Open Access. Powered by Scholars. Published by Universities.®

Biochemistry, Biophysics, and Structural Biology Commons

Open Access. Powered by Scholars. Published by Universities.®

Medical Sciences

Institution
Keyword
Publication Year
Publication
Publication Type
File Type

Articles 1 - 30 of 895

Full-Text Articles in Biochemistry, Biophysics, and Structural Biology

Hexavalent Chromium-Induced Cytotoxicity And Mutagenicity: A Study Of Protection By Ascorbic Acid And Epigallocatechin Gallate, Timothy P. Mayotte Jul 2019

Hexavalent Chromium-Induced Cytotoxicity And Mutagenicity: A Study Of Protection By Ascorbic Acid And Epigallocatechin Gallate, Timothy P. Mayotte

Honors Program Projects

Hexavalent chromium, or Cr(VI), is a potent oxidizer and known carcinogen, that is found at varying levels in the water sources of more than 200 million Americans. However, the exact mechanism of carcinogenicity remains unknown, and though the government currently regulates total chromium levels, they have yet to determine a permissible exposure limit for Cr(VI). Moreover, there is currently no preventative treatment for Cr(VI). Because of Cr(VI)’s strong oxidative power, we hypothesized that it causes DNA mutation and cell death via oxidation and that antioxidants could prevent this from occurring. To test this, we first ...


A Chromosome Folding Intermediate At The Condensin-To-Cohesin Transition During Telophase, Kristin Abramo, Anne-Laure Valton, Sergey V. Venev, Hakan Ozadam, A. Nicole Fox, Job Dekker Jun 2019

A Chromosome Folding Intermediate At The Condensin-To-Cohesin Transition During Telophase, Kristin Abramo, Anne-Laure Valton, Sergey V. Venev, Hakan Ozadam, A. Nicole Fox, Job Dekker

University of Massachusetts Medical School Faculty Publications

Chromosome folding is extensively modulated as cells progress through the cell cycle. During mitosis, condensin complexes fold chromosomes in helically arranged nested loop arrays. In interphase, the cohesin complex generates loops that can be stalled at CTCF sites leading to positioned loops and topologically associating domains (TADs), while a separate process of compartmentalization drives the spatial segregation of active and inactive chromatin domains. We used synchronized cell cultures to determine how the mitotic chromosome conformation is transformed into the interphase state. Using Hi-C, chromatin binding assays, and immunofluorescence we show that by telophase condensin-mediated loops are lost and a transient ...


Yeast Sirtuin Family Members Maintain Transcription Homeostasis To Ensure Genome Stability, Jessica L. Feldman, Craig L. Peterson Jun 2019

Yeast Sirtuin Family Members Maintain Transcription Homeostasis To Ensure Genome Stability, Jessica L. Feldman, Craig L. Peterson

Program in Molecular Medicine Publications and Presentations

The mammalian sirtuin, SIRT6, is a key tumor suppressor that maintains genome stability and regulates transcription, though how SIRT6 family members control genome stability is unclear. Here, we use multiple genome-wide approaches to demonstrate that the yeast SIRT6 homologs, Hst3 and Hst4, prevent genome instability by tuning levels of both coding and noncoding transcription. While nascent RNAs are elevated in the absence of Hst3 and Hst4, a global impact on steady-state mRNAs is masked by the nuclear exosome, indicating that sirtuins and the exosome provide two levels of regulation to maintain transcription homeostasis. We find that, in the absence of ...


Adipocyte Acly Facilitates Dietary Carbohydrate Handling To Maintain Metabolic Homeostasis In Females, Sully Fernandez, John M. Viola, Annmarie Torres, Martina Wallace, Sophie Trefely, Steven Zhao, Hayley C. Affronti, Jivani M. Gengatharan, David A. Guertin, Nathaniel W. Snyder, Christian M. Metallo, Kathryn E. Wellen May 2019

Adipocyte Acly Facilitates Dietary Carbohydrate Handling To Maintain Metabolic Homeostasis In Females, Sully Fernandez, John M. Viola, Annmarie Torres, Martina Wallace, Sophie Trefely, Steven Zhao, Hayley C. Affronti, Jivani M. Gengatharan, David A. Guertin, Nathaniel W. Snyder, Christian M. Metallo, Kathryn E. Wellen

Open Access Articles

Sugars and refined carbohydrates are major components of the modern diet. ATP-citrate lyase (ACLY) is upregulated in adipocytes in response to carbohydrate consumption and generates acetyl-coenzyme A (CoA) for both lipid synthesis and acetylation reactions. Here, we investigate the role of ACLY in the metabolic and transcriptional responses to carbohydrates in adipocytes and unexpectedly uncover a sexually dimorphic function in maintaining systemic metabolic homeostasis. When fed a high-sucrose diet, Acly(FAT-/-) females exhibit a lipodystrophy-like phenotype, with minimal fat accumulation, insulin resistance, and hepatic lipid accumulation, whereas Acly(FAT-/-) males have only mild metabolic phenotypes. We find that ACLY is ...


