Medical Molecular Biology Commons^™

Characterization Of A New Whim Syndrome Mutant Reveals Mechanistic Differences In Regulation Of The Chemokine Receptor Cxcr4, Jiansong Luo, Francesco De Pascali, G Wendell Richmond, Amer M Khojah, Jeffrey L Benovic

Department of Biochemistry and Molecular Biology Faculty Papers

WHIM syndrome is a rare immunodeficiency disorder that is characterized by warts, hypogammaglobulinemia, infections, and myelokathexis. While several gain-of-function mutations that lead to C-terminal truncations, frame shifts and point mutations in the chemokine receptor CXCR4 have been identified in WHIM syndrome patients, the functional effect of these mutations are not fully understood. Here, we report on a new WHIM syndrome mutation that results in a frame shift within the codon for Ser339 (S339fs5) and compare the properties of S339fs5 with wild-type CXCR4 and a previously identified WHIM syndrome mutant, R334X. The S339fs5 and R334X mutants exhibited significantly increased signaling compared …

Platelet Micrornas Inhibit Primary Tumor Growth Via Broad Modulation Of Tumor Cell Mrna Expression In Ectopic Pancreatic Cancer In Mice, Jeremy G.T. Wurtzel, Sophia Lazar, Sonali Sikder, Kathy Q Cai, Igor Astsaturov, Andrew S Weyrich, Jesse W Rowley, Lawrence E. Goldfinger

Department of Medicine Faculty Papers

We investigated the contributions of platelet microRNAs (miRNAs) to the rate of growth and regulation of gene expression in primary ectopic tumors using mouse models. We previously identified an inhibitory role for platelets in solid tumor growth, mediated by tumor infiltration of platelet microvesicles (microparticles) which are enriched in platelet-derived miRNAs. To investigate the specific roles of platelet miRNAs in tumor growth models, we implanted pancreatic ductal adenocarcinoma cells as a bolus into mice with megakaryocyte-/platelet-specific depletion of mature miRNAs. We observed an ~50% increase in the rate of growth of ectopic primary tumors in these mice compared to controls …

Time-Resolved Cryo-Em Visualizes Ribosomal Translocation With Ef-G And Gtp, Christine E Carbone, Anna B Loveland, Howard Gamper, Ya-Ming Hou, Gabriel Demo, Andrei A Korostelev

Department of Biochemistry and Molecular Biology Faculty Papers

During translation, a conserved GTPase elongation factor-EF-G in bacteria or eEF2 in eukaryotes-translocates tRNA and mRNA through the ribosome. EF-G has been proposed to act as a flexible motor that propels tRNA and mRNA movement, as a rigid pawl that biases unidirectional translocation resulting from ribosome rearrangements, or by various combinations of motor- and pawl-like mechanisms. Using time-resolved cryo-EM, we visualized GTP-catalyzed translocation without inhibitors, capturing elusive structures of ribosome•EF-G intermediates at near-atomic resolution. Prior to translocation, EF-G binds near peptidyl-tRNA, while the rotated 30S subunit stabilizes the EF-G GTPase center. Reverse 30S rotation releases Pi and translocates peptidyl-tRNA and …

Targeting Oncogenic Gαq/11 In Uveal Melanoma, Dominic Lapadula, Jeffrey L Benovic

Department of Biochemistry and Molecular Biology Faculty Papers

Uveal melanoma is the most common intraocular cancer in adults and arises from the transformation of melanocytes in the uveal tract. While treatment of the primary tumor is often effective, 36–50% of patients develop metastatic disease primarily to the liver. While various strategies have been used to treat the metastatic disease, there remain no effective treatments that improve survival. Significant insight has been gained into the pathways that are altered in uveal melanoma, with mutually exclusive activating mutations in the GNAQ and GNA11 genes being found in over 90% of patients. These genes encode the alpha subunits of the hetetrotrimeric …

Promoter Considerations In The Design Of Lentiviral Vectors For Use In Treating Lysosomal Storage Diseases, Estera Rintz, Takashi Higuchi, Hiroshi Kobayashi, Deni S Galileo, Grzegorz Wegrzyn, Shunji Tomatsu

