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

Life Sciences Commons

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

Cellular and Molecular Physiology

Institution
Keyword
Publication Year
Publication
Publication Type
File Type

Articles 1 - 30 of 962

Full-Text Articles in Life Sciences

Regulation Of Zebrafish Melanocyte Development By Ligand-Dependent Bmp Signaling, Alec Gramann, Arvind M. Venkatesan, Melissa Guerin, Craig J. Ceol Dec 2019

Regulation Of Zebrafish Melanocyte Development By Ligand-Dependent Bmp Signaling, Alec Gramann, Arvind M. Venkatesan, Melissa Guerin, Craig J. Ceol

Open Access Articles

Preventing terminal differentiation is important in the development and progression of many cancers including melanoma. Recent identification of the BMP ligand GDF6 as a novel melanoma oncogene showed GDF6-activated BMP signaling suppresses differentiation of melanoma cells. Previous studies have identified roles for GDF6 orthologs during early embryonic and neural crest development, but have not identified direct regulation of melanocyte development by GDF6. Here, we investigate the BMP ligand gdf6a, a zebrafish ortholog of human GDF6, during the development of melanocytes from the neural crest. We establish that the loss of gdf6a or inhibition of BMP signaling during neural crest development ...


Lattice Arrangement Of Myosin Filaments Correlates With Fiber Type In Rat Skeletal Muscle, Weikang Ma, Kyounghwan Lee, Shixin Yang, Thomas C. Irving, Roger Craig Dec 2019

Lattice Arrangement Of Myosin Filaments Correlates With Fiber Type In Rat Skeletal Muscle, Weikang Ma, Kyounghwan Lee, Shixin Yang, Thomas C. Irving, Roger Craig

Radiology Publications and Presentations

The thick (myosin-containing) filaments of vertebrate skeletal muscle are arranged in a hexagonal lattice, interleaved with an array of thin (actin-containing) filaments with which they interact to produce contraction. X-ray diffraction and EM have shown that there are two types of thick filament lattice. In the simple lattice, all filaments have the same orientation about their long axis, while in the superlattice, nearest neighbors have rotations differing by 0 degrees or 60 degrees . Tetrapods (amphibians, reptiles, birds, and mammals) typically have only a superlattice, while the simple lattice is confined to fish. We have performed x-ray diffraction and electron microscopy ...


Sptlc1 Is Essential For Myeloid Differentiation And Hematopoietic Homeostasis, Velayoudame Parthibane, Usha Acharya, Jairaj K. Acharya Nov 2019

Sptlc1 Is Essential For Myeloid Differentiation And Hematopoietic Homeostasis, Velayoudame Parthibane, Usha Acharya, Jairaj K. Acharya

Open Access Articles

Serine palmitoyltransferase (SPT) long-chain base subunit 1 (SPTLC1) is 1 of the 2 main catalytic subunits of the SPT complex, which catalyzes the first and rate-limiting step of sphingolipid biosynthesis. Here, we show that Sptlc1 deletion in adult bone marrow (BM) cells results in defective myeloid differentiation. In chimeric mice from noncompetitive BM transplant assays, there was an expansion of the Lin- c-Kit+ Sca-1+ compartment due to increased multipotent progenitor production, but myeloid differentiation was severely compromised. We also show that defective biogenesis of sphingolipids in the endoplasmic reticulum (ER) leads to ER stress that affects myeloid differentiation. Furthermore, we ...


Suppressing Aneuploidy-Associated Phenotypes Improves The Fitness Of Trisomy 21 Cells, Sunyoung Hwang, Jessica F. Williams, Maja Kneissig, Maria Lioudyno, Isabel Rivera, Pablo Helguera, Jorge Busciglio, Zuzana Storchova, Megan C. King, Eduardo M. Torres Nov 2019

Suppressing Aneuploidy-Associated Phenotypes Improves The Fitness Of Trisomy 21 Cells, Sunyoung Hwang, Jessica F. Williams, Maja Kneissig, Maria Lioudyno, Isabel Rivera, Pablo Helguera, Jorge Busciglio, Zuzana Storchova, Megan C. King, Eduardo M. Torres

Open Access Articles

An abnormal number of chromosomes, or aneuploidy, accounts for most spontaneous abortions, causes developmental defects, and is associated with aging and cancer. The molecular mechanisms by which aneuploidy disrupts cellular function remain largely unknown. Here, we show that aneuploidy disrupts the morphology of the nucleus. Mutations that increase the levels of long-chain bases suppress nuclear abnormalities of aneuploid yeast independent of karyotype identity. Quantitative lipidomics indicates that long-chain bases are integral components of the nuclear membrane in yeast. Cells isolated from patients with Down syndrome also show that abnormal nuclear morphologies and increases in long-chain bases not only suppress these ...


