Digital Commons Network^™

Loss Of Growth Differentiation Factor 15 Exacerbates Lung Injury In Neonatal Mice, Faeq Al-Mudares, Manuel Cantu Gutierrez, Abiud Cantu, Weiwu Jiang, Lihua Wang, Xiaoyu Dong, Bhagavatula Moorthy, Eniko Sajti, Krithika Lingappan

Faculty, Staff and Students Publications

Growth differentiation factor 15 (GDF15) is a divergent member of the transforming growth factor-β (TGF-β) superfamily, and its expression increases under various stress conditions, including inflammation, hyperoxia, and senescence. GDF15 expression is increased in neonatal murine bronchopulmonary dysplasia (BPD) models, and GDF15 loss exacerbates oxidative stress and decreases cellular viability in vitro. Our overall hypothesis is that the loss of GDF15 will exacerbate hyperoxic lung injury in the neonatal lung in vivo. We exposed neonatal

A Defect In Mitochondrial Fatty Acid Synthesis Impairs Iron Metabolism And Causes Elevated Ceramide Levels, Debdeep Dutta, Oguz Kanca, Seul Kee Byeon, Paul C Marcogliese, Zhongyuan Zuo, Rishi V Shridharan, Jun Hyoung Park, Undiagnosed Diseases Networ, Guang Lin, Ming Ge, Gali Heimer, Jennefer N Kohler, Matthew T Wheeler, Benny A Kaipparettu, Akhilesh Pandey, Hugo J Bellen

Faculty, Staff and Students Publications

In most eukaryotic cells, fatty acid synthesis (FAS) occurs in the cytoplasm and in mitochondria. However, the relative contribution of mitochondrial FAS (mtFAS) to the cellular lipidome is not well defined. Here we show that loss of function of Drosophila mitochondrial enoyl coenzyme A reductase (Mecr), which is the enzyme required for the last step of mtFAS, causes lethality, while neuronal loss of Mecr leads to progressive neurodegeneration. We observe a defect in Fe-S cluster biogenesis and increased iron levels in flies lacking mecr, leading to elevated ceramide levels. Reducing the levels of either iron or ceramide suppresses the neurodegenerative …

Novel Lss Variants In Alopecia And Intellectual Disability Syndrome: New Case Report And Clinical Spectrum Of Lss-Related Rare Disease Traits, Hasnaa M Elbendary, Dana Marafi, Ahmed K Saad, Rasha Elhossini, Ruizhi Duan, Karima Rafat, Shalini N Jhangiani, Richard A Gibbs, Davut Pehlivan, Daniel G Calame, Jennifer E Posey, James R Lupski, Maha S Zaki

Faculty, Staff and Students Publications

Pathogenic biallelic variants in LSS are associated with three Mendelian rare disease traits including congenital cataract type 44, autosomal recessive hypotrichosis type 14, and alopecia-intellectual disability syndrome type 4 (APMR4). We performed trio research exome sequencing on a family with a four-year-old male with global developmental delay, epilepsy and striking alopecia, and identified novel compound heterozygous LSS splice site (c.14+2T>C) and missense (c.1357 G>A; p.V453L) variant alleles. Rare features associated with APMR4 such as cryptorchidism, micropenis, mild cortical brain atrophy and thin corpus callosum were detected. Previously unreported APMR4 findings including cerebellar involvement in the form of unsteady …

Phenoscore Quantifies Phenotypic Variation For Rare Genetic Diseases By Combining Facial Analysis With Other Clinical Features Using A Machine-Learning Framework, Alexander J M Dingemans, Max Hinne, Kim M G Truijen, Lia Goltstein, Jeroen Van Reeuwijk, Nicole De Leeuw, Janneke Schuurs-Hoeijmakers, Rolph Pfundt, Illja J Diets, Joery Den Hoed, Elke De Boer, Jet Coenen-Van Der Spek, Sandra Jansen, Bregje W Van Bon, Noraly Jonis, Charlotte W Ockeloen, Anneke T Vulto-Van Silfhout, Tjitske Kleefstra, David A Koolen, Philippe M Campeau, Elizabeth E Palmer, Hilde Van Esch, Gholson J Lyon, Fowzan S Alkuraya, Anita Rauch, Ronit Marom, Diana Baralle, Pleuntje J Van Der Sluijs, Gijs W E Santen, R Frank Kooy, Marcel A J Van Gerven, Lisenka E L M Vissers, Bert B A De Vries