Department of Pediatrics Faculty Papers

More than 50 lysosomal storage diseases (LSDs) are associated with lysosomal dysfunctions with the frequency of 1:5,000 live births. As a result of missing enzyme activity, the lysosome dysfunction accumulates undegraded or partially degraded molecules, affecting the entire body. Most of them are life-threatening diseases where patients could die within the first or second decade of life. Approximately 20 LSDs have the approved treatments, which do not provide the cure for the disorder. Therefore, the delivery of missing genes through gene therapy is a promising approach for LSDs. Over the years, ex vivo lentiviral-mediated gene therapy for LSDs has been …

Tera-Seq: True End-To-End Sequencing Of Native Rna Molecules For Transcriptome Characterization, Fadia Ibrahim, Jan Oppelt, Manolis Maragkakis, Zissimos Mourelatos

Department of Biochemistry and Molecular Biology Faculty Papers

Direct sequencing of single, native RNA molecules through nanopores has a strong potential to transform research in all aspects of RNA biology and clinical diagnostics. The existing platform from Oxford Nanopore Technologies is unable to sequence the very 5′ ends of RNAs and is limited to polyadenylated molecules. Here, we develop True End-to-end RNA Sequencing (TERA-Seq), a platform that addresses these limitations, permitting more thorough transcriptome characterization. TERA-Seq describes both poly-and non-polyadenylated RNA molecules and accurately identifies their native 5′ and 3′ ends by ligating uniquely designed adapters that are sequenced along with the transcript. We find that capped, full-length …

Expression And Purification Of Phage T7 Ejection Proteins For Cryo-Em Analysis, Nicholas A. Swanson, Ravi K Lokareddy, Fenglin Li, Chun-Feng Hou, Mikhail Pavlenok, Michael Niederweis, Gino Cingolani

Department of Biochemistry and Molecular Biology Faculty Papers

Bacteriophages of the Podoviridae family densely package their genomes into precursor capsids alongside internal virion proteins called ejection proteins. In phage T7 these proteins (gp14, gp15, and gp16) are ejected into the host envelope forming a DNA-ejectosome for genome delivery. Here, we describe the purification and characterization of recombinant gp14, gp15, and gp16. This protocol was used for high-resolution cryo-EM structure analysis of the T7 periplasmic tunnel and can be adapted to study ejection proteins from other phages. For complete details on the use and execution of this protocol, please refer to Swanson et al.

Inability To Switch From Arid1a-Baf To Arid1b-Baf Impairs Exit From Pluripotency And Commitment Towards Neural Crest Formation In Arid1b-Related Neurodevelopmental Disorders, Luca Pagliaroli, Patrizia Porazzi, Alyxandra T Curtis, Chiara Scopa, Harald M M Mikkers, Christian Freund, Lucia Daxinger, Sandra Deliard, Sarah A Welsh, Sarah Offley, Connor A Ott, Bruno Calabretta, Samantha A Brugmann, Gijs W E Santen, Marco Trizzino

Department of Biochemistry and Molecular Biology Faculty Papers

Subunit switches in the BAF chromatin remodeler are essential during development. ARID1B and its paralog ARID1A encode for mutually exclusive BAF subunits. De novo ARID1B haploinsufficient mutations cause neurodevelopmental disorders, including Coffin-Siris syndrome, which is characterized by neurological and craniofacial features. Here, we leveraged ARID1B+/- Coffin-Siris patient-derived iPSCs and modeled cranial neural crest cell (CNCC) formation. We discovered that ARID1B is active only during the first stage of this process, coinciding with neuroectoderm specification, where it is part of a lineage-specific BAF configuration (ARID1B-BAF). ARID1B-BAF regulates exit from pluripotency and lineage commitment by attenuating thousands of enhancers and genes of …

Zebrafish Paralogs Brd2a And Brd2b Are Needed For Proper Circulatory, Excretory And Central Nervous System Formation And Act As Genetic Antagonists During Development, Gregory L Branigan, Kelly S Olsen, Isabella Burda, Matthew W Haemmerle, Jason Ho, Alexandra Venuto, Nicholas D D'Antonio, Ian E Briggs, Angela J Dibenedetto

