therapy in a patient with an LVAD-associated C. auris infection.

Case: The patient is a 57-year-old male with a past medical history …

Fiber Photometry Analysis Of Spontaneous Dopamine Signals: The Z-Scored Data Are Not The Data, Conner W. Wallace, Clare Y. Slinkard, Rachael Shaughnessy, Katherine M. Holleran, Samuel W. Centanni, Christopher C. Lapish, Sara R. Jones

Department of Medicine Faculty Publications

Fluorescent sensors have revolutionized the measurement of molecules in the brain, and the dLight dopamine sensor has been used extensively to examine reward- and cue-evoked dopamine release, but only recently has the field turned its attention to spontaneous release events. Analysis of spontaneous events typically requires evaluation of hundreds of events over minutes to hours, and the most common method of analysis, z-scoring, was not designed for this purpose. Here, we compare the accuracy and reliability of three different analysis methods to identify pharmacologically induced changes in dopamine release and uptake in freely moving C57BL/6J mice. The D1-like receptor antagonist …

Characterizing A Rad23 Dependent Ultraviolet Radiation Resistance In Tetrahymena Thermophila, Emma June Liimatta

Graduate Theses/Dissertations

In 2020, 10 million deaths were attributed to cancer, with multidrug resistance being responsible for over 90% of deaths in cancer patients receiving treatment. This study utilized the model organism Tetrahymena thermophila to study how cells become resistant to Ultraviolet Radiation (UV) radiation, a process similar to multidrug resistance, specifically focusing on the nucleotide excision repair and ubiquitin shuttle protein Rad23. The National Cancer Institute documented 30-60% of cancers tested had a mutation in RAD23. Knockdown of RAD23 in Tetrahymena thermophila demonstrated a UV resistance phenotype with decreased nucleotide excision repair and differential expression of proteins active within caspase-independent …

Gene-Environment Interactions In Non-Alcoholic Fatty Liver Disease: Insights From Mexican American Populations, Eron G. Manusov, Vincent P. Diego, Marcio Almeida, Jacob Galan, Auwal A. Bala, Marco Arriaga, Natasha Garcia-Rodriguez, Renee Hernandez, Satish Kumar, John Blangero, Sarah Williams-Blangero

School of Medicine Publications

Nonalcoholic Fatty Liver Disease (NAFLD) is a prevalent and complex condition influenced by both genetic and environmental factors. This chapter explores the genotype-by-environment interactions that contribute to the development and progression of NAFLD in the Mexican American population. Using advanced genetic epidemiology and bioinformatics approaches, we investigated how specific genetic variants interact with environmental factors such as depression, acculturation stress, and social determinants of health, to influence NAFLD risk and severity. Our findings reveal significant genotype-by-environment interactions for key NAFLD-related traits, including HbA1c, AST/ALT ratio, and steatosis-controlled attenuation parameter (CAP). We also discuss the application of cutting-edge proteomic and transcriptomic …

5-Fluorouracil Induced Oxidative Stress Is Variable Across Triple Negative Breast Cancer Cell Lines, Rachel L. Walker

Departmental Honors & Graduate Capstone Projects

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with treatment limited to chemotherapy. However, not all patient tumors respond to chemotherapy. The variable cytotoxic effects of chemotherapies may be due to how cancer cells regulate reactive oxygen species (ROS). In this study, we examined two mouse breast cancer cell lines: 4T1 and EO771, vary when treated with hydrogen peroxide (H2O2) and 5-Fluorouracil (5FU), known ROS-inducing substances. In 4T1 cells H2O2 increased oxidized DNA but caused minimal cell death. While in EO771 cells that same amount of H2O2 caused complete apoptosis. Cell number, ROS, and cell death showed …

Diversity And Characteristics Of The Oral Microbiome Associated With Self-Reported Ancestral/Ethnic Groups

Faculty, Staff and Student Publications

Periodontitis disproportionately affects genetic ancestral/ethnic groups. To characterize the oral microbiome from different genetic ancestral/ethnic groups, we collected 161 dental plaque samples from self-identified African Americans (AAs), Caucasian Americans (CAs), and Hispanic Americans (HAs) with clinical gingival health or biofilm-induced gingivitis on an intact periodontium. DNA was extracted from these samples, and then DNA libraries were prepared and sequenced using an Illumina NovaSeq high-throughput sequencer. We found significant differences in the diversity and abundance of microbial taxa among dental plaque samples of the AA, CA, and HA groups. We also identified unique microbial species in a self-reported ancestral/ethnic group. Moreover, …