Enhanced Cas12a Editing In Mammalian Cells And Zebrafish, Pengpeng Liu, Kevin Luk, Masahiro Shin, Feston Idrizi, Samantha F. Kwok, Benjamin P. Roscoe, Esther Mintzer, Sneha Suresh, Kyle Morrison, Josias B. Frazao, Mehmet Fatih Bolukbasi, Karthikeyan Ponnienselvan, Jeremy Luban, Lihua Julie Zhu, Nathan D. Lawson, Scot A. Wolfe May 2019

Enhanced Cas12a Editing In Mammalian Cells And Zebrafish, Pengpeng Liu, Kevin Luk, Masahiro Shin, Feston Idrizi, Samantha F. Kwok, Benjamin P. Roscoe, Esther Mintzer, Sneha Suresh, Kyle Morrison, Josias B. Frazao, Mehmet Fatih Bolukbasi, Karthikeyan Ponnienselvan, Jeremy Luban, Lihua Julie Zhu, Nathan D. Lawson, Scot A. Wolfe

Open Access Articles

Type V CRISPR-Cas12a systems provide an alternate nuclease platform to Cas9, with potential advantages for specific genome editing applications. Here we describe improvements to the Cas12a system that facilitate efficient targeted mutagenesis in mammalian cells and zebrafish embryos. We show that engineered variants of Cas12a with two different nuclear localization sequences (NLS) on the C terminus provide increased editing efficiency in mammalian cells. Additionally, we find that pre-crRNAs comprising a full-length direct repeat (full-DR-crRNA) sequence with specific stem-loop G-C base substitutions exhibit increased editing efficiencies compared with the standard mature crRNA framework. Finally, we demonstrate in zebrafish embryos that the ...


Exercise Rescues Gene Pathways Involved In Vascular Expansion And Promotes Functional Angiogenesis In Subcutaneous White Adipose Tissue, So Yun Min, Heather Learnard, Shashi Kant, Olga Gaelikman, Raziel Rojas-Rodriguez, Tiffany Desouza, Anand Desai, John F. Keaney Jr., Silvia Corvera, Siobhan M. Craige Apr 2019

Exercise Rescues Gene Pathways Involved In Vascular Expansion And Promotes Functional Angiogenesis In Subcutaneous White Adipose Tissue, So Yun Min, Heather Learnard, Shashi Kant, Olga Gaelikman, Raziel Rojas-Rodriguez, Tiffany Desouza, Anand Desai, John F. Keaney Jr., Silvia Corvera, Siobhan M. Craige

Open Access Articles

Exercise mitigates chronic diseases such as diabetes, cardiovascular diseases, and obesity; however, the molecular mechanisms governing protection from these diseases are not completely understood. Here we demonstrate that exercise rescues metabolically compromised high fat diet (HFD) fed mice, and reprograms subcutaneous white adipose tissue (scWAT). Using transcriptomic profiling, scWAT was analyzed for HFD gene expression changes that were rescued by exercise. Gene networks involved in vascularization were identified as prominent targets of exercise, which led us to investigate the vasculature architecture and endothelial phenotype. Vascular density in scWAT was found to be compromised in HFD, and exercise rescued this defect ...


Crispr-Sonic: Targeted Somatic Oncogene Knock-In Enables Rapid In Vivo Cancer Modeling, Haiwei Mou, Deniz M. Ozata, Jordan L. Smith, Ankur Sheel, Suet-Yan Kwan, Soren Hough, Alper Kucukural, Zachary Kennedy, Yueying Cao, Wen Xue Apr 2019

Crispr-Sonic: Targeted Somatic Oncogene Knock-In Enables Rapid In Vivo Cancer Modeling, Haiwei Mou, Deniz M. Ozata, Jordan L. Smith, Ankur Sheel, Suet-Yan Kwan, Soren Hough, Alper Kucukural, Zachary Kennedy, Yueying Cao, Wen Xue

RNA Therapeutics Institute Publications

CRISPR/Cas9 has revolutionized cancer mouse models. Although loss-of-function genetics by CRISPR/Cas9 is well-established, generating gain-of-function alleles in somatic cancer models is still challenging because of the low efficiency of gene knock-in. Here we developed CRISPR-based Somatic Oncogene kNock-In for Cancer Modeling (CRISPR-SONIC), a method for rapid in vivo cancer modeling using homology-independent repair to integrate oncogenes at a targeted genomic locus. Using a dual guide RNA strategy, we integrated a plasmid donor in the 3'-UTR of mouse beta-actin, allowing co-expression of reporter genes or oncogenes from the beta-actin promoter. We showed that knock-in of oncogenic Ras and ...