Department of Biochemistry and Molecular Biology Faculty Papers

Brd2 belongs to the BET family of epigenetic transcriptional co-regulators that act as adaptor-scaffolds for the assembly of chromatin-modifying complexes and other factors at target gene promoters. Brd2 is a protooncogene and candidate gene for juvenile myoclonic epilepsy in humans, a homeobox gene regulator in Drosophila, and a maternal-zygotic factor and cell death modulator that is necessary for normal development of the vertebrate central nervous system (CNS). As two copies of Brd2 exist in zebrafish, we use antisense morpholino knockdown to probe the role of paralog Brd2b, as a comparative study to Brd2a, the ortholog of human Brd2. A deficiency …

Multifunctionality Of Prostatic Acid Phosphatase In Prostate Cancer Pathogenesis, Evgenia Alpert, Armin Akhavan, Arie Gruzman, William J. Hansen, Joshua Lehrer-Graiwer, Steven C. Hall, Eric Johansen, Sean Mcallister, Mittul Gulati, Ming-Fong Lin, Vishwanath R Lingappa

Journal Articles: Biochemistry & Molecular Biology

The role of human prostatic acid phosphatase (PAcP, P15309|PPAP_HUMAN) in prostate cancer was investigated using a new proteomics tool termed signal sequence swapping (replacement of domains from the native cleaved amino terminal signal sequence of secretory/membrane proteins with corresponding regions of functionally distinct signal sequence subtypes). This manipulation preferentially redirects proteins to different pathways of biogenesis at the endoplasmic reticulum (ER), magnifying normally difficult to detect subsets of the protein of interest. For PAcP, this technique reveals three forms identical in amino acid sequence but profoundly different in physiological functions, subcellular location, and biochemical properties. These three forms of PAcP …

Global Gene Expression Analysis Of Systemic Sclerosis Myofibroblasts Demonstrates A Marked Increase In The Expression Of Multiple Nbpf Genes, Giuseppina Abignano, Heidi Hermes, Sonsoles Piera-Velazquez, Sankar Addya, Francesco Del Galdo, Sergio A. Jimenez

Kimmel Cancer Center Faculty Papers

Myofibroblasts are the key effector cells responsible for the exaggerated tissue fibrosis in Systemic Sclerosis (SSc). Despite their importance to SSc pathogenesis, the specific transcriptome of SSc myofibroblasts has not been described. The purpose of this study was to identify transcriptome differences between SSc myofibroblasts and non-myofibroblastic cells. Alpha smooth muscle actin (α-SMA) expressing myofibroblasts and α-SMA negative cells were isolated employing laser capture microdissection from dermal cell cultures from four patients with diffuse SSc of recent onset. Total mRNA was extracted from both cell populations, amplified and analyzed employing microarrays. Results for specific genes were validated by Western blots …

Cellular Origins Of Egfr-Driven Lung Cancer Cells Determine Sensitivity To Therapy, Fan Chen, Jinpeng Liu, Robert M. Flight, Kassandra J. Naughton, Alexsandr Lukyanchuk, Abigail R Edgin, Xiulong Song, Haikuo Zhang, Kwok-Kin Wong, Hunter N. B. Moseley, Chi Wang, Christine F. Brainson

Toxicology and Cancer Biology Faculty Publications

Targeting the epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors (TKIs) is one of the major precision medicine treatment options for lung adenocarcinoma. Due to common development of drug resistance to first- and second-generation TKIs, third-generation inhibitors, including osimertinib and rociletinib, have been developed. A model of EGFR-driven lung cancer and a method to develop tumors of distinct epigenetic states through 3D organotypic cultures are described here. It is discovered that activation of the EGFR T790M/L858R mutation in lung epithelial cells can drive lung cancers with alveolar or bronchiolar features, which can originate from alveolar type 2 (AT2) cells …

Exosomes From Adipose-Derived Stem Cells Alleviate Myocardial Infarction Via Microrna-31/Fih1/Hif-1Α Pathway, Dihan Zhu, Yang Wang, Miracle Thomas, Keasiah Mclaughlin, Babayewa Oguljahan, Joshua Henderson, Qinglin Yang, Y Eugene Chen, Dong Liu

