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Articles 1 - 30 of 306
Full-Text Articles in Medicine and Health Sciences
Trna Anticodon Cleavage By Target-Activated Crispr-Cas13a Effector, Ishita Jain, Matvey Kolesnik, Konstantin Kuznedelov, Leonid Minakhin, Natalia Morozova, Anna Shiriaeva, Alexandr Kirillov, Sofia Medvedeva, Alexei Livenskyi, Laura Kazieva, Kira S Makarova, Eugene V Koonin, Sergei Borukhov, Konstantin Severinov, Ekaterina Semenova
Trna Anticodon Cleavage By Target-Activated Crispr-Cas13a Effector, Ishita Jain, Matvey Kolesnik, Konstantin Kuznedelov, Leonid Minakhin, Natalia Morozova, Anna Shiriaeva, Alexandr Kirillov, Sofia Medvedeva, Alexei Livenskyi, Laura Kazieva, Kira S Makarova, Eugene V Koonin, Sergei Borukhov, Konstantin Severinov, Ekaterina Semenova
Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship
Type VI CRISPR-Cas systems are among the few CRISPR varieties that target exclusively RNA. The CRISPR RNA–guided, sequence-specific binding of target RNAs, such as phage transcripts, activates the type VI effector, Cas13. Once activated, Cas13 causes collateral RNA cleavage, which induces bacterial cell dormancy, thus protecting the host population from the phage spread. We show here that the principal form of collateral RNA degradation elicited by Leptotrichia shahii Cas13a expressed in Escherichia coli cells is the cleavage of anticodons in a subset of transfer RNAs (tRNAs) with uridine-rich anticodons. This tRNA cleavage is accompanied by inhibition of protein synthesis, thus …
Predictive And Prognostic Biomarkers And Tumor Antigens For Targeted Therapy In Urothelial Carcinoma, Aditya Eturi, Amman Bhasin, Kevin Zarrabi, William Tester
Predictive And Prognostic Biomarkers And Tumor Antigens For Targeted Therapy In Urothelial Carcinoma, Aditya Eturi, Amman Bhasin, Kevin Zarrabi, William Tester
Department of Medical Oncology Faculty Papers
Urothelial carcinoma (UC) is the fourth most prevalent cancer amongst males worldwide. While patients with non-muscle-invasive disease have a favorable prognosis, 25% of UC patients present with locally advanced disease which is associated with a 10-15% 5-year survival rate and poor overall prognosis. Muscle-invasive bladder cancer (MIBC) is associated with about 50% 5 year survival when treated by radical cystectomy or trimodality therapy; stage IV disease is associated with 10-15% 5 year survival. Current therapeutic modalities for MIBC include neoadjuvant chemotherapy, surgery and/or chemoradiation, although patients with relapsed or refractory disease have a poor prognosis. However, the rapid success of …
Discovery Of A Small-Molecule Inhibitor That Traps Polθ On Dna And Synergizes With Parp Inhibitors, William Fried, Mrityunjay Tyagi, Leonid Minakhin, Gurushankar Chandramouly, Taylor Tredinnick, Mercy Ramanjulu, William Auerbacher, Marissa L Calbert, Timur Rusanov, Trung Hoang, Nikita Borisonnik, Robert Betsch, John Krais, Yifan Wang, Umeshkumar Vekariya, John Gordon, George Morton, Tatiana Kent, Tomasz Skorski, Neil Johnson, Wayne Childers, Xiaojiang Chen, Richard Pomerantz
Discovery Of A Small-Molecule Inhibitor That Traps Polθ On Dna And Synergizes With Parp Inhibitors, William Fried, Mrityunjay Tyagi, Leonid Minakhin, Gurushankar Chandramouly, Taylor Tredinnick, Mercy Ramanjulu, William Auerbacher, Marissa L Calbert, Timur Rusanov, Trung Hoang, Nikita Borisonnik, Robert Betsch, John Krais, Yifan Wang, Umeshkumar Vekariya, John Gordon, George Morton, Tatiana Kent, Tomasz Skorski, Neil Johnson, Wayne Childers, Xiaojiang Chen, Richard Pomerantz
Department of Biochemistry and Molecular Biology Faculty Papers
The DNA damage response (DDR) protein DNA Polymerase θ (Polθ) is synthetic lethal with homologous recombination (HR) factors and is therefore a promising drug target in BRCA1/2 mutant cancers. We discover an allosteric Polθ inhibitor (Polθi) class with 4-6 nM IC50 that selectively kills HR-deficient cells and acts synergistically with PARP inhibitors (PARPi) in multiple genetic backgrounds. X-ray crystallography and biochemistry reveal that Polθi selectively inhibits Polθ polymerase (Polθ-pol) in the closed conformation on B-form DNA/DNA via an induced fit mechanism. In contrast, Polθi fails to inhibit Polθ-pol catalytic activity on A-form DNA/RNA in which the enzyme binds in …
Biomarkers For Managing Neurodegenerative Diseases, Lara Cheslow, Adam E. Snook, Scott A. Waldman
Biomarkers For Managing Neurodegenerative Diseases, Lara Cheslow, Adam E. Snook, Scott A. Waldman
Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers
Neurological disorders are the leading cause of cognitive and physical disability worldwide, affecting 15% of the global population. Due to the demographics of aging, the prevalence of neurological disorders, including neurodegenerative diseases, will double over the next two decades. Unfortunately, while available therapies provide symptomatic relief for cognitive and motor impairment, there is an urgent unmet need to develop disease-modifying therapies that slow the rate of pathological progression. In that context, biomarkers could identify at-risk and prodromal patients, monitor disease progression, track responses to therapy, and parse the causality of molecular events to identify novel targets for further clinical investigation. …
Differentially Disrupted Spinal Cord And Muscle Energy Metabolism In Spinal And Bulbar Muscular Atrophy, Danielle Debartolo, Frederick Arnold, Y Liu, Elana Molotsky, Hsin-Yao Tang, Diane Merry
Differentially Disrupted Spinal Cord And Muscle Energy Metabolism In Spinal And Bulbar Muscular Atrophy, Danielle Debartolo, Frederick Arnold, Y Liu, Elana Molotsky, Hsin-Yao Tang, Diane Merry
Department of Biochemistry and Molecular Biology Faculty Papers
Prior studies showed that polyglutamine-expanded androgen receptor (AR) is aberrantly acetylated and that deacetylation of the mutant AR by overexpression of nicotinamide adenine dinucleotide-dependent (NAD+-dependent) sirtuin 1 is protective in cell models of spinal and bulbar muscular atrophy (SBMA). Based on these observations and reduced NAD+ in muscles of SBMA mouse models, we tested the therapeutic potential of NAD+ restoration in vivo by treating postsymptomatic transgenic SBMA mice with the NAD+ precursor nicotinamide riboside (NR). NR supplementation failed to alter disease progression and had no effect on increasing NAD+ or ATP content in muscle, despite producing a modest increase of …
The Frequency Of Pathogenic Variation In The All Of Us Cohort Reveals Ancestry-Driven Disparities, Eric Venner, Karynne Patterson, Divya Kalra, Marsha M Wheeler, Yi-Ju Chen, Sara E Kalla, Bo Yuan, Jason H Karnes, Kimberly Walker, Joshua D Smith, Sean Mcgee, Aparna Radhakrishnan, Andrew Haddad, Philip E Empey, Qiaoyan Wang, Lee Lichtenstein, Diana Toledo, Gail Jarvik, Anjene Musick, Richard A Gibbs
The Frequency Of Pathogenic Variation In The All Of Us Cohort Reveals Ancestry-Driven Disparities, Eric Venner, Karynne Patterson, Divya Kalra, Marsha M Wheeler, Yi-Ju Chen, Sara E Kalla, Bo Yuan, Jason H Karnes, Kimberly Walker, Joshua D Smith, Sean Mcgee, Aparna Radhakrishnan, Andrew Haddad, Philip E Empey, Qiaoyan Wang, Lee Lichtenstein, Diana Toledo, Gail Jarvik, Anjene Musick, Richard A Gibbs
Journal Articles
Disparities in data underlying clinical genomic interpretation is an acknowledged problem, but there is a paucity of data demonstrating it. The All of Us Research Program is collecting data including whole-genome sequences, health records, and surveys for at least a million participants with diverse ancestry and access to healthcare, representing one of the largest biomedical research repositories of its kind. Here, we examine pathogenic and likely pathogenic variants that were identified in the All of Us cohort. The European ancestry subgroup showed the highest overall rate of pathogenic variation, with 2.26% of participants having a pathogenic variant. Other ancestry groups …
Ksp1 Is An Autophagic Receptor Protein For The Snx4-Assisted Autophagy Of Ssn2/Med13, Sara E Hanley, Stephen D Willis, Steven J Doyle, Randy Strich, Katrina F Cooper
Ksp1 Is An Autophagic Receptor Protein For The Snx4-Assisted Autophagy Of Ssn2/Med13, Sara E Hanley, Stephen D Willis, Steven J Doyle, Randy Strich, Katrina F Cooper
Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship
Ksp1 is a casein II-like kinase whose activity prevents aberrant macroautophagy/autophagy induction in nutrient-rich conditions in yeast. Here, we describe a kinase-independent role of Ksp1 as a novel autophagic receptor protein for Ssn2/Med13, a known cargo of Snx4-assisted autophagy of transcription factors. In this pathway, a subset of conserved transcriptional regulators, Ssn2/Med13, Rim15, and Msn2, are selectively targeted for vacuolar proteolysis following nitrogen starvation, assisted by the sorting nexin heterodimer Snx4-Atg20. Here we show that phagophores also engulf Ksp1 alongside its cargo for vacuolar proteolysis. Ksp1 directly associates with Atg8 following nitrogen starvation at the interface of an Atg8-family interacting …