The Nua4 Acetyltransferase And Histone H4 Acetylation Promote Replication Recovery After Topoisomerase I-Poisoning, Chiaki Noguchi, Tanu Singh, Melissa A. Ziegler, Jasmine D. Peake, Lyne Khair, Ana Aza, Toru M. Nakamura, Eishi Noguchi Apr 2019

The Nua4 Acetyltransferase And Histone H4 Acetylation Promote Replication Recovery After Topoisomerase I-Poisoning, Chiaki Noguchi, Tanu Singh, Melissa A. Ziegler, Jasmine D. Peake, Lyne Khair, Ana Aza, Toru M. Nakamura, Eishi Noguchi

Open Access Articles

BACKGROUND: Histone acetylation plays an important role in DNA replication and repair because replicating chromatin is subject to dynamic changes in its structures. However, its precise mechanism remains elusive. In this report, we describe roles of the NuA4 acetyltransferase and histone H4 acetylation in replication fork protection in the fission yeast Schizosaccharomyces pombe.

RESULTS: Downregulation of NuA4 subunits renders cells highly sensitive to camptothecin, a compound that induces replication fork breakage. Defects in NuA4 function or mutations in histone H4 acetylation sites lead to impaired recovery of collapsed replication forks and elevated levels of Rad52 DNA repair foci, indicating the ...


The Erk Mapk Pathway Is Essential For Skeletal Development And Homeostasis, Jung-Min Kim, Yeon-Suk Yang, Kwang Hwan Park, Hwanhee Oh, Matthew B. Greenblatt, Jae-Hyuck Shim Apr 2019

The Erk Mapk Pathway Is Essential For Skeletal Development And Homeostasis, Jung-Min Kim, Yeon-Suk Yang, Kwang Hwan Park, Hwanhee Oh, Matthew B. Greenblatt, Jae-Hyuck Shim

Open Access Articles

Mitogen-activated protein kinases (MAPKs) are a family of protein kinases that function as key signal transducers of a wide spectrum of extracellular stimuli, including growth factors and pro-inflammatory cytokines. Dysregulation of the extracellular signal-regulated kinase (ERK) MAPK pathway is associated with human skeletal abnormalities including Noonan syndrome, neurofibromatosis type 1, and cardiofaciocutaneous syndrome. Here, we demonstrate that ERK activation in osteoprogenitors is required for bone formation during skeletal development and homeostasis. Deletion of Mek1 and Mek2, kinases upstream of ERK MAPK, in osteoprogenitors (Mek1(Osx)Mek2(-/-)), resulted in severe osteopenia and cleidocranial dysplasia (CCD), similar to that seen in humans ...


Transient Kinetic Analysis Of Swr1c-Catalyzed H2a.Z Deposition Unravels The Impact Of Nucleosome Dynamics And The Asymmetry Of Histone Exchange, Raushan K. Singh, Jiayi Fan, Nathan Gioacchini, Shinya Watanabe, Osman Bilsel, Craig L. Peterson Apr 2019

Transient Kinetic Analysis Of Swr1c-Catalyzed H2a.Z Deposition Unravels The Impact Of Nucleosome Dynamics And The Asymmetry Of Histone Exchange, Raushan K. Singh, Jiayi Fan, Nathan Gioacchini, Shinya Watanabe, Osman Bilsel, Craig L. Peterson

Open Access Articles

The SWR1C chromatin remodeling enzyme catalyzes ATP-dependent replacement of nucleosomal H2A with the H2A.Z variant, regulating key DNA-mediated processes such as transcription and DNA repair. Here, we investigate the transient kinetic mechanism of the histone exchange reaction, employing ensemble FRET, fluorescence correlation spectroscopy (FCS), and the steady-state kinetics of ATP hydrolysis. Our studies indicate that SWR1C modulates nucleosome dynamics on both the millisecond and microsecond timescales, poising the nucleosome for the dimer exchange reaction. The transient kinetic analysis of the remodeling reaction performed under single turnover conditions unraveled a striking asymmetry in the ATP-dependent replacement of nucleosomal dimers, promoted ...


Characterizing Aft1/2-Grx3/4 Interaction And The Role Of Bol2 During Iron Regulation In Saccharomyces Cerevisiae, William Rivers Apr 2019

Characterizing Aft1/2-Grx3/4 Interaction And The Role Of Bol2 During Iron Regulation In Saccharomyces Cerevisiae, William Rivers

Senior Theses

Iron dysregulation has been linked to a variety of human diseases, such as anemia, Friedreich’s ataxia, X-linked sideroblastic anemia, sideroblastic-like microcytic anemia, and myopathy. Thus, it is vitally important to understand the mechanisms for regulating intracellular iron. Here, we use fluorescence microscopy techniques in live cells to study interactions of the yeast proteins Grx3/4, Aft1/2, and Bol2, which have been shown to be involved in turning off iron import when the cell has adequate iron. Modified versions of genes encoding these proteins have been incorporated into several yeast backgrounds to use fluorescence to monitor interactions under varying ...