Faculty, Staff and Students Publications

Several molecular and phenotypic algorithms exist that establish genotype-phenotype correlations, including facial recognition tools. However, no unified framework that investigates both facial data and other phenotypic data directly from individuals exists. We developed PhenoScore: an open-source, artificial intelligence-based phenomics framework, combining facial recognition technology with Human Phenotype Ontology data analysis to quantify phenotypic similarity. Here we show PhenoScore's ability to recognize distinct phenotypic entities by establishing recognizable phenotypes for 37 of 40 investigated syndromes against clinical features observed in individuals with other neurodevelopmental disorders and show it is an improvement on existing approaches. PhenoScore provides predictions for individuals with variants …

The Complete Sequence Of A Human Y Chromosome, Arang Rhie, Sergey Nurk, Monika Cechova, Savannah J Hoyt, Dylan J Taylor, Nicolas Altemose, Paul W Hook, Sergey Koren, Mikko Rautiainen, Ivan A Alexandrov, Jamie Allen, Mobin Asri, Andrey V Bzikadze, Nae-Chyun Chen, Chen-Shan Chin, Mark Diekhans, Paul Flicek, Giulio Formenti, Arkarachai Fungtammasan, Carlos Garcia Giron, Erik Garrison, Ariel Gershman, Jennifer L Gerton, Patrick G S Grady, Andrea Guarracino, Leanne Haggerty, Reza Halabian, Nancy F Hansen, Robert Harris, Gabrielle A Hartley, William T Harvey, Marina Haukness, Jakob Heinz, Thibaut Hourlier, Robert M Hubley, Sarah E Hunt, Stephen Hwang, Miten Jain, Rupesh K Kesharwani, Alexandra P Lewis, Heng Li, Glennis A Logsdon, Julian K Lucas, Wojciech Makalowski, Christopher Markovic, Fergal J Martin, Ann M Mc Cartney, Rajiv C Mccoy, Jennifer Mcdaniel, Brandy M Mcnulty, Paul Medvedev, Alla Mikheenko, Katherine M Munson, Terence D Murphy, Hugh E Olsen, Nathan D Olson, Luis F Paulin, David Porubsky, Tamara Potapova, Fedor Ryabov, Steven L Salzberg, Michael E G Sauria, Fritz J Sedlazeck, Kishwar Shafin, Valery A Shepelev, Alaina Shumate, Jessica M Storer, Likhitha Surapaneni, Angela M Taravella Oill, Françoise Thibaud-Nissen, Winston Timp, Marta Tomaszkiewicz, Mitchell R Vollger, Brian P Walenz, Allison C Watwood, Matthias H Weissensteiner, Aaron M Wenger, Melissa A Wilson, Samantha Zarate, Yiming Zhu, Justin M Zook, Evan E Eichler, Rachel J O'Neill, Michael C Schatz, Karen H Miga, Kateryna D Makova, Adam M Phillippy

Faculty, Staff and Students Publications

The human Y chromosome has been notoriously difficult to sequence and assemble because of its complex repeat structure including long palindromes, tandem repeats, and segmental duplications1–3. As a result, more than half of the Y chromosome is missing from the GRCh38 reference sequence and it remains the last human chromosome to be finished4,5. Here, the Telomere-to-Telomere (T2T) consortium presents the complete 62,460,029 base pair sequence of a human Y chromosome from the HG002 genome (T2T-Y) that corrects multiple errors in GRCh38-Y and adds over 30 million base pairs of sequence to the …