Tail-Tape-Fused Virion And Non-Virion Rna Polymerases Of A Thermophilic Virus With An Extremely Long Tail, Anastasiia Chaban, Leonid Minakhin, Ekaterina Goldobina, Brain Bae, Yue Hao, Sergei Borukhov, Leena Putzeys, Maarten Boon, Florian Kabinger, Rob Lavigne, Kira S Makarova, Eugene V Koonin, Satish K Nair, Shunsuke Tagami, Konstantin Severinov, Maria L Sokolova
Tail-Tape-Fused Virion And Non-Virion Rna Polymerases Of A Thermophilic Virus With An Extremely Long Tail, Anastasiia Chaban, Leonid Minakhin, Ekaterina Goldobina, Brain Bae, Yue Hao, Sergei Borukhov, Leena Putzeys, Maarten Boon, Florian Kabinger, Rob Lavigne, Kira S Makarova, Eugene V Koonin, Satish K Nair, Shunsuke Tagami, Konstantin Severinov, Maria L Sokolova
Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship
Thermus thermophilus bacteriophage P23-45 encodes a giant 5,002-residue tail tape measure protein (TMP) that defines the length of its extraordinarily long tail. Here, we show that the N-terminal portion of P23-45 TMP is an unusual RNA polymerase (RNAP) homologous to cellular RNAPs. The TMP-fused virion RNAP transcribes pre-early phage genes, including a gene that encodes another, non-virion RNAP, that transcribes early and some middle phage genes. We report the crystal structures of both P23-45 RNAPs. The non-virion RNAP has a crab-claw-like architecture. By contrast, the virion RNAP adopts a unique flat structure without a clamp. Structure and sequence comparisons of …
Fused In Sarcoma Regulates Glutamate Signaling And Oxidative Stress Response, Chiong-Hee Wong, Abu Rahat, Howard C Chang
Fused In Sarcoma Regulates Glutamate Signaling And Oxidative Stress Response, Chiong-Hee Wong, Abu Rahat, Howard C Chang
Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship
Mutations in fused in sarcoma (fust-1) are linked to ALS. However, how these ALS causative mutations alter physiological processes and lead to the onset of ALS remains largely unknown. By obtaining humanized fust-1 ALS mutations via CRISPR-CAS9, we generated a C. elegans ALS model. Homozygous fust-1 ALS mutant and fust-1 deletion animals are viable in C. elegans. This allows us to better characterize the molecular mechanisms of fust-1-dependent responses. We found FUST-1 plays a role in regulating superoxide dismutase, glutamate signaling, and oxidative stress. FUST-1 suppresses SOD-1 and VGLUT/EAT-4 in the nervous system. FUST-1 also regulates synaptic AMPA-type glutamate receptor …
Novel Treatments For Pxe: Targeting The Systemic And Local Drivers Of Ectopic Calcification, Ida Joely Jacobs, Qiaoli Li
Novel Treatments For Pxe: Targeting The Systemic And Local Drivers Of Ectopic Calcification, Ida Joely Jacobs, Qiaoli Li
Department of Biochemistry and Molecular Biology Faculty Papers
Pseudoxanthoma elasticum (PXE) is a heritable multisystem ectopic calcification disorder. The gene responsible for PXE, ABCC6, encodes ABCC6, a hepatic efflux transporter regulating extracellular inorganic pyrophosphate (PPi), a potent endogenous calcification inhibitor. Recent studies demonstrated that in addition to the deficiency of plasma PPi, the activated DDR/PARP signaling in calcified tissues provides an additional possible mechanism of ectopic calcification in PXE. This study examined the effects of etidronate (ETD), a stable PPi analog, and its combination with minocycline (Mino), a potent inhibitor of DDR/PARP, on ectopic calcification in an Abcc6-/- mouse model of PXE. Abcc6-/- mice, at 4 weeks of …
Profiling And Verifying The Substrates Of E3 Ubiquitin Ligase Rsp5 In Yeast Cells, Shuai Fang, Geng Chen, Yiyang Wang, Rakhee Ganti, Tatiana A Chernova, Li Zhou, Savannah E Jacobs, Duc Duong, Hiroaki Kiyokawa, Yury O Chernoff, Ming Li, Natalia Shcherbik, Bo Zhao, Jun Yin
Profiling And Verifying The Substrates Of E3 Ubiquitin Ligase Rsp5 In Yeast Cells, Shuai Fang, Geng Chen, Yiyang Wang, Rakhee Ganti, Tatiana A Chernova, Li Zhou, Savannah E Jacobs, Duc Duong, Hiroaki Kiyokawa, Yury O Chernoff, Ming Li, Natalia Shcherbik, Bo Zhao, Jun Yin
Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship
Yeast is an essential model organism for studying protein ubiquitination pathways; however, identifying the direct substrates of E3 in the cell presents a challenge. Here, we present a protocol for using the orthogonal ubiquitin transfer (OUT) cascade to profile the substrate specificity of yeast E3 Rsp5. We describe steps for OUT profiling, proteomics analysis, in vitro and in cell ubiquitination, and stability assay. The protocol can be adapted for identifying and verifying the ubiquitination targets of other E3s in yeast. For complete details on the use and execution of this protocol, please refer to Wang et al.
