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Articles 1 - 30 of 2183

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 ...


The Wet Bridge Transfer System: An Novel In Vitro Tool For Assessing Exogenous Surfactant As A Pulmonary Drug Delivery Vehicle, Brandon J. Baer Jun 2019

The Wet Bridge Transfer System: An Novel In Vitro Tool For Assessing Exogenous Surfactant As A Pulmonary Drug Delivery Vehicle, Brandon J. Baer

Western Research Forum

Background:

Due to its complex branching structure, direct drug delivery to the remote areas of the lung is a major challenge. Consequently, most therapies, such as those treating pulmonary infection and inflammation, must utilize large systemic dosing, with the potential for adverse side effects. A novel alternative strategy is to use exogenous surfactant, a material capable of distributing throughout the lung, as a pulmonary drug delivery vehicle.

Objective:

Utilize an in vitro transferring system to assess exogenous surfactant (BLES) as a pulmonary delivery vehicle for different therapeutics.

Methods:

An in vitro technique was developed to simultaneously study surfactant delivery and ...


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 ...


Ste5 Membrane Localization Allows Mapk Pathway Signaling In Trans Between Kinases On Separate Scaffold Molecules, Rachel E. Lamson, Matthew J. Winters, Peter M. Pryciak Jun 2019

Ste5 Membrane Localization Allows Mapk Pathway Signaling In Trans Between Kinases On Separate Scaffold Molecules, Rachel E. Lamson, Matthew J. Winters, Peter M. Pryciak

University of Massachusetts Medical School Faculty Publications

The MAP kinase cascade is a ubiquitous eukaryotic signaling module that can be controlled by a diverse group of scaffold proteins. In budding yeast, activation of the mating MAP kinase cascade involves regulated membrane recruitment of the archetypal scaffold protein Ste5. This event promotes activation of the first kinase, but it also enhances subsequent signal propagation through the remainder of the cascade. By studying this latter effect, we find that membrane recruitment promotes signaling in trans between kinases on separate Ste5 molecules. First, trans signaling requires all Ste5 domains that mediate membrane recruitment, including both protein-binding and membrane-binding domains. Second ...


Trim5alpha Restricts Flavivirus Replication By Targeting The Viral Protease For Proteasomal Degradation, Abhilash I. Chiramel, Nicholas R. Meyerson, Kristin L. Mcnally, Rebecca M. Broeckel, Vanessa R. Montoya, Omayra Mendez-Solis, Shelly J. Robertson, Gail L. Sturdevant, Kirk J. Lubick, Vinod Nair, Brian H. Youseff, Robin M. Ireland, Catharine M. Bosio, Kyusik Kim, Jeremy Luban, Vanessa M. Hirsch, R. Travis Taylor, Fadila Bouamr, Sara L. Sawyer, Sonja M. Best Jun 2019

Trim5alpha Restricts Flavivirus Replication By Targeting The Viral Protease For Proteasomal Degradation, Abhilash I. Chiramel, Nicholas R. Meyerson, Kristin L. Mcnally, Rebecca M. Broeckel, Vanessa R. Montoya, Omayra Mendez-Solis, Shelly J. Robertson, Gail L. Sturdevant, Kirk J. Lubick, Vinod Nair, Brian H. Youseff, Robin M. Ireland, Catharine M. Bosio, Kyusik Kim, Jeremy Luban, Vanessa M. Hirsch, R. Travis Taylor, Fadila Bouamr, Sara L. Sawyer, Sonja M. Best

Program in Molecular Medicine Publications and Presentations

Tripartite motif-containing protein 5alpha (TRIM5alpha) is a cellular antiviral restriction factor that prevents early events in retrovirus replication. The activity of TRIM5alpha is thought to be limited to retroviruses as a result of highly specific interactions with capsid lattices. In contrast to this current understanding, we show that both human and rhesus macaque TRIM5alpha suppress replication of specific flaviviruses. Multiple viruses in the tick-borne encephalitis complex are sensitive to TRIM5alpha-dependent restriction, but mosquito-borne flaviviruses, including yellow fever, dengue, and Zika viruses, are resistant. TRIM5alpha suppresses replication by binding to the viral protease NS2B/3 to promote its K48-linked ubiquitination and ...