Non-Equilibrium Critical Dynamics Of Bursts In Theta And Delta Rhythms As Fundamental Characteristic Of Sleep And Wake Micro-Architecture, Jilin W. J. L. Wang, Fabrizio Lombardi, Xiyun Zhang, Christelle Anaclet, Plamen Ch. Ivanov Nov 2019

Non-Equilibrium Critical Dynamics Of Bursts In Theta And Delta Rhythms As Fundamental Characteristic Of Sleep And Wake Micro-Architecture, Jilin W. J. L. Wang, Fabrizio Lombardi, Xiyun Zhang, Christelle Anaclet, Plamen Ch. Ivanov

Open Access Articles

Origin and functions of intermittent transitions among sleep stages, including short awakenings and arousals, constitute a challenge to the current homeostatic framework for sleep regulation, focusing on factors modulating sleep over large time scales. Here we propose that the complex micro-architecture characterizing the sleep-wake cycle results from an underlying non-equilibrium critical dynamics, bridging collective behaviors across spatio-temporal scales. We investigate theta and delta wave dynamics in control rats and in rats with lesions of sleep-promoting neurons in the parafacial zone. We demonstrate that intermittent bursts in theta and delta rhythms exhibit a complex temporal organization, with long-range power-law correlations and ...


Dietary Alpha-Ketoglutarate Promotes Beige Adipogenesis And Prevents Obesity In Middle-Aged Mice, Qiyu Tian, Junxing Zhao, Qiyuan Yang, Bo Wang, Jeanene M. Deavila, Mei-Jun Zhu, Min Du Nov 2019

Dietary Alpha-Ketoglutarate Promotes Beige Adipogenesis And Prevents Obesity In Middle-Aged Mice, Qiyu Tian, Junxing Zhao, Qiyuan Yang, Bo Wang, Jeanene M. Deavila, Mei-Jun Zhu, Min Du

Open Access Articles

Aging usually involves the progressive development of certain illnesses, including diabetes and obesity. Due to incapacity to form new white adipocytes, adipose expansion in aged mice primarily depends on adipocyte hypertrophy, which induces metabolic dysfunction. On the other hand, brown adipose tissue burns fatty acids, preventing ectopic lipid accumulation and metabolic diseases. However, the capacity of brown/beige adipogenesis declines inevitably during the aging process. Previously, we reported that DNA demethylation in the Prdm16 promoter is required for beige adipogenesis. DNA methylation is mediated by ten-eleven family proteins (TET) using alpha-ketoglutarate (AKG) as a cofactor. Here, we demonstrated that the ...


#9 - Lipid Induced-Ev Proteins And Their Association To Diabetic Kidney Disease, Amanda Haney Nov 2019

#9 - Lipid Induced-Ev Proteins And Their Association To Diabetic Kidney Disease, Amanda Haney

Georgia Undergraduate Research Conference (GURC)

Abnormal lipid metabolism in association with type 2 diabetes, plays a major role in the development of diabetic kidney disease (DKD). Lipotoxicity, an accumulation of intracellular lipid metabolites, has been proposed as a mechanism which mediates renal tubulointerstitial damage. Extracellular vesicles (EVs) are cell secreted molecules that are believed to be vital in mediating intracellular communication and immune regulation. Our lab investigated the effect of fatty acids on EVs released from cultured renal proximal tubular cells (PTCs). NRK-52E cells were treated with palmitic acid (PA) and 1% BSA. Secreted EVs were isolated through ultracentrifugation and proteins were identified using liquid ...


Single Cell Transcriptomic Profiling Of Large Intestinal Enteroendocrine Cells In Mice - Identification Of Selective Stimuli For Insulin-Like Peptide-5 And Glucagon-Like Peptide-1 Co-Expressing Cells, Lawrence J. Billing, Pierre Larraufie, Jo Lewis, Andrew B. Leiter, Joyce H. Li, Brian Lam, Giles Sh. Yeo, Deborah A. Goldspink, Richard G. Kay, Fiona M. Gribble, Frank Reimann Nov 2019

Single Cell Transcriptomic Profiling Of Large Intestinal Enteroendocrine Cells In Mice - Identification Of Selective Stimuli For Insulin-Like Peptide-5 And Glucagon-Like Peptide-1 Co-Expressing Cells, Lawrence J. Billing, Pierre Larraufie, Jo Lewis, Andrew B. Leiter, Joyce H. Li, Brian Lam, Giles Sh. Yeo, Deborah A. Goldspink, Richard G. Kay, Fiona M. Gribble, Frank Reimann

Open Access Articles

OBJECTIVE: Enteroendocrine cells (EECs) of the large intestine, found scattered in the epithelial layer, are known to express different hormones, with at least partial co-expression of different hormones in the same cell. Here we aimed to categorize colonic EECs and to identify possible targets for selective recruitment of hormones.