Modeling Biphasic, Non-Sigmoidal Dose-Response Relationships: Comparison Of Brain- Cousens And Cedergreen Models For A Biochemical Dataset, Venkat D. Abbaraju, Tamaraty L. Robinson, Brian P. Weiser
Modeling Biphasic, Non-Sigmoidal Dose-Response Relationships: Comparison Of Brain- Cousens And Cedergreen Models For A Biochemical Dataset, Venkat D. Abbaraju, Tamaraty L. Robinson, Brian P. Weiser
Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship
Biphasic, non-sigmoidal dose-response relationships are frequently observed in biochemistry and pharmacology, but they are not always analyzed with appropriate statistical methods. Here, we examine curve fitting methods for “hormetic” dose-response relationships where low and high doses of an effector produce opposite responses. We provide the full dataset used for modeling, and we provide the code for analyzing the dataset in SAS using two established mathematical models of hormesis, the Brain-Cousens model and the Cedergreen model. We show how to obtain and interpret curve parameters such as the ED50 that arise from modeling, and we discuss how curve parameters might change …
Structures Of Channelrhodopsin Paralogs In Peptidiscs Explain Their Contrasting K+ And Na+ Selectivities, Takefumi Morizumi, Kyumhyuk Kim, Hai Li, Elena G Govorunova, Oleg A Sineshchekov, Yumei Wang, Lei Zheng, Éva Bertalan, Ana-Nicoleta Bondar, Azam Askari, Leonid S Brown, John L Spudich, Oliver P Ernst
Structures Of Channelrhodopsin Paralogs In Peptidiscs Explain Their Contrasting K+ And Na+ Selectivities, Takefumi Morizumi, Kyumhyuk Kim, Hai Li, Elena G Govorunova, Oleg A Sineshchekov, Yumei Wang, Lei Zheng, Éva Bertalan, Ana-Nicoleta Bondar, Azam Askari, Leonid S Brown, John L Spudich, Oliver P Ernst
Journal Articles
Kalium channelrhodopsin 1 from Hyphochytrium catenoides (HcKCR1) is a light-gated channel used for optogenetic silencing of mammalian neurons. It selects K+ over Na+ in the absence of the canonical tetrameric K+ selectivity filter found universally in voltage- and ligand-gated channels. The genome of H. catenoides also encodes a highly homologous cation channelrhodopsin (HcCCR), a Na+ channel with >100-fold larger Na+ to K+ permeability ratio. Here, we use cryo-electron microscopy to determine atomic structures of these two channels embedded in peptidiscs to elucidate structural foundations of their dramatically different cation selectivity. Together with structure-guided mutagenesis, we show that K+ versus Na+ …
Loss Of Pml Nuclear Bodies In Familial Amyotrophic Lateral Sclerosis-Frontotemporal Dementia, Francesco Antoniani, Marco Cimino, Laura Mediani, Jonathan Vinet, Enza M. Verde, Valentina Secco, Alfred Yamoah, Priyanka Tripathi, Eleonora Aronica, Maria Elena Cicardi, Davide Trotti, Jared Sterneckert, Anand Goswami, Serena Carra
Loss Of Pml Nuclear Bodies In Familial Amyotrophic Lateral Sclerosis-Frontotemporal Dementia, Francesco Antoniani, Marco Cimino, Laura Mediani, Jonathan Vinet, Enza M. Verde, Valentina Secco, Alfred Yamoah, Priyanka Tripathi, Eleonora Aronica, Maria Elena Cicardi, Davide Trotti, Jared Sterneckert, Anand Goswami, Serena Carra
Farber Institute for Neuroscience Faculty Papers
Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two neurodegenerative disorders that share genetic causes and pathogenic mechanisms. The critical genetic players of ALS and FTD are the TARDBP, FUS and C9orf72 genes, whose protein products, TDP-43, FUS and the C9orf72-dipeptide repeat proteins, accumulate in form of cytoplasmic inclusions. The majority of the studies focus on the understanding of how cells control TDP-43 and FUS aggregation in the cytoplasm, overlooking how dysfunctions occurring at the nuclear level may influence the maintenance of protein solubility outside of the nucleus. However, protein quality control (PQC) systems that maintain protein homeostasis comprise …
High-Resolution Cryo-Em Structure Of The Pseudomonas Bacteriophage E217, Fenglin Li, Chun-Feng Hou, Ravi K. Lokareddy, Ruoyu Yang, Francesca Forti, Federica Briani, Gino Cingolani
High-Resolution Cryo-Em Structure Of The Pseudomonas Bacteriophage E217, Fenglin Li, Chun-Feng Hou, Ravi K. Lokareddy, Ruoyu Yang, Francesca Forti, Federica Briani, Gino Cingolani
Department of Biochemistry and Molecular Biology Faculty Papers