Itaconate Transporter Slc13a3 Impairs Tumor Immunity Via Endowing Ferroptosis Resistance, Heng Lin, Kole Tison, Yuheng Du, Paul Kirchhoff, Chan Kim, Weichao Wang, Hannah Yang, Michael Pitter, Jiali Yu, Peng Liao, Jiajia Zhou, Linda Vatan, Sara Grove, Shuang Wei, Thomas Vigil, Yatrik M Shah, Richard Mortensen, Ilona Kryczek, Lana Garmire, Jwala P Sivaccumar, Ashwin Kumar Ramesh, Ningyan Zhang, Zhiqiang An, Shaomeng Wang, Weiping Zou

The Brown Foundation: Institute of Molecular Medicine

Immune checkpoint blockade (ICB) triggers tumor ferroptosis. However, most patients are unresponsive to ICB. Tumors might evade ferroptosis in the tumor microenvironment (TME). Here, we discover SLC13A3 is an itaconate transporter in tumor cells and endows tumor ferroptosis resistance, diminishing tumor immunity and ICB efficacy. Mechanistically, tumor cells uptake itaconate via SLC13A3 from tumor-associated macrophages (TAMs), thereby activating the NRF2-SLC7A11 pathway and escaping from immune-mediated ferroptosis. Structural modeling and molecular docking analysis identify a functional inhibitor for SLC13A3 (SLC13A3i). Deletion of ACOD1 (an essential enzyme for itaconate synthesis) in macrophages, genetic ablation of SLC13A3 in tumors, or treatment with SLC13A3i …

Exploring The Potential Of Epiregulin And Amphiregulin As Prognostic, Predictive, And Therapeutic Targets In Colorectal Cancer, Cara Guernsey-Biddle, Peyton High, Kendra S Carmon

The Brown Foundation: Institute of Molecular Medicine

The epidermal growth factor receptor (EGFR) plays a critical role in regulating essential cellular processes that are frequently hijacked to promote cancer. In colorectal cancer (CRC) in particular, the EGFR signaling pathway is frequently hyperactivated via receptor and/or ligand overexpression and downstream oncogenic mutations. Current EGFR-targeted therapies for metastatic CRC (mCRC) include the monoclonal antibodies (mAbs) cetuximab and panitumumab. However, intrinsic and acquired resistance to EGFR-targeted mAbs are commonly observed. Thus, additional biomarkers are necessary to better understand patient sensitivity to EGFR-targeted therapies. Furthermore, therapeutic targeting of alternative EGFR pathway components may serve as one mechanism to overcome EGFR-targeted mAb …

Three Decades Of Rat Genomics: Approaching The Finish(Ed) Line, Theodore S Kalbfleisch, Melissa L Smith, Julia L Ciosek, Kai Li, Peter A Doris

The Brown Foundation: Institute of Molecular Medicine

The rat, Rattus norvegicus, has provided an important model for investigation of a range of characteristics of biomedical importance. Here we survey the origins of this species, its introduction into laboratory research, and the emergence of genetic and genomic methods that utilize this model organism. Genomic studies have yielded important progress and provided new insight into several biologically important traits. However, some studies have been impeded by the lack of a complete and accurate reference genome for this species. New sequencing and genome assembly methods applied to the rat have resulted in a new reference genome assembly, GRCr8, which …

Anxiety-Like Behaviors In Mice Unmasked: Revealing Sex Differences In Anxiety Using A Novel Light-Heat Conflict Test, Sydney E Lee, Sung-Hoon Park, John C Aldrich, Laura K Fonken, Andrew D Gaudet

The Brown Foundation: Institute of Molecular Medicine

Anxiety and chronic pain afflict hundreds of millions worldwide. Anxiety and pain are more prevalent in females compared to males. Unfortunately, robust sex differences in human anxiety are not recapitulated in rodent tests, and results from rodent pain studies frequently fail to translate clinically. Therefore, there is a need to develop tests that reflect the differential salience of anxiety or pain-related stimuli between the sexes. Accordingly, here we introduce the Thermal Increments Dark-Light (TIDAL) conflict test. The TIDAL test places an anxiety-relevant stimulus (dark vs. illuminated chamber) in conflict with a heat-related stimulus (incrementally heated vs. isothermic chamber); mice freely …

Ecological And Pathological Applications Of The Heat Shock Response, Taylor Rae Stanley

Theses and Dissertations

The heat shock response (HSR) is a cytoprotective stress response pathway that regulates cellular proteostasis. The HSR is an evolutionarily conserved pathway that is essential for normal cellular functioning. Here, we explore the broad ecological and pathological impacts of the HSR. In an ecological context, we perform gene level analysis of the transcriptomes of two closely related sunfish. We found that the more invasive bluegill sunfish has gene expansions in two HSR gene families, the HSP70 family and the HSP90 family compared to the redear sunfish. These gene expansions were also observed in several other teleost fish species and were …

