Medical Biochemistry Commons^™

Chloride Sensing By Wnk1 Regulates Nlrp3 Inflammasome Activation And Pyroptosis., Lindsey Mayes-Hopfinger, Aura Enache, Jian Xie, Chou-Long Huang, Robert Köchl, Victor L.J. Tybulewicz, Teresa Fernandes-Alnemri, Emad S. Alnemri

Department of Biochemistry and Molecular Biology Faculty Papers

The NLRP3 inflammasome mediates the production of proinflammatory cytokines and initiates inflammatory cell death. Although NLRP3 is essential for innate immunity, aberrant NLRP3 inflammasome activation contributes to a wide variety of inflammatory diseases. Understanding the pathways that control NLRP3 activation will help develop strategies to treat these diseases. Here we identify WNK1 as a negative regulator of the NLRP3 inflammasome. Macrophages deficient in WNK1 protein or kinase activity have increased NLRP3 activation and pyroptosis compared with control macrophages. Mice with conditional knockout of WNK1 in macrophages have increased IL-1β production in response to NLRP3 stimulation compared with control mice. Mechanistically, …

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, …

Astrocyte-Derived Thrombospondin Induces Cortical Synaptogenesis In A Sex-Specific Manner, Anna Mazur, Ean H. Bills, Kayla M. Deschepper, James C. Williams, Brandon J. Henderson, W. Christopher Risher

Biomedical Sciences

The regulation of synaptic connectivity in the brain is vital to proper functioning and development of the CNS. Formation of neural networks in the CNS has been shown to be heavily influenced by astrocytes, which secrete factors, including thrombospondin (TSP) family proteins, that promote synaptogenesis. However, whether this process is different between males and females has not been thoroughly investigated. In this study, we found that cortical neurons purified from newborn male rats showed a significantly more robust synaptogenic response compared with female-derived cells when exposed to factors secreted from astrocytes. This difference was driven largely by the neuronal response …

Trojan Horses And Tunneling Nanotubes Enable Α-Synuclein Pathology To Spread In Parkinson Disease, Santhanasabapathy Rajasekaran, Stephan N. Witt

School of Graduate Studies Faculty Publications

No abstract provided.

Investigating The Protective Role Of Irbp Against Oxidative Stress In Diabetic Retinopathy, Matthew N. Parvus, Federico Gonzalez-Fernandez, Reanna Rodriguez, Daniela Gonzalez, Andrew Tsin

MEDI 9331 Scholarly Activities Clinical Years

Introduction:

Diabetic retinopathy is an ocular condition caused by a multitude of factors as a result of elevated blood glucose. One of the primary mechanisms of damage is a result of oxidative stress. It has been found that levels of IRBP in the vitreous are decreased in the setting of diabetic retinopathy, which could be associated with damage from resulting oxidative stress.

Purpose:

This article will address the protective role of IRBP in diabetic retinopathy by discussing the overexpression and under expression of IRBP and its resulting effect on the retina. Increased levels of IRBP in rats with diabetic retinopathy …

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 …

Cd8+ T Cells Inhibit Metastasis And Cxcl4 Regulates Its Function, Robiya Joseph, Rama Soundararajan, Suhas Vasaikar, Fei Yang, Kendra L Allton, Lin Tian, Petra Den Hollander, Sevinj Isgandarova, Monika Haemmerle, Barbara Mino, Tieling Zhou, Crystal Shin, Melisa Martinez-Paniagua, Aysegul A Sahin, Jaime Rodriguez-Canales, Juri Gelovani, Jeffrey T Chang, Ghanashyam Acharya, Anil K Sood, Ignacio I Wistuba, Don L Gibbons, Luisa M Solis, Michelle C Barton, Navin Varadarajan, Jeffrey M Rosen, Xiang H Zhang, Sendurai A Mani

Faculty, Staff and Students Publications

Background

The mechanism by which immune cells regulate metastasis is unclear. Understanding the role of immune cells in metastasis will guide the development of treatments improving patient survival.