Measuring The Reproducibility And Quality Of Hi-C Data, Galip Gurkan Yardimci, Hakan Ozadam, Bryan R. Lajoie, Ye Zhan, Job Dekker, William S. Noble Mar 2019

Measuring The Reproducibility And Quality Of Hi-C Data, Galip Gurkan Yardimci, Hakan Ozadam, Bryan R. Lajoie, Ye Zhan, Job Dekker, William S. Noble

Open Access Articles

BACKGROUND: Hi-C is currently the most widely used assay to investigate the 3D organization of the genome and to study its role in gene regulation, DNA replication, and disease. However, Hi-C experiments are costly to perform and involve multiple complex experimental steps; thus, accurate methods for measuring the quality and reproducibility of Hi-C data are essential to determine whether the output should be used further in a study.

RESULTS: Using real and simulated data, we profile the performance of several recently proposed methods for assessing reproducibility of population Hi-C data, including HiCRep, GenomeDISCO, HiC-Spector, and QuASAR-Rep. By explicitly controlling noise ...


Optimization Of Ribosome Profiling Using Low-Input Brain Tissue From Fragile X Syndrome Model Mice, Botao Liu, Gemma Molinaro, Huan Shu, Emily E. Stackpole, Kimberly M. Huber, Joel D. Richter Mar 2019

Optimization Of Ribosome Profiling Using Low-Input Brain Tissue From Fragile X Syndrome Model Mice, Botao Liu, Gemma Molinaro, Huan Shu, Emily E. Stackpole, Kimberly M. Huber, Joel D. Richter

Open Access Articles

Dysregulated protein synthesis is a major underlying cause of many neurodevelopmental diseases including fragile X syndrome. In order to capture subtle but biologically significant differences in translation in these disorders, a robust technique is required. One powerful tool to study translational control is ribosome profiling, which is based on deep sequencing of mRNA fragments protected from ribonuclease (RNase) digestion by ribosomes. However, this approach has been mainly applied to rapidly dividing cells where translation is active and large amounts of starting material are readily available. The application of ribosome profiling to low-input brain tissue where translation is modest and gene ...


Purification And Characterization Of A Nonspecific Lipid Transfer Protein 1 (Nsltp1) From Ajwain (Trachyspermum Ammi) Seeds, Meshal Nazeer, Humera Waheed, Maria Saeed, Saman Yousuf Ali, M. Iqbal Choudhary, Zaheer Ul-Haq, Aftab Ahmed Mar 2019

Purification And Characterization Of A Nonspecific Lipid Transfer Protein 1 (Nsltp1) From Ajwain (Trachyspermum Ammi) Seeds, Meshal Nazeer, Humera Waheed, Maria Saeed, Saman Yousuf Ali, M. Iqbal Choudhary, Zaheer Ul-Haq, Aftab Ahmed

Pharmacy Faculty Articles and Research

Ajwain (Trachyspermum ammi) belongs to the family Umbelliferae, is commonly used in traditional, and folk medicine due to its carminative, stimulant, antiseptic, diuretic, antihypertensive, and hepatoprotective activities. Non-specific lipid transfer proteins (nsLTPs) reported from various plants are known to be involved in transferring lipids between membranes and in plants defense response. Here, we describe the complete primary structure of a monomeric non-specific lipid transfer protein 1 (nsLTP1), with molecular weight of 9.66 kDa, from ajwain seeds. The nsLTP1 has been purified by combination of chromatographic techniques, and further characterized by mass spectrometry, and Edman degradation. The ajwain nsLTP1 is ...


Supervised Dimension Reduction For Large-Scale "Omics" Data With Censored Survival Outcomes Under Possible Non-Proportional Hazards, Lauren Spirko-Burns, Karthik Devarajan Mar 2019

Supervised Dimension Reduction For Large-Scale "Omics" Data With Censored Survival Outcomes Under Possible Non-Proportional Hazards, Lauren Spirko-Burns, Karthik Devarajan

COBRA Preprint Series

The past two decades have witnessed significant advances in high-throughput ``omics" technologies such as genomics, proteomics, metabolomics, transcriptomics and radiomics. These technologies have enabled simultaneous measurement of the expression levels of tens of thousands of features from individual patient samples and have generated enormous amounts of data that require analysis and interpretation. One specific area of interest has been in studying the relationship between these features and patient outcomes, such as overall and recurrence-free survival, with the goal of developing a predictive ``omics" profile. Large-scale studies often suffer from the presence of a large fraction of censored observations and potential ...