School of Graduate Studies Faculty Publications

Our previous study has revealed that exosomes from adipose-derived stem cells (ASCs) promote angiogenesis in subcutaneously transplanted gels by delivery of microRNA-31 (miR-31) which targets factor inhibiting hypoxia-inducible factor-1 (FIH1) in recipient cells. Here we hypothesized that ASC exosomes alleviate ischemic diseases through miR-31/FIH1/hypoxia-inducible factor-1α (HIF-1α) signaling pathway. Exosomes from ASCs were characterized with nanoparticle tracking analysis, transmission electron microscopy, and immunoblotting analysis for exosomal markers. Results from immunoblotting and laser imaging of ischemic mouse hindlimb revealed that miR-31 enriched ASC exosomes inhibited FIH1 expression and enhanced the blood perfusion, respectively. These effects were impaired when using miR-31-depleted exosomes. Immunohistochemistry …

The Penn State Protein Ladder System For Inexpensive Protein Molecular Weight Markers, Ryan T Santilli, John E Williamson, Yoshitaka Shibata, Rosalie P Sowers, Andrew N. Fleischman, Song Tan

Department of Anesthesiology Faculty Papers

We have created the Penn State Protein Ladder system to produce protein molecular weight markers easily and inexpensively (less than a penny a lane). The system includes plasmids which express 10, 15, 20, 30, 40, 50, 60, 80 and 100 kD proteins in E. coli. Each protein migrates appropriately on SDS-PAGE gels, is expressed at very high levels (10–50 mg per liter of culture), is easy to purify via histidine tags and can be detected directly on Western blots via engineered immunoglobulin binding domains. We have also constructed plasmids to express 150 and 250 kD proteins. For more efficient production, …

Dna Polymerase Θ: A Cancer Drug Target With Reverse Transcriptase Activity, Xiaojiang Chen, Richard T. Pomerantz

Department of Biochemistry and Molecular Biology Faculty Papers

The emergence of precision medicine from the development of Poly (ADP‐ribose) polymerase (PARP) inhibitors that preferentially kill cells defective in homologous recombination has sparked wide interest in identifying and characterizing additional DNA repair enzymes that are synthetic lethal with HR factors. DNA polymerase theta (Polθ) is a validated anti‐cancer drug target that is synthetic lethal with HR factors and other DNA repair proteins and confers cellular resistance to various genotoxic cancer therapies. Since its initial characterization as a helicase‐polymerase fusion protein in 2003, many exciting and unexpected activities of Polθ in microhomology‐mediated end‐joining (MMEJ) and translesion synthesis (TLS) have been …

Characterization Of Hnrnpa1 Mutations Defines Diversity In Pathogenic Mechanisms And Clinical Presentation., Danique Beijer, Hong Joo Kim, Lin Guo, Kevin O'Donovan, Inès Mademan, Tine Deconinck, Kristof Van Schil, Charlotte M Fare, Lauren E Drake, Alice F Ford, Andrzej Kochański, Dagmara Kabzińska, Nicolas Dubuisson, Peter Van Den Bergh, Nicol C Voermans, Richard Jlf Lemmers, Silvère M Van Der Maarel, Devon Bonner, Jacinda B Sampson, Matthew T Wheeler, Anahit Mehrabyan, Steven Palmer, Peter De Jonghe, James Shorter, J Paul Taylor, Jonathan Baets

Department of Biochemistry and Molecular Biology Faculty Papers

Mutations in HNRNPA1 encoding heterogeneous nuclear ribonucleoprotein (hnRNP) A1 are a rare cause of amyotrophic lateral sclerosis (ALS) and multisystem proteinopathy (MSP). hnRNPA1 is part of the group of RNA-binding proteins (RBPs) that assemble with RNA to form RNPs. hnRNPs are concentrated in the nucleus and function in pre-mRNA splicing, mRNA stability, and the regulation of transcription and translation. During stress, hnRNPs, mRNA, and other RBPs condense in the cytoplasm to form stress granules (SGs). SGs are implicated in the pathogenesis of (neuro-)degenerative diseases, including ALS and inclusion body myopathy (IBM). Mutations in RBPs that affect SG biology, including FUS, …

Analysis Of The Dna-Binding Properties Of Alx1, An Evolutionarily Conserved Regulator Of Skeletogenesis In Echinoderms, Jennifer Guerrero-Santoro, Jian Ming Khor, Ayşe Haruka Açıkbaş, James B. Jaynes, Charles A Ettensohn