E217 is a Pseudomonas phage used in an experimental cocktail to eradicate cystic fibrosis-associated Pseudomonas aeruginosa. Here, we describe the structure of the whole E217 virion before and after DNA ejection at 3.1 Å and 4.5 Å resolution, respectively, determined using cryogenic electron microscopy (cryo-EM). We identify and build de novo structures for 19 unique E217 gene products, resolve the tail genome-ejection machine in both extended and contracted states, and decipher the complete architecture of the baseplate formed by 66 polypeptide chains. We also determine that E217 recognizes the host O-antigen as a receptor, and we resolve the N-terminal portion …
Fibrosis-The Tale Of H3k27 Histone Methyltransferases And Demethylases, Morgan D. Basta, Svetlana Petruk, Alexander Mazo, Janice L. Walker
Fibrosis-The Tale Of H3k27 Histone Methyltransferases And Demethylases, Morgan D. Basta, Svetlana Petruk, Alexander Mazo, Janice L. Walker
Department of Biochemistry and Molecular Biology Faculty Papers
Fibrosis, or excessive scarring, is characterized by the emergence of alpha-smooth muscle actin (αSMA)-expressing myofibroblasts and the excessive accumulation of fibrotic extracellular matrix (ECM). Currently, there is a lack of effective treatment options for fibrosis, highlighting an unmet need to identify new therapeutic targets. The acquisition of a fibrotic phenotype is associated with changes in chromatin structure, a key determinant of gene transcription activation and repression. The major repressive histone mark, H3K27me3, has been linked to dynamic changes in gene expression in fibrosis through alterations in chromatin structure. H3K27-specific homologous histone methylase (HMT) enzymes, Enhancer of zeste 1 and 2 …
Sequential Absorption Of Two Photons Creates A Bistable Form Of Rubyacr Responsible For Its Strong Desensitization, Oleg A Sineshchekov, Elena G Govorunova, Hai Li, Yumei Wang, John L Spudich
Sequential Absorption Of Two Photons Creates A Bistable Form Of Rubyacr Responsible For Its Strong Desensitization, Oleg A Sineshchekov, Elena G Govorunova, Hai Li, Yumei Wang, John L Spudich
Journal Articles
Channelrhodopsins with red-shifted absorption, rare in nature, are highly desired for optogenetics because light of longer wavelengths more deeply penetrates biological tissue. RubyACRs (Anion ChannelRhodopsins), a group of four closely related anion-conducting channelrhodopsins from thraustochytrid protists, are the most red-shifted channelrhodopsins known with absorption maxima up to 610 nm. Their photocurrents are large, as is typical of blue- and green-absorbing ACRs, but they rapidly decrease during continuous illumination (desensitization) and extremely slowly recover in the dark. Here, we show that long-lasting desensitization of RubyACRs results from photochemistry not observed in any previously studied channelrhodopsins. Absorption of a second photon by …
Elucidating The Impact Of Sos-Response Timing In On Escherichia Coli Survival Following Treatment With Fluoroquinolone Topoisomerase Inhibitors, Stephanie Schofield
Elucidating The Impact Of Sos-Response Timing In On Escherichia Coli Survival Following Treatment With Fluoroquinolone Topoisomerase Inhibitors, Stephanie Schofield
Honors Scholar Theses
Antibiotic treatment failure is a public health crisis, with a 2019 report stating that roughly 35,000 deaths occur in the United States yearly due to bacterial infections that are unresponsive to antibiotics (1). One complication in the treatment of bacterial infection is antibiotic persistence which further compromises our battle to effectively treat infection. Bacterial persisters can exist in clonal bacterial cultures and can tolerate antibiotic treatment by undergoing reversible phenotypic changes. They can survive drug concentrations that their genetically identical kin cannot. Some persisters remain in a slow growing state and are difficult to target with current antibiotics. A specific …
Lipid Nanoparticle-Mediated Mrna Delivery In Lung Fibrosis, Matteo Massaro, Suhong Wu, Gherardo Baudo, Haoran Liu, Scott Collum, Hyunho Lee, Cinzia Stigliano, Victor Segura-Ibarra, Harry Karmouty-Quintana, Elvin Blanco