Mutations In The Glycosyltransferase Domain Of Glt8d1 Are Associated With Familial Amyotrophic Lateral Sclerosis, Johnathan Cooper-Knock, John E. Landers, Pamela J. Shaw Feb 2019

Mutations In The Glycosyltransferase Domain Of Glt8d1 Are Associated With Familial Amyotrophic Lateral Sclerosis, Johnathan Cooper-Knock, John E. Landers, Pamela J. Shaw

Open Access Articles

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder without effective neuroprotective therapy. Known genetic variants impair pathways, including RNA processing, axonal transport, and protein homeostasis. We report ALS-causing mutations within the gene encoding the glycosyltransferase GLT8D1. Exome sequencing in an autosomal-dominant ALS pedigree identified p.R92C mutations in GLT8D1, which co-segregate with disease. Sequencing of local and international cohorts demonstrated significant ALS association in the same exon, including additional rare deleterious mutations in conserved amino acids. Mutations are associated with the substrate binding site, and both R92C and G78W changes impair GLT8D1 enzyme activity. Mutated GLT8D1 exhibits in vitro ...


Diverse Lipid Conjugates For Functional Extra-Hepatic Sirna Delivery In Vivo, Annabelle Biscans, Andrew H. Coles, Reka A. Haraszti, Dimas Echeverria, Matthew R. Hassler, Maire F. Osborn, Anastasia Khvorova Feb 2019

Diverse Lipid Conjugates For Functional Extra-Hepatic Sirna Delivery In Vivo, Annabelle Biscans, Andrew H. Coles, Reka A. Haraszti, Dimas Echeverria, Matthew R. Hassler, Maire F. Osborn, Anastasia Khvorova

RNA Therapeutics Institute Publications

Small interfering RNA (siRNA)-based therapies are proving to be efficient for treating liver-associated disorders. However, extra-hepatic delivery remains challenging, limiting therapeutic siRNA utility. We synthesized a panel of fifteen lipid-conjugated siRNAs and systematically evaluated the impact of conjugate on siRNA tissue distribution and efficacy. Generally, conjugate hydrophobicity defines the degree of clearance and the liver-to-kidney distribution profile. In addition to primary clearance tissues, several conjugates achieve significant siRNA accumulation in muscle, lung, heart, adrenal glands and fat. Oligonucleotide distribution to extra-hepatic tissues with some conjugates was significantly higher than with cholesterol, a well studied conjugate, suggesting that altering conjugate ...


Hydrophobicity Drives The Systemic Distribution Of Lipid-Conjugated Sirnas Via Lipid Transport Pathways, Maire F. Osborn, Andrew H. Coles, Annabelle Biscans, Reka A. Haraszti, Loic Roux, Sarah M. Davis, Socheata Ly, Dimas Echeverria, Matthew R. Hassler, Bruno M. D. C. Godinho, Mehran Nikan, Anastasia Khvorova Feb 2019

Hydrophobicity Drives The Systemic Distribution Of Lipid-Conjugated Sirnas Via Lipid Transport Pathways, Maire F. Osborn, Andrew H. Coles, Annabelle Biscans, Reka A. Haraszti, Loic Roux, Sarah M. Davis, Socheata Ly, Dimas Echeverria, Matthew R. Hassler, Bruno M. D. C. Godinho, Mehran Nikan, Anastasia Khvorova

RNA Therapeutics Institute Publications

Efficient delivery of therapeutic RNA beyond the liver is the fundamental obstacle preventing its clinical utility. Lipid conjugation increases plasma half-life and enhances tissue accumulation and cellular uptake of small interfering RNAs (siRNAs). However, the mechanism relating lipid hydrophobicity, structure, and siRNA pharmacokinetics is unclear. Here, using a diverse panel of biologically occurring lipids, we show that lipid conjugation directly modulates siRNA hydrophobicity. When administered in vivo, highly hydrophobic lipid-siRNAs preferentially and spontaneously associate with circulating low-density lipoprotein (LDL), while less lipophilic lipid-siRNAs bind to high-density lipoprotein (HDL). Lipid-siRNAs are targeted to lipoprotein receptor-enriched tissues, eliciting significant mRNA silencing in ...