METHODS: Single cell RNA-sequencing of sorted enteroendocrine cells, using NeuroD1-Cre x Rosa26-EYFP mice, was used to cluster EECs from the colon and rectum according to their transcriptome. G-protein coupled receptors differentially expressed across clusters were identified, and, as a proof of principle, agonists of Agtr1a and Avpr1b were tested as candidate ...


Phosphorylation On Pstp Controls Cell Wall Metabolism And Antibiotic Tolerance In Mycobacterium Smegmatis, Farah Shamma, Kadamba Papavinasasundaram, Aditya Bandekar, Christopher M. Sassetti, Cara C. Boutte Oct 2019

Phosphorylation On Pstp Controls Cell Wall Metabolism And Antibiotic Tolerance In Mycobacterium Smegmatis, Farah Shamma, Kadamba Papavinasasundaram, Aditya Bandekar, Christopher M. Sassetti, Cara C. Boutte

University of Massachusetts Medical School Faculty Publications

The mycobacterial cell wall is a dynamic structure that protects Mycobacterium tuberculosis and its relatives from environmental stresses. Modulation of cell wall metabolism under stress is thought to be responsible for decreased cell wall permeability and increased tolerance to antibiotics. The signaling pathways that control cell wall metabolism under stress, however, are poorly understood. Here, we examine the signaling capacity of a cell wall master regulator, the Serine Threonine Phosphatase PstP, in the model organism Mycobacterium smegmatis. We studied how interference with a regulatory phosphorylation site on PstP affects growth, cell wall metabolism and antibiotic tolerance. We find that a ...


Coronary Disease Is Not Associated With Robust Alterations In Inflammatory Gene Expression In Human Epicardial Fat, Timothy P. Fitzgibbons, Nancy Lee, Khanh-Van T. Tran, Sarah M. Nicoloro, Mark Kelly, Stanley Kc Tam, Michael P. Czech Oct 2019

Coronary Disease Is Not Associated With Robust Alterations In Inflammatory Gene Expression In Human Epicardial Fat, Timothy P. Fitzgibbons, Nancy Lee, Khanh-Van T. Tran, Sarah M. Nicoloro, Mark Kelly, Stanley Kc Tam, Michael P. Czech

Open Access Articles

Epicardial adipose tissue (EAT) is the visceral fat depot of the heart. Inflammation of EAT is thought to contribute to coronary artery disease (CAD). Therefore, we hypothesized that the EAT of patients with CAD would have increased inflammatory gene expression compared with controls without CAD. Cardiac surgery patients with (n = 13) or without CAD (n = 13) were consented, and samples of EAT and subcutaneous adipose tissue (SAT) were obtained. Transcriptomic analysis was performed using Affymetrix Human Gene 1.0 ST arrays. Differential expression was defined as a 1.5-fold change (ANOVA P < 0.05). Six hundred ninety-three genes were differentially expressed between SAT and EAT in controls and 805 in cases. Expression of 326 genes was different between EAT of cases and controls; expression of 14 genes was increased in cases, while 312 were increased in controls. Quantitative reverse transcription PCR confirmed that there was no difference in expression of CCL2, CCR2, TNF-alpha, IL-6, IL-8, and PAI1 between groups. Immunohistochemistry showed more macrophages in EAT than SAT, but there was no difference in their number or activation state between groups. In contrast to prior studies, we did not find increased inflammatory gene expression in the EAT of patients with CAD. We conclude that the specific adipose tissue depot, rather than CAD status, is responsible for the majority of differential gene expression.