Lipid Nanoparticle-Mediated Mrna Delivery In Lung Fibrosis, Matteo Massaro, Suhong Wu, Gherardo Baudo, Haoran Liu, Scott Collum, Hyunho Lee, Cinzia Stigliano, Victor Segura-Ibarra, Harry Karmouty-Quintana, Elvin Blanco
Journal Articles
mRNA delivery enables the specific synthesis of proteins with therapeutic potential, representing a powerful strategy in diseases lacking efficacious pharmacotherapies. Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by excessive extracellular matrix (ECM) deposition and subsequent alveolar remodeling. Alveolar epithelial type 2 cells (AEC2) and fibroblasts represent important targets in IPF given their role in initiating and driving aberrant wound healing responses that lead to excessive ECM deposition. Our objective was to examine a lipid nanoparticle (LNP)-based mRNA construct as a viable strategy to target alveolar epithelial cells and fibroblasts in IPF. mRNA-containing LNPs measuring ∼34 nm had …
Anterior And Posterior Tongue Regions And Taste Papillae: Distinct Roles And Regulatory Mechanisms With An Emphasis On Hedgehog Signaling And Antagonism., Archana Kumari, Charlotte M. Mistretta
Anterior And Posterior Tongue Regions And Taste Papillae: Distinct Roles And Regulatory Mechanisms With An Emphasis On Hedgehog Signaling And Antagonism., Archana Kumari, Charlotte M. Mistretta
Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship
Sensory receptors across the entire tongue are engaged during eating. However, the tongue has distinctive regions with taste (fungiform and circumvallate) and non-taste (filiform) organs that are composed of specialized epithelia, connective tissues, and innervation. The tissue regions and papillae are adapted in form and function for taste and somatosensation associated with eating. It follows that homeostasis and regeneration of distinctive papillae and taste buds with particular functional roles require tailored molecular pathways. Nonetheless, in the chemosensory field, generalizations are often made between mechanisms that regulate anterior tongue fungiform and posterior circumvallate taste papillae, without a clear distinction that highlights …
Dpc29 Promotes Post-Initiation Mitochondrial Translation In Saccharomyces Cerevisiae, Kyle A. Hubble, Michael F. Henry
Dpc29 Promotes Post-Initiation Mitochondrial Translation In Saccharomyces Cerevisiae, Kyle A. Hubble, Michael F. Henry
Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship
Mitochondrial ribosomes synthesize essential components of the oxidative phosphorylation (OXPHOS) system in a tightly regulated process. In the yeast Saccharomyces cerevisiae, mitochondrial mRNAs require specific translational activators, which orchestrate protein synthesis by recognition of their target gene's 5'-untranslated region (UTR). Most of these yeast genes lack orthologues in mammals, and only one such gene-specific translational activator has been proposed in humans-TACO1. The mechanism by which TACO1 acts is unclear because mammalian mitochondrial mRNAs do not have significant 5'-UTRs, and therefore must promote translation by alternative mechanisms. In this study, we examined the role of the TACO1 orthologue in yeast. We …
Gating Intermediates Reveal Inhibitory Role Of The Voltage Sensor In A Cyclic Nucleotide-Modulated Ion Channel, Xiaolong Gao, Philipp A M Schmidpeter, Vladimir Berka, Ryan J Durham, Chen Fan, Vasanthi Jayaraman, Crina M Nimigean
Gating Intermediates Reveal Inhibitory Role Of The Voltage Sensor In A Cyclic Nucleotide-Modulated Ion Channel, Xiaolong Gao, Philipp A M Schmidpeter, Vladimir Berka, Ryan J Durham, Chen Fan, Vasanthi Jayaraman, Crina M Nimigean
Journal Articles
Understanding how ion channels gate is important for elucidating their physiological roles and targeting them in pathophysiological states. Here, we used SthK, a cyclic nucleotide-modulated channel from Spirochaeta thermophila, to define a ligand-gating trajectory that includes multiple on-pathway intermediates. cAMP is a poor partial agonist for SthK and depolarization increases SthK activity. Tuning the energy landscape by gain-of-function mutations in the voltage sensor domain (VSD) allowed us to capture multiple intermediates along the ligand-activation pathway, highlighting the allosteric linkage between VSD, cyclic nucleotide-binding (CNBD) and pore domains. Small, lateral displacements of the VSD S4 segment were necessary to open the …