Complement Immune System In Pulmonary Hypertension-Cooperating Roles Of Circadian Rhythmicity In Complement-Mediated Vascular Pathology, Hunter Devaughn, Haydn E Rich, Anthony Shadid, Priyanka K Vaidya, Marie-Francoise Doursout, Pooja Shivshankar

The Brown Foundation: Institute of Molecular Medicine

Originally discovered in the 1890s, the complement system has traditionally been viewed as a "compliment" to the body's innate and adaptive immune response. However, emerging data have shown that the complement system is a much more complex mechanism within the body involved in regulating inflammation, gene transcription, attraction of macrophages, and many more processes. Sustained complement activation contributes to autoimmunity and chronic inflammation. Pulmonary hypertension is a disease with a poor prognosis and an average life expectancy of 2-3 years that leads to vascular remodeling of the pulmonary arteries; the pulmonary arteries are essential to host homeostasis, as they divert …

Estimating The Number Of Polygenic Diseases Among Six Mutually Exclusive Entities Of Non-Tumors And Cancer, C I Edvard Smith, Jan A Burger, Rula Zain

Faculty, Staff and Student Publications

In the era of precision medicine with increasing amounts of sequenced cancer and non-cancer genomes of different ancestries, we here enumerate the resulting polygenic disease entities. Based on the cell number status, we first identified six fundamental types of polygenic illnesses, five of which are non-cancerous. Like complex, non-tumor disorders, neoplasms normally carry alterations in multiple genes, including in 'Drivers' and 'Passengers'. However, tumors also lack certain genetic alterations/epigenetic changes, recently named 'Goners', which are toxic for the neoplasm and potentially constitute therapeutic targets. Drivers are considered essential for malignant transformation, whereas environmental influences vary considerably among both types of …

Mechanisms Of Extracellular Vesicle Uptake And Implications For The Design Of Cancer Therapeutics, Stephanie R Jackson Cullison, Joseph P Flemming, Kubra Karagoz, Peter J Wermuth, Mỹ G Mahoney

Rowan-Virtua School of Osteopathic Medicine Departmental Research

The translation of pre-clinical anti-cancer therapies to regulatory approval has been promising, but slower than hoped. While innovative and effective treatments continue to achieve or seek approval, setbacks are often attributed to a lack of efficacy, failure to achieve clinical endpoints, and dose-limiting toxicities. Successful efforts have been characterized by the development of therapeutics designed to specifically deliver optimal and effective dosing to tumour cells while minimizing off-target toxicity. Much effort has been devoted to the rational design and application of synthetic nanoparticles to serve as targeted therapeutic delivery vehicles. Several challenges to the successful application of this modality as …

Allosteric Competition And Inhibition In Ampa Receptors, W Dylan Hale, Alejandra Montaño Romero, Cuauhtemoc U Gonzalez, Vasanthi Jayaraman, Albert Y Lau, Edward C Twomey

Faculty, Staff and Student Publications

Excitatory neurotransmission is principally mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-subtype ionotropic glutamate receptors (AMPARs). Negative allosteric modulators are therapeutic candidates that inhibit AMPAR activation and can compete with positive modulators to control AMPAR function through unresolved mechanisms. Here we show that allosteric inhibition pushes AMPARs into a distinct state that prevents both activation and positive allosteric modulation. We used cryo-electron microscopy to capture AMPARs bound to glutamate, while a negative allosteric modulator, GYKI-52466, and positive allosteric modulator, cyclothiazide, compete for control of the AMPARs. GYKI-52466 binds in the ion channel collar and inhibits AMPARs by decoupling the ligand-binding domains from the …

Genetic Regulation Of Human Brain Proteome Reveals Proteins Implicated In Psychiatric Disorders, Yi Jiang, Gina Giase, Kay Grennan, Kevin P White, Chao Chen, Sidney H Wang, Dalila Pinto, Yue Wang, Chunyu Liu, Junmin Peng, Xusheng Wang