Thioredoxin Modulates Protein Arginine Deiminase 4 (Pad4)-Catalyzed Citrullination, Mitesh Nagar, Ronak Tilvawala, Paul R. Thompson Feb 2019

Thioredoxin Modulates Protein Arginine Deiminase 4 (Pad4)-Catalyzed Citrullination, Mitesh Nagar, Ronak Tilvawala, Paul R. Thompson

Open Access Articles

Protein citrullination is a post-translational modification catalyzed by the protein arginine deiminases (PADs). This modification plays a crucial role in the pathophysiology of numerous autoimmune disorders including RA. Recently, there has been a growing interest in investigating physiological regulators of PAD activity to understand the primary cause of the associated disorders. Apart from calcium, it is well-documented that a reducing environment activates the PADs. Although the concentration of thioredoxin (hTRX), an oxidoreductase that maintains the cellular reducing environment, is elevated in RA patients, its contribution toward RA progression or PAD activity has not been explored. Herein, we demonstrate that hTRX ...


Hypomorphic Mutations Of Trip11 Cause Odontochondrodysplasia, Anika Wehrle, John A. Follit, Gregory J. Pazour, Andrea Superti-Furga, Martin Lowe, Ekkehart Lausch Feb 2019

Hypomorphic Mutations Of Trip11 Cause Odontochondrodysplasia, Anika Wehrle, John A. Follit, Gregory J. Pazour, Andrea Superti-Furga, Martin Lowe, Ekkehart Lausch

Open Access Articles

Odontochondrodysplasia (ODCD) is an unresolved genetic disorder of skeletal and dental development. Here, we show that ODCD is caused by hypomorphic TRIP11 mutations, and we identify ODCD as the nonlethal counterpart to achondrogenesis 1A (ACG1A), the known null phenotype in humans. TRIP11 encodes Golgi-associated microtubule-binding protein 210 (GMAP-210), an essential tether protein of the Golgi apparatus that physically interacts with intraflagellar transport 20 (IFT20), a component of the ciliary intraflagellar transport complex B. This association and extraskeletal disease manifestations in ODCD point to a cilium-dependent pathogenesis. However, our functional studies in patient-derived primary cells clearly support a Golgi-based disease mechanism ...


Senp3-Mediated Host Defense Response Contains Hbv Replication And Restores Protein Synthesis, Rui Xi, Botao Liu, Yan Han, Xiling Shen Jan 2019

Senp3-Mediated Host Defense Response Contains Hbv Replication And Restores Protein Synthesis, Rui Xi, Botao Liu, Yan Han, Xiling Shen

Open Access Articles

Certain organs are capable of containing the replication of various types of viruses. In the liver, infection of Hepatitis B virus (HBV), the etiological factor of Hepatitis B and hepatocellular carcinoma (HCC), often remains asymptomatic and leads to a chronic carrier state. Here we investigated how hepatocytes contain HBV replication and promote their own survival by orchestrating a translational defense mechanism via the stress-sensitive SUMO-2/3-specific peptidase SENP3. We found that SENP3 expression level decreased in HBV-infected hepatocytes in various models including HepG2-NTCP cell lines and a humanized mouse model. Downregulation of SENP3 reduced HBV replication and boosted host protein ...


A Persistence Detector For Metabolic Network Rewiring In An Animal, Jote T. Bulcha, Gabrielle E. Giese, Zulfikar Ali, Yong-Uk Lee, Melissa D. Walker, Amy D. Holdorf, L. Safak Yilmaz, Robert C. Brewster, Albertha J. M. Walhout Jan 2019

A Persistence Detector For Metabolic Network Rewiring In An Animal, Jote T. Bulcha, Gabrielle E. Giese, Zulfikar Ali, Yong-Uk Lee, Melissa D. Walker, Amy D. Holdorf, L. Safak Yilmaz, Robert C. Brewster, Albertha J. M. Walhout

Open Access Articles

Biological systems must possess mechanisms that prevent inappropriate responses to spurious environmental inputs. Caenorhabditis elegans has two breakdown pathways for the short-chain fatty acid propionate: a canonical, vitamin B12-dependent pathway and a propionate shunt that is used when vitamin B12 levels are low. The shunt pathway is kept off when there is sufficient flux through the canonical pathway, likely to avoid generating shunt-specific toxic intermediates. Here, we discovered a transcriptional regulatory circuit that activates shunt gene expression upon propionate buildup. Nuclear hormone receptor 10 (NHR-10) and NHR-68 function together as a "persistence detector" in a type 1, coherent feed-forward loop ...


Debrowser: Interactive Differential Expression Analysis And Visualization Tool For Count Data, Alper Kucukural, Onur Yukselen, Deniz M. Ozata, Melissa J. Moore, Manuel Garber Jan 2019

Debrowser: Interactive Differential Expression Analysis And Visualization Tool For Count Data, Alper Kucukural, Onur Yukselen, Deniz M. Ozata, Melissa J. Moore, Manuel Garber

Program in Bioinformatics and Integrative Biology Publications and Presentations

BACKGROUND: Sequencing data has become a standard measure of diverse cellular activities. For example, gene expression is accurately measured by RNA sequencing (RNA-Seq) libraries, protein-DNA interactions are captured by chromatin immunoprecipitation sequencing (ChIP-Seq), protein-RNA interactions by crosslinking immunoprecipitation sequencing (CLIP-Seq) or RNA immunoprecipitation (RIP-Seq) sequencing, DNA accessibility by assay for transposase-accessible chromatin (ATAC-Seq), DNase or MNase sequencing libraries. The processing of these sequencing techniques involves library-specific approaches. However, in all cases, once the sequencing libraries are processed, the result is a count table specifying the estimated number of reads originating from each genomic locus. Differential analysis to determine which loci ...