Department of Biochemistry and Molecular Biology Faculty Papers

Alx1, a homeodomain-containing transcription factor, is a highly conserved regulator of skeletogenesis in echinoderms. In sea urchins, Alx1 plays a central role in the differentiation of embryonic primary mesenchyme cells (PMCs) and positively regulates the transcription of most biomineralization genes expressed by these cells. The alx1 gene arose via duplication and acquired a skeletogenic function distinct from its paralog (alx4) through the exonization of a 41-amino acid motif (the D2 domain). Alx1 and Alx4 contain glutamine-50 paired-type homeodomains, which interact preferentially with palindromic binding sites in vitro. Chromatin immunoprecipitation sequencing (ChIP-seq) studies have shown, however, that Alx1 binds both to …

Polθ Reverse Transcribes Rna And Promotes Rna-Templated Dna Repair, Gurushankar Chandramouly, Jiemin Zhao, Shane Mcdevitt, Timur Rusanov, Trung Hoang, Nikita Borisonnik, Taylor Treddinick, Felicia Wednesday Lopezcolorado, Tatiana Kent, Labiba Siddique, Joseph Mallon, Jacklyn Huhn, Zainab Shoda, Ekaterina Kashkina, Alessandra Brambati, Jeremy M Stark, Xiaojiang S Chen, Richard Pomerantz

Department of Biochemistry and Molecular Biology Faculty Papers

Genome-embedded ribonucleotides arrest replicative DNA polymerases (Pols) and cause DNA breaks. Whether mammalian DNA repair Pols efficiently use template ribonucleotides and promote RNA-templated DNA repair synthesis remains unknown. We find that human Polθ reverse transcribes RNA, similar to retroviral reverse transcriptases (RTs). Polθ exhibits a significantly higher velocity and fidelity of deoxyribonucleotide incorporation on RNA versus DNA. The 3.2-Å crystal structure of Polθ on a DNA/RNA primer-template with bound deoxyribonucleotide reveals that the enzyme undergoes a major structural transformation within the thumb subdomain to accommodate A-form DNA/RNA and forms multiple hydrogen bonds with template ribose 2'-hydroxyl groups like retroviral RTs. …

Candida Cell-Surface-Specific Monoclonal Antibodies Protect Mice Against Candida Auris Invasive Infection, Jonothan Rosario-Colon, Karen Eberle, Abby Adams, Evan Courville, Hong Xin

School of Graduate Studies Faculty Publications

Candida auris is a multidrug-resistant fungal pathogen that can cause disseminated bloodstream infections with up to 60% mortality in susceptible populations. Of the three major classes of antifungal drugs, most C. auris isolates show high resistance to azoles and polyenes, with some clinical isolates showing resistance to all three drug classes. We reported in this study a novel approach to treating C. auris disseminated infections through passive transfer of monoclonal antibodies (mAbs) targeting cell surface antigens with high homology in medically important Candida species. Using an established A/J mouse model of disseminated infection that mimics human candidiasis, we showed that …

Co-Targeting Plk1 And Dnmt3a In Advanced Prostate Cancer, Zhuangzhuang Zhang, Lijun Cheng, Qiongsi Zhang, Yifan Kong, Daheng He, Kunyu Li, Matthew Rea, Jianlin Wang, Ruixin Wang, Jinghui Liu, Zhiguo Li, Chongli Yuan, Enze Liu, Yvonne N. Fondufe-Mittendorf, Lang Li, Tao Han, Chi Wang, Xiaoqi Liu

Toxicology and Cancer Biology Faculty Publications

Because there is no effective treatment for late-stage prostate cancer (PCa) at this moment, identifying novel targets for therapy of advanced PCa is urgently needed. A new network-based systems biology approach, XDeath, is developed to detect crosstalk of signaling pathways associated with PCa progression. This unique integrated network merges gene causal regulation networks and protein-protein interactions to identify novel co-targets for PCa treatment. The results show that polo-like kinase 1 (Plk1) and DNA methyltransferase 3A (DNMT3a)-related signaling pathways are robustly enhanced during PCa progression and together they regulate autophagy as a common death mode. Mechanistically, it is shown that Plk1 …

Androgen Receptor, Although Not A Specific Marker For, Is A Novel Target To Suppress Glioma Stem Cells As A Therapeutic Strategy For Glioblastoma, Nan Zhao, Fei Wang, Shaheen Ahmed, Kan Liu, Chi Zhang, Sahara J. Cathcart, Dominick J. Dimaio, Michael Punsoni, Bingjie Guan, Ping Zhou, Shuo Wang, Surinder K. Batra, Tatiana K. Bronich, Tom K. Hei, Chi Lin, Chi Zhang