Mdt-28/Plin-1 Mediates Lipid Droplet-Microtubule Interaction Via Dlc-1 In Caenorhabditis Elegans, Kang Xie, Peng Zhang, Huimin Na, Yangli Liu, Hong Zhang, Pingsheng Liu Oct 2019

Mdt-28/Plin-1 Mediates Lipid Droplet-Microtubule Interaction Via Dlc-1 In Caenorhabditis Elegans, Kang Xie, Peng Zhang, Huimin Na, Yangli Liu, Hong Zhang, Pingsheng Liu

Open Access Articles

Ectopic lipid accumulation in lipid droplets (LD) has been linked to many metabolic diseases. In this study, DHS-3::GFP was used as a LD marker in C. elegans and a forward genetic screen was carried out to find novel LD regulators. There were 140 mutant alleles identified which were divided into four phenotypic categories: enlarged, aggregated, aggregated and small, and decreased. After genetic mapping, mutations in three known LD regulatory genes (maoc-1, dhs-28, daf-22) and a peroxisome-related gene (acox-3) were found to enlarge LDs, demonstrating the reliability of using DHS-3 as a living marker. In the screen, the cytoskeleton protein ...


Ripk1 Mediates Tnf-Induced Intestinal Crypt Apoptosis During Chronic Nf-Kappab Activation, Jerry Wong, Matija Zelic, John Bertin, Michelle A. Kelliher, Monica Guma Oct 2019

Ripk1 Mediates Tnf-Induced Intestinal Crypt Apoptosis During Chronic Nf-Kappab Activation, Jerry Wong, Matija Zelic, John Bertin, Michelle A. Kelliher, Monica Guma

Open Access Articles

BACKGROUND AND AIMS: Tumor necrosis factor (TNF) is a major pathogenic effector and a therapeutic target in inflammatory bowel disease (IBD), yet the basis for TNF-induced intestinal epithelial cell (IEC) death is unknown, because TNF does not kill normal IECs. Here, we investigated how chronic nuclear factor (NF)- kappaB activation, which occurs in human IBD, promotes TNF-dependent IEC death in mice.

METHODS: Human IBD specimens were stained for p65 and cleaved caspase-3. C57BL/6 mice with constitutively active IKKbeta in IEC (Ikkbeta(EE)(IEC)), Ripk1(D138N/D138N) knockin mice, and Ripk3(-/-) mice were injected with TNF or lipopolysaccharide. Enteroids were ...


Excess No Stabilizes The Luminal Domain Of Stim2 In A Cys-Specific Manner Thereby Regulating Basal Calcium Homeostasis And Store-Operated Calcium Entry, Matthew Novello Sep 2019

Excess No Stabilizes The Luminal Domain Of Stim2 In A Cys-Specific Manner Thereby Regulating Basal Calcium Homeostasis And Store-Operated Calcium Entry, Matthew Novello

Electronic Thesis and Dissertation Repository

Stromal-interaction molecule 2 (STIM2) is an endoplasmic reticulum (ER) membrane-inserted Ca2+-sensing protein which, together with the plasma membrane Ca2+ channel Orai1, regulates basal Ca2+ homeostasis and store-operated Ca2+ entry (SOCE). Recent evidence suggests that S-nitrosylation, which is the covalent attachment of a nitric oxide (NO) moiety to a cysteine thiol, can attenuate the function of the paralog STIM1 protein. Compared to STIM1, STIM2 also functions as a basal Ca2+ homeostatic feedback regulator. Therefore, the objective of my study was to evaluate the susceptibility of STIM2 to S-nitrosylation and the effects that this ...


A Critical Role Of Vmp1 In Lipoprotein Secretion, Hideaki Morishita, Yan G. Zhao, Norito Tamura, Taki Nishimura, Yuki Kanda, Yuriko Sakamaki, Mitsuyo Okazaki, Dongfang Li, Noboru Mizushima Sep 2019

A Critical Role Of Vmp1 In Lipoprotein Secretion, Hideaki Morishita, Yan G. Zhao, Norito Tamura, Taki Nishimura, Yuki Kanda, Yuriko Sakamaki, Mitsuyo Okazaki, Dongfang Li, Noboru Mizushima

Open Access Articles

Lipoproteins are lipid-protein complexes that are primarily generated and secreted from the intestine, liver, and visceral endoderm and delivered to peripheral tissues. Lipoproteins, which are assembled in the endoplasmic reticulum (ER) membrane, are released into the ER lumen for secretion, but its mechanism remains largely unknown. Here, we show that the release of lipoproteins from the ER membrane requires VMP1, an ER transmembrane protein essential for autophagy and certain types of secretion. Loss of vmp1, but not other autophagy-related genes, in zebrafish causes lipoprotein accumulation in the intestine and liver. Vmp1 deficiency in mice also leads to lipid accumulation in ...