Principles For Enhancing Virus Capsid Capacity And Stability From A Thermophilic Virus Capsid Structure, Nicholas P. Stone, Gabriel Demo, Emily Agnello, Brian A. Kelch Jan 2019

Principles For Enhancing Virus Capsid Capacity And Stability From A Thermophilic Virus Capsid Structure, Nicholas P. Stone, Gabriel Demo, Emily Agnello, Brian A. Kelch

University of Massachusetts Medical School Faculty Publications

The capsids of double-stranded DNA viruses protect the viral genome from the harsh extracellular environment, while maintaining stability against the high internal pressure of packaged DNA. To elucidate how capsids maintain stability in an extreme environment, we used cryoelectron microscopy to determine the capsid structure of the thermostable phage P74-26. We find the P74-26 capsid exhibits an overall architecture that is very similar to those of other tailed bacteriophages, allowing us to directly compare structures to derive the structural basis for enhanced stability. Our structure reveals lasso-like interactions that appear to function like catch bonds. This architecture allows the capsid ...


Novel Amphiphilic Cyclobutene And Cyclobutane Cis-C18 Fatty Acid Derivatives Inhibit Mycobacterium Avium Subsp. Paratuberculosis Growth, Denise K. Zinniel, Wantanee Sittiwong, Darrell D. Marshall, Govardhan Rathnaiah, Isin T. Sakallioglu, Robert Powers, Patrick H. Dussault, Raul G. Barletta Jan 2019

Novel Amphiphilic Cyclobutene And Cyclobutane Cis-C18 Fatty Acid Derivatives Inhibit Mycobacterium Avium Subsp. Paratuberculosis Growth, Denise K. Zinniel, Wantanee Sittiwong, Darrell D. Marshall, Govardhan Rathnaiah, Isin T. Sakallioglu, Robert Powers, Patrick H. Dussault, Raul G. Barletta

Papers in Veterinary and Biomedical Science

Mycobacterium avium subspecies paratuberculosis (Map) is the etiologic agent of Johne’s disease in ruminants and has been associated with Crohn’s disease in humans. An effective control of Map by either vaccines or chemoprophylaxis is a paramount need for veterinary and possibly human medicine. Given the importance of fatty acids in the biosynthesis of mycolic acids and the mycobacterial cell wall, we tested novel amphiphilic C10 and C18 cyclobutene and cyclobutane fatty acid derivatives for Map inhibition. Microdilution minimal inhibitory concentrations (MIC) with 5 or 7 week endpoints were measured in Middlebrook 7H9 base broth media. We ...


Relationship Of Sociodemographic Factors With Serum Levels Of Vitamin D In A Healthy Population Of Pakistan, Khalida Iqbal, Najmul Islam, Naseema Mehboobali, Ali Asghar, Saleem Perwaiz Iqbal, Mohammad Perwaiz Iqbal Jan 2019

Relationship Of Sociodemographic Factors With Serum Levels Of Vitamin D In A Healthy Population Of Pakistan, Khalida Iqbal, Najmul Islam, Naseema Mehboobali, Ali Asghar, Saleem Perwaiz Iqbal, Mohammad Perwaiz Iqbal

Department of Biological & Biomedical Sciences

High prevalence of vitamin D deficiency has been reported from Pakistan. Association of sociodemographic factors with vitamin D status has received little attention in this region. Therefore, we embarked on investigating the relationship of sociodemographic factors with vitamin D levels in a healthy Pakistani population. Venous blood from 226 healthy participants (age range 19-69 years) was collected and analyzed for serum concentrations of 25(OH) vitamin D [25(OH)D] and other related biomarkers. Demographic characteristics of the study participants were collected. Vitamin D deficiency (25(OH)D levels less than 20 ng/ml) was found to be 75% in ...