Journal Articles: Biochemistry & Molecular Biology

Targeting androgen receptor (AR) has been shown to be promising in treating glioblastoma (GBM) in cell culture and flank implant models but the mechanisms remain unclear. AR antagonists including enzalutamide are available for treating prostate cancer patients in clinic and can pass the blood-brain barrier, thus are potentially good candidates for GBM treatment but have not been tested in GBM orthotopically. Our current studies confirmed that in patients, a majority of GBM tumors overexpress AR in both genders. Enzalutamide inhibited the proliferation of GBM cells both in vitro and in vivo. Although confocal microscopy demonstrated that AR is expressed …

Tumor- And Osteoclast-Derived Nrp2 In Prostate Cancer Bone Metastases, Navatha S. Polavaram, Samikshan Dutta, Ridwan Islam, Arup K. Bag, Sohini Roy, David Poitz, Jeffrey Karnes, Lorenz C. Hofbauer, Manish Kohli, Brian A. Costello, Raffael Jimenez, Surinder K. Batra, Benjamin A. Teply, Michael H. Muders, K Datta

Journal Articles: Biochemistry & Molecular Biology

Understanding the role of neuropilin 2 (NRP2) in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone metastasis. We observed a significant upregulation of NRP2 in prostate cancer cells metastasized to bone. Here, we report that targeting NRP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis, implicating NRP2 as a promising therapeutic target. Since, osteoclasts present in the tumor microenvironment express NRP2, we have investigated the potential effect of targeting NRP2 in osteoclasts. Our results …

The Effects Of Mapk Signaling On The Development Of Cerebellar Granule Cells, Kerry Morgan

Honors Scholar Theses

The granule cells are the most abundant neuronal type in the human brain. Rapid proliferation of granule cell progenitors results in dramatic expansion and folding of the cerebellar cortex during postnatal development. Mis-regulation of this proliferation process causes medulloblastoma, the most prevalent childhood brain tumor. In the developing cerebellum, granule cells are derived from Atoh1-expressing cells, which arise from the upper rhombic lip (the interface between the roof plate and neuroepithelium). In addition to granule cells, the Atoh1 lineage also gives rise to different types of neurons including cerebellar nuclei neurons. In the current study, I have investigated the …

Hypercalcemia Of Malignancy Attributed To Cosecretion Of Pth And Pthrp In Lung Adenocarcinoma, Jeffrey Kroopnick, Ubaldo E. Martinez-Outshoorn, Madalina Tuluc, Caroline S Kim

Department of Medical Oncology Faculty Papers

Introduction: Hypercalcemia of malignancy (HCM) portends a very poor prognosis, and no established guidelines exist regarding its management. Most instances of HCM are due to local osteolysis or secretion of parathyroid hormone related-peptide, while less than 1% of all cases are due to ectopic secretion of parathyroid hormone.

Case report: We present an unusual case of HCM due to proposed cosecretion of both parathyroid hormone and parathyroid hormone-related protein in a 36-year-old man with a poorly differentiated lung adenocarcinoma. The patient's hypercalcemia was refractory to conventional measures, including intravenous bisphosphonate therapy (zoledronic acid), and was improved with administration of denosumab. …

An Insulator Blocks Access To Enhancers By An Illegitimate Promoter, Preventing Repression By Transcriptional Interference., Miki Fujioka, Anastasiya Nezdyur, James B. Jaynes

Department of Biochemistry and Molecular Biology Faculty Papers

Several distinct activities and functions have been described for chromatin insulators, which separate genes along chromosomes into functional units. Here, we describe a novel mechanism of functional separation whereby an insulator prevents gene repression. When the homie insulator is deleted from the end of a Drosophila even skipped (eve) locus, a flanking P-element promoter is activated in a partial eve pattern, causing expression driven by enhancers in the 3' region to be repressed. The mechanism involves transcriptional read-through from the flanking promoter. This conclusion is based on the following. Read-through driven by a heterologous enhancer is sufficient to repress, even …

Vitamin D3 Induces Mesenchymal-To-Endothelial Transition And Promotes A Proangiogenic Niche Through Igf-1 Signaling, Lei Chen, Anweshan Samanta, Lin Zhao, Nathaniel R. Dudley, Tanner Buehler, Robert J. Vincent, Jeryl Hauptman, Magdy Girgis, Buddhadeb Dawn