Regulation Of The Drosophila Imd Pathway By Signaling Amyloids, Anni Kleino, Neal S. Silverman Jun 2019

Regulation Of The Drosophila Imd Pathway By Signaling Amyloids, Anni Kleino, Neal S. Silverman

Neal Silverman

Fruit flies elicit effective defense responses against numerous microbes. The responses against Gram-negative bacteria are mediated by the Imd pathway, an evolutionarily conserved NF-kappaB pathway recognizing meso-diaminopimelic acid (DAP)-type peptidoglycan from bacterial cell walls. Several reviews already provide a detailed view of ligand recognition and signal transduction during Imd signaling, but the formation and regulation of the signaling complex immediately downstream of the peptidoglycan-sensing receptors is still elusive. In this review, we focus on the formation of the Imd amyloidal signaling center and post-translational modifications in the assembly and disassembly of the Imd signaling complex.


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 ...


An Order-To-Disorder Structural Switch Activates The Foxm1 Transcription Factor, Aimee H. Marceau, Caileen M. Brison, Santrupti Nerli, Heather E. Arsenault, Andrew C. Mcshan, Eefei Chen, Hsiau-Wei Lee, Jennifer A. Benanti, Nikolaos G. Sgourakis, Seth M. Rubin May 2019

An Order-To-Disorder Structural Switch Activates The Foxm1 Transcription Factor, Aimee H. Marceau, Caileen M. Brison, Santrupti Nerli, Heather E. Arsenault, Andrew C. Mcshan, Eefei Chen, Hsiau-Wei Lee, Jennifer A. Benanti, Nikolaos G. Sgourakis, Seth M. Rubin

Open Access Articles

Intrinsically disordered transcription factor transactivation domains (TADs) function through structural plasticity, adopting ordered conformations when bound to transcriptional co-regulators. Many transcription factors contain a negative regulatory domain (NRD) that suppresses recruitment of transcriptional machinery through autoregulation of the TAD. We report the solution structure of an autoinhibited NRD-TAD complex within FoxM1, a critical activator of mitotic gene expression. We observe that while both the FoxM1 NRD and TAD are primarily intrinsically disordered domains, they associate and adopt a structured conformation. We identify how Plk1 and Cdk kinases cooperate to phosphorylate FoxM1, which releases the TAD into a disordered conformation that ...


Serum Deprivation Of Mesenchymal Stem Cells Improves Exosome Activity And Alters Lipid And Protein Composition, Reka A. Haraszti, Rachael Miller, Michelle L. Dubuke, Andrew H. Coles, Marie C. Didiot, Dimas Echeverria, Matteo Stoppato, Yves Y. Sere, John D. Leszyk, Julia F. Alterman, Bruno M. D. C. Godinho, Matthew R. Hassler, Rachel Wollacott, Yan Wang, Scott A. Shaffer, Neil Aronin, Anastasia Khvorova May 2019

Serum Deprivation Of Mesenchymal Stem Cells Improves Exosome Activity And Alters Lipid And Protein Composition, Reka A. Haraszti, Rachael Miller, Michelle L. Dubuke, Andrew H. Coles, Marie C. Didiot, Dimas Echeverria, Matteo Stoppato, Yves Y. Sere, John D. Leszyk, Julia F. Alterman, Bruno M. D. C. Godinho, Matthew R. Hassler, Rachel Wollacott, Yan Wang, Scott A. Shaffer, Neil Aronin, Anastasia Khvorova

Open Access Articles

Exosomes can serve as delivery vehicles for advanced therapeutics. The components necessary and sufficient to support exosomal delivery have not been established. Here we connect biochemical composition and activity of exosomes to optimize exosome-mediated delivery of small interfering RNAs (siRNAs). This information is used to create effective artificial exosomes. We show that serum-deprived mesenchymal stem cells produce exosomes up to 22-fold more effective at delivering siRNAs to neurons than exosomes derived from control cells. Proteinase treatment of exosomes stops siRNA transfer, indicating that surface proteins on exosomes are involved in trafficking. Proteomic and lipidomic analyses show that exosomes derived in ...


Extraction, Purification And Evaluation Of Prmt5-Inhibitory Phytochemical Compounds For The Treatment Of Prostate Adenocarcinoma, Oliver H. Richmond Iii May 2019

Extraction, Purification And Evaluation Of Prmt5-Inhibitory Phytochemical Compounds For The Treatment Of Prostate Adenocarcinoma, Oliver H. Richmond Iii

Electronic Theses & Dissertations Collection for Atlanta University & Clark Atlanta University

The development and advancement of prostate cancer is supported by a plethora of genetic and proteomic abnormalities, including events of post-translational modifications. The protein arginine methyltransferase 5 (PRMT5) enzyme regulates epigenetic events of histone modifications and protein post-translational modifications within protein signaling pathways. PRMT5 functions by catalyzing the symmetric dimethylation of terminal arginine residues on target protein substrates. Under abnormal conditions of overexpression and upregulation, PRMT5 methyltransferase activity constitutively drives the growth and proliferation of dysregulated cells. Overexpression or upregulation of PRMT5 correlates with disease progression as observed among numerous cancer types, including breast, colorectal, leukemia, lung, melanoma and prostate ...