The Childhood Acute Illness And Nutrition (Chain) Network Nested Case-Cohort Study Protocol: A Multi-Omics Approach To Understanding Mortality Among Children In Sub-Saharan Africa And South Asia, James M. Njunge, Kirkby Tickell, Abdoulaye Hama Diallo, Abu Sadat Mohammad Sayeem Bin Shahi, Md Amran Gazi, Ali Faisal Saleem, Zaubina Kazi, Syed Ali, Caroline Tigoi, Ezekiel Mupere
The Childhood Acute Illness And Nutrition (Chain) Network Nested Case-Cohort Study Protocol: A Multi-Omics Approach To Understanding Mortality Among Children In Sub-Saharan Africa And South Asia, James M. Njunge, Kirkby Tickell, Abdoulaye Hama Diallo, Abu Sadat Mohammad Sayeem Bin Shahi, Md Amran Gazi, Ali Faisal Saleem, Zaubina Kazi, Syed Ali, Caroline Tigoi, Ezekiel Mupere
Department of Paediatrics and Child Health
Introduction: Many acutely ill children in low- and middle-income settings have a high risk of mortality both during and after hospitalisation despite guideline-based care. Understanding the biological mechanisms underpinning mortality may suggest optimal pathways to target for interventions to further reduce mortality. The Childhood Acute Illness and Nutrition (CHAIN) Network ( www.chainnnetwork.org) Nested Case-Cohort Study (CNCC) aims to investigate biological mechanisms leading to inpatient and post-discharge mortality through an integrated multi-omic approach.
Methods and analysis; The CNCC comprises a subset of participants from the CHAIN cohort (1278/3101 hospitalised participants, including 350 children who died and 658 survivors, and …
Occurrence Of Kanamycin-Resistant Bacteria Relative To Anthropogenic Pollution Along Richland Creek In Nashville, Tn, Jolene Ho Mach, Annie Le, Brandon Torres Ramirez
Occurrence Of Kanamycin-Resistant Bacteria Relative To Anthropogenic Pollution Along Richland Creek In Nashville, Tn, Jolene Ho Mach, Annie Le, Brandon Torres Ramirez
Science University Research Symposium (SURS)
The overuse of antibiotics has caused an increase in antibiotic-resistant (AR) bacteria, which is a serious public health concern. Previous studies showed a significant correlation between anthropogenic pollution and AR bacteria. This project aims to identify AR bacteria in Richland Creek relative to local anthropogenic pollution. Water samples were collected at four locations along Richland Creek in Nashville, Tennessee. Bacteria resistant to the antibiotic kanamycin were isolated from the water samples, identified to genera using DNA barcoding, and compared among the sites. We expect to see a greater abundance and diversity of kanamycin-resistant bacteria closer to the end than near …
The Emerging Role Of Notch3 Receptor Signalling In Human Lung Diseases, Manish Bodas, Bharathiraja Subramaniyan, Harry Karmouty-Quintana, Peter F Vitiello, Matthew S Walters
The Emerging Role Of Notch3 Receptor Signalling In Human Lung Diseases, Manish Bodas, Bharathiraja Subramaniyan, Harry Karmouty-Quintana, Peter F Vitiello, Matthew S Walters
Journal Articles
The mammalian respiratory system or lung is a tree-like branching structure, and the main site of gas exchange with the external environment. Structurally, the lung is broadly classified into the proximal (or conducting) airways and the distal alveolar region, where the gas exchange occurs. In parallel with the respiratory tree, the pulmonary vasculature starts with large pulmonary arteries that subdivide rapidly ending in capillaries adjacent to alveolar structures to enable gas exchange. The NOTCH signalling pathway plays an important role in lung development, differentiation and regeneration post-injury. Signalling via the NOTCH pathway is mediated through activation of four NOTCH receptors …
A Conserved Mechanism For Hormesis In Molecular Systems, Sharon N. Greenwood, Regina G. Belz, Brian P. Weiser
A Conserved Mechanism For Hormesis In Molecular Systems, Sharon N. Greenwood, Regina G. Belz, Brian P. Weiser
Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship
Hormesis refers to dose-response phenomena where low dose treatments elicit a response that is opposite the response observed at higher doses. Hormetic dose-response relationships have been observed throughout all of biology, but the underlying determinants of many reported hormetic dose-responses have not been identified. In this report, we describe a conserved mechanism for hormesis on the molecular level where low dose treatments enhance a response that becomes reduced at higher doses. The hormetic mechanism relies on the ability of protein homo-multimers to simultaneously interact with a substrate and a competitor on different subunits at low doses of competitor. In this …
Discovery Of First-In-Class Small Molecule Agonists Of The Rxfp2 Receptor As Therapeutic Candidates For Osteoporosis, Maria Esteban Lopez
Discovery Of First-In-Class Small Molecule Agonists Of The Rxfp2 Receptor As Therapeutic Candidates For Osteoporosis, Maria Esteban Lopez
FIU Electronic Theses and Dissertations
Osteoporosis is a chronic bone disease characterized by decreased bone mass and increased risk of developing fractures, predominantly observed in the elderly. The pathophysiological cause of the disease is a decrease in the activity of the bone-forming cells (osteoblasts) that alters bone remodeling in favor of bone resorption, leading to a decrease in bone mass. Recent studies identified the relaxin family peptide receptor 2 (RXFP2), the G protein-coupled receptor (GPCR) for insulin-like 3 peptide (INSL3), as an attractive target expressed in osteoblast cells to increase bone formation. The goal of this dissertation is to discover and characterize small molecule agonists …
Eskape Pathogens: The Clinical Prevalence And Molecular Mechanisms Of Antibiotic Resistance, Anusha Attre
Eskape Pathogens: The Clinical Prevalence And Molecular Mechanisms Of Antibiotic Resistance, Anusha Attre
Honors Scholar Theses
The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are the leading cause of all nosocomial, or healthcare-associated (HAI), infections (Navidinia, 2016). The purpose of this research study is to determine the burden of ESKAPE infections on healthcare and study the antibiotic resistance in these high-risk pathogens to provide direction for researchers to develop new antimicrobial innovations to reduce ESKAPE infectivity and improve patient outcomes. To study the burden of ESKAPE infections, this review analyzes the current statistics explaining the clinical prevalence of each pathogen in causing HAIs. Additionally, each pathogen is …
Unraveling The Molecular Foundations Behind The Diverged Behaviors Of Mouse Insulin 1 And Insulin 2, Connecting Diabetes Risk With Glucocorticoid Treatment And Chronic Migraine Through The Analysis Of Islet Chemistry, And Capturing Key Posttranslational Modifications All Through The Application Of A Novel Lc-Ims-Ms Workflow, Connor Christopher Long
Select or Award-Winning Individual Scholarship
We display the capabilities of our established liquid chromatography-ion mobility spectrometry-mass spectrometry (LC-IMS-MS) workflow in the investigations of islet chemistry at the sub-single-islet level. We begin by characterizing the structural differences of Ins1 and Ins2 to present novel insights as to why their behaviors diverge. We then examine the effects of the stress hormone corticosterone, the rodent equivalent of human cortisol that is often used as a therapeutic, on pancreatic peptide hormone secretion. We also uncover the molecular connection behind the inverse relationship between type 2 diabetes (T2D) risk and chronic migraine via the neuropeptides CGRP and PACAP. Lastly, we …
Investigating The Efficacy Of Tazemetosttat For In Vitro Treatment Of Human Triple Negative Breast Cancer Cells, Harshita Indukuri
Investigating The Efficacy Of Tazemetosttat For In Vitro Treatment Of Human Triple Negative Breast Cancer Cells, Harshita Indukuri
Honors Scholars Collaborative Projects
Cancer is a formidable, genetic disease that affects many people, either directly or indirectly. Breast cancer is the most commonly diagnosed cancer worldwide (31). Triple-negative breast cancer (TNBC) is a type of breast cancer that has a higher lethality compared to other breast cancers and has a poor prognosis due to its highly invasive nature and limited treatment options. Finding safe, effective, and accessible treatment for TNBC is integral to treating TNBC patients. Tazemetostat is an EZH2-inhibitor that has recently been approved for use in epithelioid sarcoma (23). EZH2 is an overexpressed protein in many cancers, including TNBC (11). However, …