Loss Of The Maternal Effect Gene Nlrp2 Alters The Transcriptome Of Ovulated Mouse Oocytes And Impacts Expression Of Histone Demethylase Kdm1b, Zahra Anvar, Imen Chakchouk, Momal Sharif, Sangeetha Mahadevan, Eleni Theodora Nasiotis, Li Su, Zhandong Liu, Ying-Wooi Wan, Ignatia B Van Den Veyver

Faculty, Staff and Students Publications

The subcortical maternal complex (SCMC) is a multiprotein complex in oocytes and preimplantation embryos that is encoded by maternal effect genes. The SCMC is essential for zygote-to-embryo transition, early embryogenesis, and critical zygotic cellular processes, including spindle positioning and symmetric division. Maternal deletion of Nlrp2, which encodes an SCMC protein, results in increased early embryonic loss and abnormal DNA methylation in embryos. We performed RNA sequencing on pools of meiosis II (MII) oocytes from wild-type and Nlrp2-null female mice that were isolated from cumulus-oocyte complexes (COCs) after ovarian stimulation. Using a mouse reference genome-based analysis, we found 231 …

Il17a Blockade With Ixekizumab Suppresses Muvb Signaling In Clinical Psoriasis, Scott A Ochsner, Mesias Pedroza, Rudolf T Pillich, Venkatesh Krishnan, Bruce W Konicek, Ernst R Dow, So Young Park, Sandeep K Agarwal, Neil J Mckenna

Faculty, Staff and Students Publications

Unbiased informatics approaches have the potential to generate insights into uncharacterized signaling pathways in human disease. In this study, we generated longitudinal transcriptomic profiles of plaque psoriasis lesions from patients enrolled in a clinical trial of the anti-IL17A antibody ixekizumab (IXE). This dataset was then computed against a curated matrix of over 700 million data points derived from published psoriasis and signaling node perturbation transcriptomic and chromatin immunoprecipitation-sequencing datasets. We observed substantive enrichment within both psoriasis-induced and IXE-repressed gene sets of transcriptional targets of members of the MuvB complex, a master regulator of the mitotic cell cycle. These gene sets …

Global Sumoylation In Mouse Oocytes Maintains Oocyte Identity And Regulates Chromatin Remodeling And Transcriptional Silencing At The End Of Folliculogenesis, Shawn M Briley, Avery A Ahmed, Tessa E Steenwinkel, Peixin Jiang, Sean M Hartig, Karen Schindler, Stephanie A Pangas

Faculty, Staff and Students Publications

Meiotically competent oocytes in mammals undergo cyclic development during folliculogenesis. Oocytes within ovarian follicles are transcriptionally active, producing and storing transcripts required for oocyte growth, somatic cell communication and early embryogenesis. Transcription ceases as oocytes transition from growth to maturation and does not resume until zygotic genome activation. Although SUMOylation, a post-translational modification, plays multifaceted roles in transcriptional regulation, its involvement during oocyte development remains poorly understood. In this study, we generated an oocyte-specific knockout of Ube2i, encoding the SUMO E2 enzyme UBE2I, using Zp3-cre+ to determine how loss of oocyte SUMOylation during folliculogenesis affects oocyte development. Ube2i Zp3-cre+ female …

Loss Of Stearoyl-Coa Desaturase 2 Disrupts Inflammatory Response In Macrophages, Joseph B Lin, Amy Mora, Tzu Jui Wang, Andrea Santeford, Darksha Usmani, Marianne M Ligon, Indira U Mysorekar, Rajendra S Apte

Faculty, Staff and Students Publications

Macrophages are innate immune cells that patrol tissues and are the first responders to detect infection. They orchestrate the host immune response in eliminating invading pathogens and the subsequent transition from inflammation to tissue repair. Macrophage dysfunction contributes to age-related pathologies, including low-grade inflammation in advanced age that is termed "inflammaging." Our laboratory has previously identified that macrophage expression of a fatty acid desaturase, stearoyl-CoA desaturase 2 (SCD2), declines with age. Herein, we delineate the precise cellular effects of SCD2 deficiency in murine macrophages. We found that deletion of