Further Characterization Of The Skeletal Phenotype In A Hurler Syndrome Mouse Model And The Ethical Treatment Of Children In Medicine, Anna Marie Mcwoods May 2019

Further Characterization Of The Skeletal Phenotype In A Hurler Syndrome Mouse Model And The Ethical Treatment Of Children In Medicine, Anna Marie Mcwoods

MSU Graduate Theses

Mucopolysaccharidosis type I (MPS I) is a rare, autosomal recessive disorder caused by the deficiency of the lysosomal enzyme α-L-iduronidase (IDUA). Absence of IDUA results in the accumulation of dermatan and heparin sulfate and ultimately causes multi-system dysfunction. The most severe form of MPS I is Hurlers syndrome, a rapidly progressive disorder that, if left untreated, is fatal. Current treatment options for diagnosed individuals includes hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT). These treatments are able to ameliorate the majority of symptoms with the exception of the bone phenotype. This investigation aimed to further characterize the bone ...


Stochastic Modeling Of Neuronal Transport In Various Cellular Geometries, Abhishek Choudhary Mr., Peter Kramer May 2019

Stochastic Modeling Of Neuronal Transport In Various Cellular Geometries, Abhishek Choudhary Mr., Peter Kramer

Biology and Medicine Through Mathematics Conference

No abstract provided.


Bridging From Intramuscular To Limb Perfusion Delivery Of Raav: Optimization In A Non-Human Primate Study, Alisha Gruntman, Gwladys Gernoux, Qiushi Tang, Guo-Jie Ye, Dave R. Knop, Gensheng Wang, Janet Benson, Kristen E. Coleman, Allison M. Keeler, Christian Mueller, Louis G. Chicoine, Jeffrey D. Chulay, Terence R. Flotte May 2019

Bridging From Intramuscular To Limb Perfusion Delivery Of Raav: Optimization In A Non-Human Primate Study, Alisha Gruntman, Gwladys Gernoux, Qiushi Tang, Guo-Jie Ye, Dave R. Knop, Gensheng Wang, Janet Benson, Kristen E. Coleman, Allison M. Keeler, Christian Mueller, Louis G. Chicoine, Jeffrey D. Chulay, Terence R. Flotte

Christian Mueller

Phase 1 and phase 2 gene therapy trials using intramuscular (IM) administration of a recombinant adeno-associated virus serotype 1 (rAAV1) for replacement of serum alpha-1 antitrypsin (AAT) deficiency have shown long-term (5-year) stable transgene expression at approximately 2% to 3% of therapeutic levels, arguing for the long-term viability of this approach to gene replacement of secreted serum protein deficiencies. However, achieving these levels required 100 IM injections to deliver 135 mL of vector, and further dose escalation is limited by the scalability of direct IM injection. To further advance the dose escalation, we sought to bridge the rAAV-AAT clinical development ...


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 ...


The Effect Of Cysteine-Reactive Catechol Antioxidants On Alcohol Dehydrogenase As A Model For Oxidative Stress In Neurodegenerative Disease, Rachel Smith May 2019

The Effect Of Cysteine-Reactive Catechol Antioxidants On Alcohol Dehydrogenase As A Model For Oxidative Stress In Neurodegenerative Disease, Rachel Smith

Undergraduate Honors Theses

The cellular mechanisms underlying age-related neurodegeneration, especially in disease states, are poorly understood. Oxidative stress has been heavily implicated as one factor both produced by and contributing to the progression of neurodegenerative diseases such as Alzheimer’s disease. In particular, it can destroy a cell’s ability to produce energy through aerobic and anaerobic respiration, thus leading to the death of individual cells and brain tissues as a whole. This study focuses on the relationship between oxidative stress and energy production in disease states. In particular, we examine the ability of catechol molecules to take on pro-oxidative properties and modify ...