School of Medicine Faculty Publications

Biological Sciences; Physiology; Molecular Biology; Cell Biology

Implications Of The Quantum Dna Model For Information Sciences, F. Matthew Mihelic

Faculty Publications

The DNA molecule can be modeled as a quantum logic processor, and this model has been supported by pilot research that experimentally demonstrated non-local communication between cells in separated cell cultures. This modeling and pilot research have important implications for information sciences, providing a potential architecture for quantum computing that operates at room temperature and is scalable to millions of qubits, and including the potential for an entanglement communication system based upon the quantum DNA architecture. Such a system could be used to provide non-local quantum key distribution that could not be blocked by any shielding or water depth, would …

Magnetic Vector Potential Manipulation Of Majorana Fermions In Dna Quantum Logic, F. Matthew Mihelic

Faculty Publications

In the quantum logic of the DNA molecule, electrons are held and conducted coherently as spinless Cooper pairs and are shielded from electromagnetic energy by a Faraday cage effect of the double lipid bilayer of the nuclear membrane. The magnetic vector potential generated by cellular depolarization can synchronize logical activity in portions of the DNA molecule by affecting spin directions of appropriately oriented spinless electrons via the Aharonov-Bohm effect, but is not blocked by that Faraday cage effect. Within the logically and thermodynamically reversible chiral enantiomeric symmetry of the deoxyribose moieties the decoherent transition of Cooper pair to Dirac pair …

St6galnac-I Promotes Lung Cancer Metastasis By Altering Muc5ac Sialylation, Imayavaramban Lakshmanan, Sanjib Chaudhary, Raghupathy Vengoji, Parthasarathy Seshacharyulu, Satyanarayana Rachagani, Joseph Carmicheal, Rahat Jahan, Pranita Atri, Ramakanth C. Venkata, Rohitesh Gupta, Saravanakumar Marimuthu, Naveenkumar Perumal, Sanchita Rauth, Sukhwinder Kaur, Kavita Mallya, Lynette M. Smith, Subodh M. Lele, Moorthy P. Ponnusamy, Mohd W. Nasser, Ravi Salgia, Surinder K. Batra, Apar Kishor Ganti

Journal Articles: Biochemistry & Molecular Biology

Lung cancer (LC) is the leading cause of cancer-related mortality. However, the molecular mechanisms associated with the development of metastasis is poorly understood. Understanding the biology of LC metastasis is critical to unveil the molecular mechanisms for designing targeted therapies. We developed two genetically engineered LC mouse models- Kras^G12D ;Trp53^R172H/+ ;Ad-Cre (KPA) and Kras^G12D ; Ad-Cre (KA). Survival analysis showed significantly (P=0.0049) shorter survival in KPA tumor-bearing mice as compared to KA, suggesting the aggressiveness of the model. Our transcriptomic data showed high expression of St6galnac-I in KPA compared to KA tumors. ST6GalNAc-I is an O-glycosyltransferase, which …

Amyloid Precursor-Like Protein 2 Expression Increases During Pancreatic Cancer Development And Shortens The Survival Of A Spontaneous Mouse Model Of Pancreatic Cancer., Brittany J. Poelaert, Shelby M. Knoche, Alaina C. Larson, Poomy Pandey, Parthasarathy Seshacharyulu, Nuzhat Khan, H. Carlo Maurer, Kenneth P. Olive, Yuri Sheinin, Rizwan Ahmad, Amar B. Singh, Surinder K. Batra, Satyanarayana Rachagani, Joyce C. Solheim

Journal Articles: Biochemistry & Molecular Biology

In the United States, pancreatic cancer is a major cause of cancer-related deaths. Although substantial efforts have been made to understand pancreatic cancer biology and improve therapeutic efficacy, patients still face a bleak chance of survival. A greater understanding of pancreatic cancer development and the identification of novel treatment targets are desperately needed. Our analysis of gene expression data from patient samples showed an increase in amyloid precursor-like protein 2 (APLP2) expression within primary tumor epithelium relative to pancreatic intraepithelial neoplasia (PanIN) epithelial cells. Augmented expression of APLP2 in primary tumors compared to adjacent stroma was also observed. Genetically engineered …