A Comprehensive Drosophila Resource To Identify Key Functional Interactions Between Sars-Cov-2 Factors And Host Proteins, Annabel Guichard, Shenzhao Lu, Oguz Kanca, Daniel Bressan, Yan Huang, Mengqi Ma, Sara Sanz Juste, Jonathan C Andrews, Kristy L Jay, Marketta Sneider, Ruth Schwartz, Mei-Chu Huang, Danqing Bei, Hongling Pan, Liwen Ma, Wen-Wen Lin, Ankush Auradkar, Pranjali Bhagwat, Soo Park, Kenneth H Wan, Takashi Ohsako, Toshiyuki Takano-Shimizu, Susan E Celniker, Michael F Wangler, Shinya Yamamoto, Hugo J Bellen, Ethan Bier

Faculty, Staff and Students Publications

Development of effective therapies against SARS-CoV-2 infections relies on mechanistic knowledge of virus-host interface. Abundant physical interactions between viral and host proteins have been identified, but few have been functionally characterized. Harnessing the power of fly genetics, we develop a comprehensive Drosophila COVID-19 resource (DCR) consisting of publicly available strains for conditional tissue-specific expression of all SARS-CoV-2 encoded proteins, UAS-human cDNA transgenic lines encoding established host-viral interacting factors, and GAL4 insertion lines disrupting fly homologs of SARS-CoV-2 human interacting proteins. We demonstrate the utility of the DCR to functionally assess SARS-CoV-2 genes and candidate human binding partners. We show that …

Daam2 Phosphorylation By Ck2Α Negatively Regulates Wnt Activity During White Matter Development And Injury, Chih-Yen Wang, Zhongyuan Zuo, Juyeon Jo, Kyoung In Kim, Christine Madamba, Qi Ye, Sung Yun Jung, Hugo J Bellen, Hyun Kyoung Lee

Faculty, Staff and Students Publications

Wnt signaling plays a vital role in oligodendrocyte (OL) development and has been implicated as an adverse event for myelin repair after white matter injury. Emerging studies have shed light on multimodal roles of Wnt effectors in the OL lineage, but the underlying molecular mechanisms and modifiable targets in OL remyelination remain unclear. Using genetic mouse development and injury model systems, we delineate a unique stage-specific function of Daam2 in Wnt signaling and OL development via a S704/T705 phosphorylation mechanism and determine a different role of the kinase CK2α in the regulation of OL development and myelin regeneration.

An Update On The Healthy Soldier Effect In U.S. Veterans, Erin Sullivan-Baca, Rizwana Rehman, Zulfi Haneef

Faculty, Staff and Students Publications

Introduction: The healthy soldier effect (HSE) describes a phenomenon of enduring health and lower mortality among veterans due in part to initial screening procedures and health care access. Although early data were supportive of a broad HSE among former military members, more recent investigations have suggested a possible attenuation of the effect with older age. The present study aimed to provide an update of the HSE using an expansive Veterans Health Administration (VHA)-wide sample with a particular focus on age and sex effects.

Materials and methods: Mortality data for veterans within the VHA were obtained from the VHA Support Service …

Aggregated Molecular Phenotype Scores: Enhancing Assessment And Visualization Of Mass Spectrometry Imaging Data For Tissue-Based Diagnostics, Jessie R Chappel, Mary E King, Jonathon Fleming, Livia S Eberlin, David M Reif, Erin S Baker

Faculty, Staff and Students Publications

Mass spectrometry imaging (MSI) has gained increasing popularity for tissue-based diagnostics due to its ability to identify and visualize molecular characteristics unique to different phenotypes within heterogeneous samples. Data from MSI experiments are often assessed and visualized using various supervised and unsupervised statistical approaches. However, these approaches tend to fall short in identifying and concisely visualizing subtle, phenotype-relevant molecular changes. To address these shortcomings, we developed aggregated molecular phenotype (AMP) scores. AMP scores are generated using an ensemble machine learning approach to first select features differentiating phenotypes, weight the features using logistic regression, and combine the weights and feature abundances. …

Flavonoids Quercetin And Kaempferol Are Nr4a1 Antagonists And Suppress Endometriosis In Female Mice, Lei Zhang, Kumaravel Mohankumar, Gregory Martin, Fuada Mariyam, Yuri Park, Sang Jun Han, Stephen Safe