Targeting Sec61Α By Ipomoeassin F Leads To Highly Cytotoxic Effect, Zhijian Hu May 2019

Targeting Sec61Α By Ipomoeassin F Leads To Highly Cytotoxic Effect, Zhijian Hu

Theses and Dissertations

Ipomoeassin F is a flagship congener of a resin glycoside family that inhibits growth of many tumor cell lines with only single-digital nanomolar IC50 values. However, biological and pharmacological mechanisms of ipomoeassin F have been undefined. To facilitate exploration of the biological and pharmacological properties, we performed sophisticate SAR (Structure–activity relationship) studies of ipomoeassin F to understand its pharmacophore and structure properties so that we can design favorable probes for further biological investigation. By applying appropriate deviates that possess fluorescent groups and similar bio-activity, the target protein was found to be localized in endoplasmic reticulum (ER). Through biotin affinity ...


Brown Fat Organogenesis And Maintenance Requires Akt1 And Akt2, Joan Sanchez-Gurmaches, Camila Martinez Calejman, Su Myung Jung, Huawei Li, David A. Guertin May 2019

Brown Fat Organogenesis And Maintenance Requires Akt1 And Akt2, Joan Sanchez-Gurmaches, Camila Martinez Calejman, Su Myung Jung, Huawei Li, David A. Guertin

Open Access Articles

OBJECTIVE: Understanding the signaling mechanisms that control brown adipose tissue (BAT) development is relevant to understanding energy homeostasis and obesity. The AKT kinases are insulin effectors with critical in vivo functions in adipocytes; however, their role in adipocyte development remains poorly understood. The goal of this study was to investigate AKT function in BAT development.

METHODS: We conditionally deleted Akt1 and Akt2 either individually or together with Myf5-Cre, which targets early mesenchymal precursors that give rise to brown adipocytes. Because Myf5-Cre also targets skeletal muscle and some white adipocyte lineages, comparisons were made between AKT function in BAT versus white ...


The Effects Of Eicosapentaenoic Acid (Epa) And Docosahexaenoic Acid (Dha) On Brown Adipogenesis In Stem Cell Culture, Darynne Dahlem May 2019

The Effects Of Eicosapentaenoic Acid (Epa) And Docosahexaenoic Acid (Dha) On Brown Adipogenesis In Stem Cell Culture, Darynne Dahlem

Animal Science Undergraduate Honors Theses

Polyunsaturated fatty acids (PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are major maternal dietary supplements due to their positive benefits on neurological tissue growth during the first 12 weeks of gestation. Previous studies show that EPA and DHA inhibit muscle formation but promote adipogenesis. However, no research has addressed the question whether high intake of EPA and DHA affects brown fat development during gestation. The objective of this study was to measure the effect of EPA and DHA supplement on brown adipogenesis and potential pathways related to mitochondrial biosynthesis using fibroblasts as in vitro model. Using Oil-Red-O staining ...


Regulation Of The Drosophila Imd Pathway By Signaling Amyloids, Anni Kleino, Neal S. Silverman May 2019

Regulation Of The Drosophila Imd Pathway By Signaling Amyloids, Anni Kleino, Neal S. Silverman

Open Access Articles

Fruit flies elicit effective defense responses against numerous microbes. The responses against Gram-negative bacteria are mediated by the Imd pathway, an evolutionarily conserved NF-kappaB pathway recognizing meso-diaminopimelic acid (DAP)-type peptidoglycan from bacterial cell walls. Several reviews already provide a detailed view of ligand recognition and signal transduction during Imd signaling, but the formation and regulation of the signaling complex immediately downstream of the peptidoglycan-sensing receptors is still elusive. In this review, we focus on the formation of the Imd amyloidal signaling center and post-translational modifications in the assembly and disassembly of the Imd signaling complex.


Ouabain Enhances Cell-Cell Adhesion Mediated By Beta1 Subunits Of The Na(+),K(+)-Atpase In Cho Fibroblasts, Claudia Andrea Vilchis-Nestor, Maria Luisa Roldan, Angelina Leonardi, Juan G. Navea, Teresita Padilla-Benavides, Liora Shoshani Apr 2019

Ouabain Enhances Cell-Cell Adhesion Mediated By Beta1 Subunits Of The Na(+),K(+)-Atpase In Cho Fibroblasts, Claudia Andrea Vilchis-Nestor, Maria Luisa Roldan, Angelina Leonardi, Juan G. Navea, Teresita Padilla-Benavides, Liora Shoshani

Open Access Articles

Adhesion is a crucial characteristic of epithelial cells to form barriers to pathogens and toxic substances from the environment. Epithelial cells attach to each other using intercellular junctions on the lateral membrane, including tight and adherent junctions, as well as the Na(+),K(+)-ATPase. Our group has shown that non-adherent chinese hamster ovary (CHO) cells transfected with the canine beta1 subunit become adhesive, and those homotypic interactions amongst beta1 subunits of the Na(+),K(+)-ATPase occur between neighboring epithelial cells. Ouabain, a cardiotonic steroid, binds to the alpha subunit of the Na(+),K(+)-ATPase, inhibits the pump activity and induces ...