Methods

We used syngeneic orthotopic mouse tumour models (wild-type, NOD/scid and Nude), employed knockout (CD8 and CD4) models and administered CXCL4. Tumours and lungs were analysed for cancer cells by bioluminescence, and circulating tumour cells were isolated from blood. Immunohistochemistry on the mouse tumours was performed to confirm cell type, and on a tissue microarray with 180 TNBCs for human relevance. TCGA data from over 10,000 patients were analysed as …

The Effect Of Diazepam On Early Neural Stem Cells Proliferative Activity And Hippocampal-Dependent Memory After Traumatic Brain Injury, Van Khanh Doan

University Honors Theses

Traumatic brain injury (TBI) induces an upregulation of neurogenesis in the brain specifically in the hippocampus, an area pertaining to learning and memory formation. Although this upregulated response is intuitively thought to be restorative, previous studies show that the nascent neurons generated after TBI exhibit abnormalities, such as aberrant morphologies and early migrations, which could suggest to be maladaptive. The GABA-A agonist diazepam has been shown to inhibit this upregulation in neurogenesis and normalizes dendrites after TBI. To determine whether this modulation of neurogenesis is ultimately beneficial or detrimental to cognitive recovery, diazepam was administered to C57BI/6J wild-type mice following …

Diabetes Mellitus And Immunomodulation: A Double-Edged Sword., James Harte

International Undergraduate Journal of Health Sciences

Diabetes is an endocrinological disorder characterised by chronic hyperglycaemia due to abnormalities in insulin secretion, insulin action or a combination of both. According to the International Diabetes Federation, 463 million people worldwide are living with diabetes; 700 million people will be affected by 2045. The severity of the disease is dependent on the type and the stage of progression; when not correctly managed, diabetes can lead to potentially life-threatening micro- and macrovascular complications.

Prior to the discovery of insulin in 1922, the life expectancy of children with diabetes was short and the prognosis was very poor. The advocated treatment for …

Full Issue: The International Undergraduate Journal Of Health Sciences, Volume 1, Issue 1, June 2021, Iujhs Full Issue

International Undergraduate Journal of Health Sciences

The full June 2021 issue (Volume 1, Issue 1) of the International Undergraduate Journal of Health Sciences

The Roles Of Tumor-Derived Exosomes In Altered Differentiation, Maturation And Function Of Dendritic Cells, Reza Hosseini, Leila Asef-Kabiri, Hassan Yousefi, Hamzeh Sarvnaz, Majid Salehi, Mohammad Esmaeil Akbari, Nahid Eskandari

School of Graduate Studies Faculty Publications

Tumor-derived exosomes (TDEs) have been shown to impede anti-tumor immune responses via their immunosuppressive cargo. Since dendritic cells (DCs) are the key mediators of priming and maintenance of T cell-mediated responses; thus it is logical that the exosomes released by tumor cells can exert a dominant influence on DCs biology. This paper intends to provide a mechanistic insight into the TDEs-mediated DCs abnormalities in the tumor context. More importantly, we discuss extensively how tumor exosomes induce subversion of DCs differentiation, maturation and function in separate sections. We also briefly describe the importance of TDEs at therapeutic level to help guide …

The Synergy Of Bet Inhibitors With Aurora A Kinase Inhibitors In Mycn-Amplified Neuroblastoma Is Heightened With Functional Tp53, Joanna S Yi, Oscar Sias-Garcia, Nicole Nasholm, Xiaoyu Hu, Amanda Balboni Iniguez, Matthew D Hall, Mindy Davis, Rajarshi Guha, Myrthala Moreno-Smith, Eveline Barbieri, Kevin Duong, Jessica Koach, Jun Qi, James E Bradner, Kimberly Stegmaier, William A Weiss, W Clay Gustafson

Faculty, Staff and Students Publications

Amplification of MYCN is a poor prognostic feature in neuroblastoma (NBL) indicating aggressive disease. We and others have shown BET bromodomain inhibitors (BETi) target MYCN indirectly by downregulating its transcription. Here we sought to identify agents that synergize with BETi and to identify biomarkers of resistance. We previously performed a viability screen of ∼1,900 oncology-focused compounds combined with BET bromodomain inhibitors against MYCN-amplified NBL cell lines. Reanalysis of our screening results prominently identified inhibitors of aurora kinase A (AURKAi) to be highly synergistic with BETi. We confirmed the anti-proliferative effects of several BETi+AURKAi combinations in MYCN-amplified NBL cell lines. Compared …

Removing The Noise From X-Ray Image Using Image Processing Technology: A Bibliometric Survey And Future Research Directions, Ayushi Kamboj, Mrinal Bachute