Faculty, Staff and Students Publications

Nuclear receptor 4A1 (NR4A1) plays an important role in endometriosis progression; levels of NR4A1 in endometriotic lesions are higher than in normal endometrium, and substituted bis-indole analogs (NR4A1) antagonists suppress endometriosis progression in mice with endometriosis. In addition, the flavonoids kaempferol and quercetin are natural products that directly bind NR4A1 and significantly repress the intrinsic NR4A1-dependent transcriptional activity in human endometriotic epithelial and stromal cells and Ishikawa endometrial cancer cells. NR4A1 knockdown and inhibition of NR4A1 by kaempferol and quercetin suppressed proliferation of human endometriotic epithelial cells and Ishikawa cells by inhibiting epidermal growth factor receptor/c-Myc/survivin-mediated growth-promoting and survival pathways, …

A Non-Coding Insertional Mutation Of Grhl2 Causes Gene Over-Expression And Multiple Structural Anomalies Including Cleft Palate, Spina Bifida And Encephalocele, Zoe Crane-Smith, Sandra C P De Castro, Evanthia Nikolopoulou, Paul Wolujewicz, Damian Smedley, Yunping Lei, Emma Mather, Chloe Santos, Mark Hopkinson, Andrew A Pitsillides, Richard H Finnell, M Elisabeth Ross, Andrew J Copp, Nicholas D E Greene

Faculty, Staff and Students Publications

Orofacial clefts, including cleft lip and palate (CL/P) and neural tube defects (NTDs) are among the most common congenital anomalies, but knowledge of the genetic basis of these conditions remains incomplete. The extent to which genetic risk factors are shared between CL/P, NTDs and related anomalies is also unclear. While identification of causative genes has largely focused on coding and loss of function mutations, it is hypothesized that regulatory mutations account for a portion of the unidentified heritability. We found that excess expression of Grainyhead-like 2 (Grhl2) causes not only spinal NTDs in Axial defects (Axd) mice but also multiple …

Structures Of The Insecticidal Toxin Complex Subunit Xpta2 Highlight Roles For Flexible Domains, Cole L Martin, David W Chester, Christopher D Radka, Lurong Pan, Zhengrong Yang, Rachel C Hart, Elad M Binshtein, Zhao Wang, Lisa Nagy, Lawrence J Delucas, Stephen G Aller

Faculty, Staff and Students Publications

The Toxin Complex (Tc) superfamily consists of toxin translocases that contribute to the targeting, delivery, and cytotoxicity of certain pathogenic Gram-negative bacteria. Membrane receptor targeting is driven by the A-subunit (TcA), which comprises IgG-like receptor binding domains (RBDs) at the surface. To better understand XptA2, an insect specific TcA secreted by the symbiont

Ant-Dependent Mptp Underlies Necrotic Myofiber Death In Muscular Dystrophy, Michael J Bround, Julian R Havens, Allen J York, Michelle A Sargent, Jason Karch, Jeffery D Molkentin

Faculty, Staff and Students Publications

Mitochondrial permeability transition pore (MPTP) formation contributes to ischemia-reperfusion injury in the heart and several degenerative diseases, including muscular dystrophy (MD). MD is a family of genetic disorders characterized by progressive muscle necrosis and premature death. It has been proposed that the MPTP has two molecular components, the adenine nucleotide translocase (ANT) family of proteins and an unknown component that requires the chaperone cyclophilin D (CypD) to activate. This model was examined in vivo by deleting the gene encoding ANT1 (Slc25a4) or CypD (Ppif) in a δ-sarcoglycan (Sgcd) gene–deleted mouse model of MD, revealing …

Effect Of Various Types Of Extracellular Dna On V Hyugaensis Biofilm Formation, Carmen Gu Liu, Anthony W Maresso