Pesticides And Parkinson's: An Investigation Of The Effect Of Roundup Exposure On Drosophila Melanogaster, Siobhan O'Neill Apr 2019

Pesticides And Parkinson's: An Investigation Of The Effect Of Roundup Exposure On Drosophila Melanogaster, Siobhan O'Neill

Carroll College Student Undergraduate Research Festival

From commercial farms to private households, Roundup is the most commonly used herbicide in the United States. In recent years, exposure to Roundup has been correlated with a variety of health problems including Celiac Disease, birth defects, kidney and liver diseases, Alzheimer's Disease, and Parkinson's Disease. To date, the use of Roundup has been banned or restricted in several foreign countries, including the Netherlands, Portugal, Germany and Italy, because it has been classified as a possible carcinogen by the World Health Organization. The goal of this research was to determine the effects of Roundup exposure on dopaminergic neurons ...


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 ...


The Er-Localized Protein Dfcp1 Modulates Er-Lipid Droplet Contact Formation, Dongfang Li, Yan G. Zhao, Di Li, Hongyu Zhao, Jie Huang, Guangyan Miao, Du Feng, Pingsheng Liu, Dong Li, Hong Zhang Apr 2019

The Er-Localized Protein Dfcp1 Modulates Er-Lipid Droplet Contact Formation, Dongfang Li, Yan G. Zhao, Di Li, Hongyu Zhao, Jie Huang, Guangyan Miao, Du Feng, Pingsheng Liu, Dong Li, Hong Zhang

Open Access Articles

Very little is known about the spatiotemporal generation of lipid droplets (LDs) from the endoplasmic reticulum (ER) and the factors that mediate ER-LD contacts for LD growth. Using super-resolution grazing incidence structured illumination microscopy (GI-SIM) live-cell imaging, we reveal that upon LD induction, the ER-localized protein DFCP1 redistributes to nascent puncta on the ER, whose formation depends on triglyceride synthesis. These structures move along the ER and fuse to form expanding LDs. Fusion and expansion of DFCP1-labeled nascent structures is controlled by BSCL2. BSCL2 depletion causes accumulation of nascent DFCP1 structures. DFCP1 overexpression increases LD size and enhances ER-LD contacts ...


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 ...


Peptide Conjugation Of Branched Amphiphilic Peptide Capsules, Baltazar Claro-Martinez Apr 2019

Peptide Conjugation Of Branched Amphiphilic Peptide Capsules, Baltazar Claro-Martinez

Kansas State University Undergraduate Research Conference

In recent years, nanocarrier cellular therapy has been a rapidly growing area for research in the treatment of malignant and infectious diseases – most notably cancer. Conventional cancer treatment has consisted of highly toxic, highly insoluble, untargeted delivery of drugs that kill both cancerous and healthy cells. Research in the Tomich lab consists of the synthesis of Branched Amphiphilic Peptide Capsules (BAPCs), which are self-assembling peptide nanospheres composed of one or both of these branched peptide sequences: h5 and h9. These peptides possess similar molecular characteristics of phosphoglycerides but are synthesized chemically within the lab. Previous publications by the Tomich group ...


Transfer Rna Genes Affect Chromosome Structure And Function Via Local Effects, Omar Hamdani, Tsung-Han S. Hsieh, Oliver J. Rando, Rohinton T. Kamakaka Apr 2019

Transfer Rna Genes Affect Chromosome Structure And Function Via Local Effects, Omar Hamdani, Tsung-Han S. Hsieh, Oliver J. Rando, Rohinton T. Kamakaka

Open Access Articles

The genome is packaged and organized in an ordered, non-random manner and specific chromatin segments contact nuclear substructures to mediate this organization. Transfer RNA genes (tDNAs) are binding sites for transcription factors and architectural proteins and are thought to play an important role in the organization of the genome. In this study, we investigate the role of tDNAs in genomic organization and chromosome function by editing a chromosome so that it lacks any tDNAs. Surprisingly our analyses of this tDNA-less chromosome show that loss of tDNAs does not grossly affect chromatin architecture or chromosome tethering and mobility. However, loss of ...