Faculty, Staff and Student Publications

Psychiatric disorders are highly heritable yet polygenic, potentially involving hundreds of risk genes. Genome-wide association studies have identified hundreds of genomic susceptibility loci with susceptibility to psychiatric disorders; however, the contribution of these loci to the underlying psychopathology and etiology remains elusive. Here we generated deep human brain proteomics data by quantifying 11,608 proteins across 268 subjects using 11-plex tandem mass tag coupled with two-dimensional liquid chromatography-tandem mass spectrometry. Our analysis revealed 788 cis-acting protein quantitative trait loci associated with the expression of 883 proteins at a genome-wide false discovery rate < 5%. In contrast to expression at the transcript level and complex diseases that are found to be mainly influenced by noncoding variants, we found protein expression level tends to be regulated by non-synonymous variants. We also provided evidence of 76 shared regulatory signals between gene expression and protein abundance. Mediation analysis revealed that for most (88%) of the colocalized genes, the expression levels of their corresponding proteins are regulated by cis-pQTLs via gene transcription. Using summary data-based Mendelian randomization analysis, we identified 4 proteins and 19 genes that are causally associated with schizophrenia. We further integrated multiple omics data with network analysis to prioritize candidate genes for schizophrenia risk loci. Collectively, our findings underscore the potential of proteome-wide linkage analysis in gaining mechanistic insights into the pathogenesis of psychiatric disorders.

Circulating Exosomes Alter Skeletal Muscle Gene Expression To Impair Insulin Sensitivity In Type 2 Diabetes And Mediate Adaptive Response To Exercise In Healthy Mice, Christopher R. Pitzer

Alternative Theses and Dissertations (AETDs)

Current evidence from the literature suggests a role for circulating extracellular vesicles (EVs) in the pathogenesis of multiple diseases as well as a potential therapeutic role via delivery of vesicular cargo. Type 2 Diabetes is among the most prevalent and costly metabolic diseases in the world. Lifestyle intervention including exercise can cause Type 2 Diabetes to enter effective remission but remain ineffective due to poor adherence. Exercise stimulates the release of EVs from the skeletal muscle (and other tissues), and these vesicles are thought to confer a portion of the metabolic benefits of exercise. However, the direct effects of EV’s …

Tfeb Controls Syncytiotrophoblast Formation And Hormone Production In Placenta, Marcella Cesana, Gennaro Tufano, Francesco Panariello, Nicolina Zampelli, Chiara Soldati, Margherita Mutarelli, Sandro Montefusco, Giuseppina Grieco, Lucia Vittoria Sepe, Barbara Rossi, Edoardo Nusco, Giada Rossignoli, Giorgia Panebianco, Fabrizio Merciai, Emanuela Salviati, Eduardo Maria Sommella, Pietro Campiglia, Graziano Martello, Davide Cacchiarelli, Diego Luis Medina, Andrea Ballabio

Duncan NRI Faculty and Staff Publications

TFEB, a bHLH-leucine zipper transcription factor belonging to the MiT/TFE family, globally modulates cell metabolism by regulating autophagy and lysosomal functions. Remarkably, loss of TFEB in mice causes embryonic lethality due to severe defects in placentation associated with aberrant vascularization and resulting hypoxia. However, the molecular mechanism underlying this phenotype has remained elusive. By integrating in vivo analyses with multi-omics approaches and functional assays, we have uncovered an unprecedented function for TFEB in promoting the formation of a functional syncytiotrophoblast in the placenta. Our findings demonstrate that constitutive loss of TFEB in knock-out mice is associated with defective formation of …

Tumour-Intrinsic Pdl1 Signals Regulate The Chk2 Dna Damage Response In Cancer Cells And Mediate Resistance To Chk1 Inhibitors, Clare E Murray, Anand V R Kornepati, Carlos Ontiveros, Yiji Liao, Bárbara De La Peña Avalos, Zexuan Liu, Haiyan Bai, Suresh Kari, Alvaro S Padron, Jacob T Boyd, Ryan Reyes, Curtis A Clark, Robert S Svatek, Rong Li, Yanfen Hu, Meiling Wang, José R Conejo-Garcia, Lauren A Byers, Kavya Ramkumar, Anil K Sood, Jung-Min Lee, Christin E Burd, Ratna K Vadlamudi, Harshita B Gupta, Weixing Zhao, Eloïse Dray, Patrick Sung, Tyler J Curiel

Faculty, Staff and Student Publications

Background: Aside from the canonical role of PDL1 as a tumour surface-expressed immune checkpoint molecule, tumour-intrinsic PDL1 signals regulate non-canonical immunopathological pathways mediating treatment resistance whose significance, mechanisms, and therapeutic targeting remain incompletely understood. Recent reports implicate tumour-intrinsic PDL1 signals in the DNA damage response (DDR), including promoting homologous recombination DNA damage repair and mRNA stability of DDR proteins, but many mechanistic details remain undefined.

Methods: We genetically depleted PDL1 from transplantable mouse and human cancer cell lines to understand consequences of tumour-intrinsic PDL1 signals in the DNA damage response. We complemented this work with studies of primary human tumours …