Faculty, Staff and Students Publications

Marine bacteria face a constant influx of new extracellular DNA (exDNA) due to the massive viral lysis that occurs in the ocean on a daily basis. Generally, biofilms have shown to be induced by self-secreted exDNA. However, the effect of various types of exDNA with varying lengths, self vs non-self, as well as guanine-cytosine content (GC) content on biofilm formation has not been explored, despite being a critical component of the extracellular polymeric substance. To test the effect of such exDNA on biofilms, a marine bioluminescent bacterium (Vibrio hyugaensis) was isolated from the Sippewissett Salt Marsh, USA, and …

Clot Retraction And Its Correlation With The Function Of Platelet Integrin Α, Daniel Gao, Caroline W Sun, Angela B Woodley, Jing-Fei Dong

Faculty, Staff and Students Publications

Clot retraction results from retractions of platelet filopodia and fibrin fibers and requires the functional platelet αIIbβ3 integrin. This assay is widely used to test the functions of platelets and fibrinogen as well as the efficacy of fibrinolysis. Changes in clot retraction have been found in a variety of hemostatic abnormalities and, more recently, in arterial thrombosis. Despite its broad clinical use and low cost, many aspects of clot retraction are poorly understood. In the present study, we performed two clinical standard clot retraction assays using whole-blood and platelet-rich plasma (PRP) samples to determine how clot retraction correlates with platelet …

Identification Of Usp9x As A Leukemia Susceptibility Gene, Saumya Dushyant Sisoudiya, Pamela Mishra, He Li, Jeremy M Schraw, Michael E Scheurer, Sejal Salvi, Harsha Doddapaneni, Donna Muzny, Danielle Mitchell, Olga Taylor, Aniko Sabo, Philip J Lupo, Sharon E Plon

Faculty, Staff and Students Publications

We recently reported that children with multiple birth defects have a significantly higher risk of childhood cancer. We performed whole-genome sequencing on a cohort of probands from this study with birth defects and cancer and their parents. Structural variant analysis identified a novel 5 kb de novo heterozygous inframe deletion overlapping the catalytic domain of USP9X in a female proband with multiple birth defects, developmental delay, and B-cell acute lymphoblastic leukemia (B-ALL). Her phenotype was consistent with female-restricted X-linked syndromic intellectual developmental disorder-99 (MRXS99F). Genotype-phenotype analysis including previously reported female probands (n = 42) demonstrated that MRXS99F probands with B-ALL …

Early Detection Of Lung Cancer Using Artificial Intelligence-Enhanced Optical Nanosensing Of Chromatin Alterations In Field Carcinogenesis, Ali Daneshkhah, Sravya Prabhala, Parvathi Viswanathan, Hariharan Subramanian, Jianan Lin, Andrew S Chang, Ankit Bharat, Hemant Kumar Roy, Vadim Backman

Faculty, Staff and Students Publications

Supranucleosomal chromatin structure, including chromatin domain conformation, is involved in the regulation of gene expression and its dysregulation has been associated with carcinogenesis. Prior studies have shown that cells in the buccal mucosa carry a molecular signature of lung cancer among the cigarette-smoking population, the phenomenon known as field carcinogenesis or field of injury. Thus, we hypothesized that chromatin structural changes in buccal mucosa can be predictive of lung cancer. However, the small size of the chromatin chain (approximately 20 nm) folded into chromatin packing domains, themselves typically below 300 nm in diameter, preclude the detection of alterations in intradomain …

Clinical Predictors And Outcomes After Left Ventricular Assist Device Implantation And Tracheostomy, Harveen K Lamba, Lucy D Hart, Qianzi Zhang, Jackquelin M Loera, Andrew B Civitello, Ajith P Nair, Mourad H Senussi, Gabriel Loor, Kenneth K Liao, Alexis E Shafii, Subhasis Chatterjee

Faculty, Staff and Students Publications

BACKGROUND: Postoperative respiratory failure is a major complication that affects up to 10% of patients who undergo cardiac surgery and has a high in-hospital mortality rate. Few studies have investigated whether patients who require tracheostomy for postoperative respiratory failure after continuous-flow left ventricular assist device (CF-LVAD) implantation have worse survival outcomes than patients who do not.