A Mutation In Cav2.1 Linked To A Severe Neurodevelopmental Disorder Impairs Channel Gating, Sidharth Tyagi Jan 2019

A Mutation In Cav2.1 Linked To A Severe Neurodevelopmental Disorder Impairs Channel Gating, Sidharth Tyagi

Integrative Physiology Graduate Theses & Dissertations

Ca2+ flux via voltage-gated Ca2+ channels is essential to the regulation of membrane excitability, neurotransmission, and a variety of intracellular signaling processes. CaV2.1 is the predominant Ca2+ channel present in the presynaptic terminals of both neuromuscular junctions and many central synapses. Point mutations in CaV2.1 can drastically alter channel gating and expression, and indeed have been linked to two paroxysmal disorders – Episodic Ataxia Type 2, and Familial Hemiplegic Migraine Type 1. With the novel whole-exome sequencing technique, mutations linked to a new class of more severe disorders have been found with phenotypes like Episodic Ataxia ...


Pancreas Of Coxsackievirus-Infected Dams And Their Challenged Pups: A Complex Issue, Sona Sarmirova, Maria Borsanyiova, Brigita Benkoova, Michaela Pospisilova, Rajkumar Rajasekaran, Katarina Berakova, Pavol Gomolcak, Jay Reddy, Shubhada Bopegamage Jan 2019

Pancreas Of Coxsackievirus-Infected Dams And Their Challenged Pups: A Complex Issue, Sona Sarmirova, Maria Borsanyiova, Brigita Benkoova, Michaela Pospisilova, Rajkumar Rajasekaran, Katarina Berakova, Pavol Gomolcak, Jay Reddy, Shubhada Bopegamage

Papers in Veterinary and Biomedical Science

Enteroviral infections are frequent, often asymptomatic in humans and during gravidity. The present study is an extension of our previous investigations where we had shown pancreatitis in challenged pups of CVB4-E2-infected dams. Present investigation describes the effect of gestational infection with this virus on the pancreas of both dams and their challenged pups. Gravid CD1 outbred mice were orally infected with CVB4-E2 virus at different gestation times. Pups were challenged orally with the same virus after 25 days of birth. Organs were collected at selected intervals postinfection (p.i.), and replicating virus and viral-RNA copies were analyzed. Additional readouts included ...


The Role Of Isothiocyanates As Cancer Chemo‐Preventive, Chemo‐Therapeutic And Anti‐Melanoma Agents, Melina Mitsiogianni, Georgios Koutsidis, Nikos Mavroudis, Dimitrios T. Trafalis, Sotiris Botaitis, Rodrigo Franco, Vasilis Zoumpourlis, Tom Amery, Alex Galanis, Aglaia Pappa, Mihalis I. Panayiotidis Jan 2019

The Role Of Isothiocyanates As Cancer Chemo‐Preventive, Chemo‐Therapeutic And Anti‐Melanoma Agents, Melina Mitsiogianni, Georgios Koutsidis, Nikos Mavroudis, Dimitrios T. Trafalis, Sotiris Botaitis, Rodrigo Franco, Vasilis Zoumpourlis, Tom Amery, Alex Galanis, Aglaia Pappa, Mihalis I. Panayiotidis

Papers in Veterinary and Biomedical Science

Many studies have shown evidence in support of the beneficial effects of phytochemicals in preventing chronic diseases, including cancer. Among such phytochemicals, sulphur‐containing compounds (e.g., isothiocyanates (ITCs)) have raised scientific interest by exerting unique chemopreventive properties against cancer pathogenesis. ITCs are the major biologically active compounds capable of mediating the anticancer effect of cruciferous vegetables. Recently, many studies have shown that a higher intake of cruciferous vegetables is associated with reduced risk of developing various forms of cancers primarily due to a plurality of effects, including (i) metabolic activation and detoxification, (ii) inflammation, (iii) angiogenesis, (iv) metastasis and ...


The Trim-Nhl Protein Nhl-2 Is A Co-Factor In The Nuclear And Somatic Rnai Pathways In C. Elegans, Gregory M. Davis, Shikui Tu, Jacqueline A. Wilce, Julie M. Claycomb, Zhiping Weng, Peter R. Boag Dec 2018

The Trim-Nhl Protein Nhl-2 Is A Co-Factor In The Nuclear And Somatic Rnai Pathways In C. Elegans, Gregory M. Davis, Shikui Tu, Jacqueline A. Wilce, Julie M. Claycomb, Zhiping Weng, Peter R. Boag

Program in Bioinformatics and Integrative Biology Publications and Presentations

Proper regulation of germline gene expression is essential for fertility and maintaining species integrity. In the C. elegans germline, a diverse repertoire of regulatory pathways promote the expression of endogenous germline genes and limit the expression of deleterious transcripts to maintain genome homeostasis. Here we show that the conserved TRIM-NHL protein, NHL-2, plays an essential role in the C. elegans germline, modulating germline chromatin and meiotic chromosome organization. We uncover a role for NHL-2 as a co-factor in both positively (CSR-1) and negatively (HRDE-1) acting germline 22G-small RNA pathways and the somatic nuclear RNAi pathway. Furthermore, we demonstrate that NHL-2 ...