Library Philosophy and Practice (e-journal)

The retrieval of superior-quality photographs with a minimal exposure is an interesting subject in radiography. Pre-processing is a key phase in signal and image processing such as healthcare, telecommunications, and satellite, and it focuses on reducing or eliminating the extent of noise in the image. Denoising aids in the recovery of finer data and relevant material. Medical images including ECG, Ultrasound, CT-scan, and X-ray provide incredibly fine data that has to be precise and noise-free in order for the knowledge and aspects of interest to be retained during diagnosis. Various noise reduction technologies for medical images, such as wavelet transform, …

Polymorphisms Of Vascular Endothelial Growth Factor -2578c/A Rs699947 Are Risk Factors For Diabetic Retinopathy In Type-2 Diabetes Mellitus Patients In Bali, Indonesia, Audrey Rachel Wijaya, I Wayan Surudarma, Desak Made Wihandani, I Wayan Ardyan Sudharta Putra

BioMedicine

Background: Diabetic retinopathy (DR) is one of the complications in diabetes mellitus (DM) which caused by microvascular damage in the retina due to long term metabolic changes in diabetes. To date, there has been much research targeted on the determinant of genetic identification in DR patients. In DR, Vascular Endothelial Growth Factor (VEGF) gene is accountable for breaking down the blood-retinal barrier and implicated in the role of neovascularization. It is thought that the polymorphism of VEGF -2578C/A (rs699947) contributed to the development of diabetic retinopathy in type 2 DM.

Aim: To determine whether the polymorphisms of VEGF-2578C/A are the …

Evaluation Of Liver Kinase B1 Downstream Signaling Expression In Various Breast Cancers And Relapse Free Survival After Systemic Chemotherapy Treatment, Khoa Nguyen, Andrew Rivera, Madlin Alzoubi, Henri Wathieu, Shengli Dong, Hassan Yousefi, Margarite Matossian, Suresh Alahari, David Drewry, Matthew Burow, Bridgette Collins-Burow

School of Medicine Faculty Publications

LKB1-signaling has prominent roles in cancer development and metastasis. This report evaluates LKB1-signaling pathway gene expression associations with patient survival in overall breast cancer, specific subtypes, as well as pre- and post-chemotherapy. Subtypes analyzed were based on intrinsic molecular subtyping and traditional biomarker classifications. Intrinsic molecular subtypes included were Luminal-A, Luminal-B, HER2-enriched, and Basal-like. The biomarker subtypes assessed were Estrogen-Receptor Positive (ER+) and Negative (ER-), Wild-Type TP53 (WT-TP53) & Mutant-TP53, and Triple-Negative Breast Cancer (TNBC). Additionally, comparisons were made between these subtypes and breast cancer overall, and analyses between LKB1 signaling to patient survival before and after chemotherapy were made. …

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 …

Untargeted Metabolomic Identification Of Diagnostic Biomarkers In Ectopic Pregnancy, Onur Turkoglu

Conference Presentation Abstracts

No abstract provided.

Myeloid Arginase 1 Insufficiency Exacerbates Amyloid-Β Associated Neurodegenerative Pathways And Glial Signatures In A Mouse Model Of Alzheimer’S Disease: A Targeted Transcriptome Analysis, Chao Ma, Jerry B. Hunt, Andrii Kovalenko, Huimin Liang, Maj-Linda B. Selenica, Michael B. Orr, Bei Zhang, John C. Gensel, David J. Feola, Marcia N. Gordon, Dave Morgan, Paula C. Bickford, Daniel C. Lee

Sanders-Brown Center on Aging Faculty Publications

Brain myeloid cells, include infiltrating macrophages and resident microglia, play an essential role in responding to and inducing neurodegenerative diseases, such as Alzheimer’s disease (AD). Genome-wide association studies (GWAS) implicate many AD casual and risk genes enriched in brain myeloid cells. Coordinated arginine metabolism through arginase 1 (Arg1) is critical for brain myeloid cells to perform biological functions, whereas dysregulated arginine metabolism disrupts them. Altered arginine metabolism is proposed as a new biomarker pathway for AD. We previously reported Arg1 deficiency in myeloid biased cells using lysozyme M (LysM) promoter-driven deletion worsened amyloidosis-related neuropathology and behavioral impairment. However, …