OBJECTIVE: To identify risk factors for respiratory failure necessitating tracheostomy in CF-LVAD recipients and to compare survival outcomes between those who did and did not require tracheostomy.

METHODS: Consecutive patients who underwent primary CF-LVAD placement at a single institution between August 1, 2002, and …

Identifying The Reactive Metabolites Of Tyrosine Kinase Inhibitor Pexidartinib In Vitro Using Lc-Ms-Based Metabolomic Approaches, Xuan Qin, Yong Wang, Kevin R Mackenzie, John M Hakenjos, Si Chen, Saleh M Khalil, Sung Yun Jung, Damian W Young, Lei Guo, Feng Li

Faculty, Staff and Students Publications

Pexidartinib (PEX, TURALIO), a selective and potent inhibitor of the macrophage colony-stimulating factor-1 receptor, has been approved for the treatment of tenosynovial giant cell tumor. However, frequent and severe adverse effects have been reported in the clinic, resulting in a boxed warning on PEX for its risk of liver injury. The mechanisms underlying PEX-related hepatotoxicity, particularly metabolism-related toxicity, remain unknown. In the current study, the metabolic activation of PEX was investigated in human/mouse liver microsomes (HLM/MLM) and primary human hepatocytes (PHH) using glutathione (GSH) and methoxyamine (NH2OMe) as trapping reagents. A total of 11 PEX-GSH and 7 PEX-NH2OMe adducts were …

Multiomic Investigations Into Lung Health And Disease, Sarah E Blutt, Cristian Coarfa, Josef Neu, Mohan Pammi

Faculty, Staff and Students Publications

Diseases of the lung account for more than 5 million deaths worldwide and are a healthcare burden. Improving clinical outcomes, including mortality and quality of life, involves a holistic understanding of the disease, which can be provided by the integration of lung multi-omics data. An enhanced understanding of comprehensive multiomic datasets provides opportunities to leverage those datasets to inform the treatment and prevention of lung diseases by classifying severity, prognostication, and discovery of biomarkers. The main objective of this review is to summarize the use of multiomics investigations in lung disease, including multiomics integration and the use of machine learning …

A Defective Mechanosensing Pathway Affects Fibroblast-To-Myofibroblast Transition In The Old Male Mouse Heart, Aude Angelini, Joann Trial, Alexander B Saltzman, Anna Malovannaya, Katarzyna A Cieslik

Faculty, Staff and Students Publications

The cardiac fibroblast interacts with an extracellular matrix (ECM), enabling myofibroblast maturation via a process called mechanosensing. Although in the aging male heart, ECM is stiffer than in the young mouse, myofibroblast development is impaired, as demonstrated in 2-D and 3-D experiments. In old male cardiac fibroblasts, we found a decrease in actin polymerization, α-smooth muscle actin (α-SMA), and Kindlin-2 expressions, the latter an effector of the mechanosensing. When Kindlin-2 levels were manipulated via siRNA interference, young fibroblasts developed an old-like fibroblast phenotype, whereas Kindlin-2 overexpression in old fibroblasts reversed the defective phenotype. Finally, inhibition of overactivated extracellular regulated kinases …

Increased Sirt3 Combined With Parp Inhibition Rescues Motor Function Of Sbma Mice, David R Garcia Castro, Joseph R Mazuk, Erin M Heine, Daniel Simpson, R Seth Pinches, Caroline Lozzi, Kathryn Hoffman, Phillip Morrin, Dylan Mathis, Maria V Lebedev, Elyse Nissley, Kang Hoo Han, Tyler Farmer, Diane E Merry, Qiang Tong, Maria Pennuto, Heather L Montie

Faculty, Staff and Students Publications

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease with substantial mitochondrial and metabolic dysfunctions. SBMA is caused by polyglutamine (polyQ) expansion in the androgen receptor (AR). Activating or increasing the NAD+-dependent deacetylase, SIRT3, reduced oxidative stress and death of cells modeling SBMA. However, increasing diminished SIRT3 in AR100Q mice failed to reduce acetylation of the SIRT3 target/antioxidant, SOD2, and had no effect on increased total acetylated peptides in quadriceps. Yet, overexpressing SIRT3 resulted in a trend of motor recovery, and corrected TCA cycle activity by decreasing acetylation of SIRT3 target proteins. We sought to boost blunted SIRT3 activity …

The Rise Of Degrader Drugs, Mingxing Teng, Nathanael S Gray

Faculty, Staff and Students Publications

The cancer genomics revolution has served up a plethora of promising and challenging targets for the drug discovery community. The field of targeted protein degradation (TPD) uses small molecules to reprogram the protein homeostasis system to destroy desired target proteins. In the last decade, remarkable progress has enabled the rational development of degraders for a large number of target proteins, with over 20 molecules targeting more than 12 proteins entering clinical development. While TPD has been fully credentialed by the prior development of immunomodulatory drug (IMiD) class for the treatment of multiple myeloma, the field is poised for a "Gleevec …

Genome-Wide Association Studies And Fine-Mapping Identify Genomic Loci For N-3 And N-6 Polyunsaturated Fatty Acids In Hispanic American And African American Cohorts, Chaojie Yang, Jenna Veenstra, Traci M Bartz, Matthew C Pahl, Brian Hallmark, Yii-Der Ida Chen, Jason Westra, Lyn M Steffen, Christopher D Brown, David Siscovick, Michael Y Tsai, Alexis C Wood, Stephen S Rich, Caren E Smith, Timothy D O'Connor, Dariush Mozaffarian, Struan F A Grant, Floyd H Chilton, Nathan L Tintle, Rozenn N Lemaitre, Ani Manichaikul

Faculty, Staff and Students Publications

Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) play critical roles in human health. Prior genome-wide association studies (GWAS) of n-3 and n-6 PUFAs in European Americans from the CHARGE Consortium have documented strong genetic signals in/near the FADS locus on chromosome 11. We performed a GWAS of four n-3 and four n-6 PUFAs in Hispanic American (n = 1454) and African American (n = 2278) participants from three CHARGE cohorts. Applying a genome-wide significance threshold of P < 5 × 10

Class-Driven Synergy And Antagonism Between A Pseudomonas Phage And Antibiotics, Paul Nicholls, Justin R Clark, Carmen Gu Liu, Austen Terwilliger, Anthony W Maresso

Faculty, Staff and Students Publications

The ubiquitous bacterial pathogen Pseudomonas aeruginosa is responsible for severe infections in patients with burns, cystic fibrosis, and neutropenia. Biofilm formation gives physical refuge and a protected microenvironment for sessile cells, rendering cure by antibiotics a challenge. Bacteriophages have evolved to prey on these biofilms over millions of years, using hydrolases and depolymerases to penetrate biofilms and reach cellular targets. Here, we assessed how a newly discovered KMV-like phage (ΦJB10) interacts with antibiotics to treat P. aeruginosa more effectively in both planktonic and biofilm forms. By testing representatives of four classes of antibiotics (cephalosporins, aminoglycosides, fluoroquinolones, and carbapenems), we demonstrated …

Impact Of Geroscience On Therapeutic Strategies For Older Adults With Cardiovascular Disease: Jacc Scientific Statement, Daniel E Forman, George A Kuchel, John C Newman, James L Kirkland, Elena Volpi, George E Taffet, Nir Barzilai, Ambarish Pandey, Dalane W Kitzman, Peter Libby, Luigi Ferrucci

Faculty, Staff and Students Publications

Geroscience posits that cardiovascular disease (CVD) and other chronic diseases result from progressive erosion of the effectiveness of homeostatic mechanisms that oppose age-related accumulation of molecular damage. This hypothetical common root to chronic diseases explains why patients with CVD are often affected by multimorbidity and frailty and why older age negatively affects CVD prognosis and treatment response. Gerotherapeutics enhance resilience mechanisms that counter age-related molecular damage to prevent chronic diseases, frailty, and disability, thereby extending healthspan. Here, we describe the main resilience mechanisms of mammalian aging, with a focus on how they can affect CVD pathophysiology. We next present novel …