Neural Jnk3 Regulates Blood Flow Recovery After Hindlimb Ischemia In Mice Via An Egr1/Creb1 Axis, Shashi Kant, Siobhan M. Craige, Kai Chen, Michaella M. Reif, Heather Learnard, Mark Kelly, Amada D. Caliz, Khanh-Van T. Tran, Kasmir Ramo, Owen M. Peters, Marc R. Freeman, Roger J. Davis, John F. Keaney Jr. Sep 2019

Neural Jnk3 Regulates Blood Flow Recovery After Hindlimb Ischemia In Mice Via An Egr1/Creb1 Axis, Shashi Kant, Siobhan M. Craige, Kai Chen, Michaella M. Reif, Heather Learnard, Mark Kelly, Amada D. Caliz, Khanh-Van T. Tran, Kasmir Ramo, Owen M. Peters, Marc R. Freeman, Roger J. Davis, John F. Keaney Jr.

University of Massachusetts Medical School Faculty Publications

Diseases related to impaired blood flow such as peripheral artery disease (PAD) impact nearly 10 million people in the United States alone, yet patients with clinical manifestations of PAD (e.g., claudication and limb ischemia) have limited treatment options. In ischemic tissues, stress kinases such as c-Jun N-terminal kinases (JNKs), are activated. Here, we show that inhibition of the JNK3 (Mapk10) in the neural compartment strikingly potentiates blood flow recovery from mouse hindlimb ischemia. JNK3 deficiency leads to upregulation of growth factors such as Vegfa, Pdgfb, Pgf, Hbegf and Tgfb3 in ischemic muscle by activation of the transcription factors Egr1 ...


Expression Of Mitochondrial Membrane-Linked Sab Determines Severity Of Sex-Dependent Acute Liver Injury, Sanda Win, Robert W. M. Min, Christopher Q. Chen, Jun Zhang, Yibu Chen, Meng Li, Ayako Suzuki, Manal F. Abdelmalek, Ying Wang, Mariam Aghajan, Filbert W. M. Aung, Anna Mae Diehl, Roger J. Davis, Tin A. Than, Neil Kaplowitz Sep 2019

Expression Of Mitochondrial Membrane-Linked Sab Determines Severity Of Sex-Dependent Acute Liver Injury, Sanda Win, Robert W. M. Min, Christopher Q. Chen, Jun Zhang, Yibu Chen, Meng Li, Ayako Suzuki, Manal F. Abdelmalek, Ying Wang, Mariam Aghajan, Filbert W. M. Aung, Anna Mae Diehl, Roger J. Davis, Tin A. Than, Neil Kaplowitz

University of Massachusetts Medical School Faculty Publications

SAB is an outer membrane docking protein for JNK mediated impaired mitochondrial function. Deletion of Sab in hepatocytes inhibits sustained JNK activation and cell death. Current work demonstrated that increasing SAB enhanced the severity of APAP liver injury. Female mice were resistant to liver injury and exhibited markedly decreased hepatic SAB protein expression versus males. The mechanism of SAB repression involved a pathway from ERalpha to p53 expression which induced miR34a-5p. miR34a-5p targeted the Sab mRNA coding region, repressing SAB expression. Fulvestrant or p53 knockdown decreased miR34a-5p and increased SAB in females leading to increased injury from APAP and TNF ...


Diverse Repertoire Of Human Adipocyte Subtypes Develops From Transcriptionally Distinct Mesenchymal Progenitor Cells, So Yun Min, Anand Desai, Zinger Yang, Agastya Sharma, Tiffany Desouza, Ryan Genga, Alper Kucukural, Lawrence M. Lifshitz, Soren Nielsen, Camilla Scheele, Rene Maehr, Manuel Garber, Silvia Corvera Sep 2019

Diverse Repertoire Of Human Adipocyte Subtypes Develops From Transcriptionally Distinct Mesenchymal Progenitor Cells, So Yun Min, Anand Desai, Zinger Yang, Agastya Sharma, Tiffany Desouza, Ryan Genga, Alper Kucukural, Lawrence M. Lifshitz, Soren Nielsen, Camilla Scheele, Rene Maehr, Manuel Garber, Silvia Corvera

Open Access Articles

Single-cell sequencing technologies have revealed an unexpectedly broad repertoire of cells required to mediate complex functions in multicellular organisms. Despite the multiple roles of adipose tissue in maintaining systemic metabolic homeostasis, adipocytes are thought to be largely homogenous with only 2 major subtypes recognized in humans so far. Here we report the existence and characteristics of 4 distinct human adipocyte subtypes, and of their respective mesenchymal progenitors. The phenotypes of these distinct adipocyte subtypes are differentially associated with key adipose tissue functions, including thermogenesis, lipid storage, and adipokine secretion. The transcriptomic signature of "brite/beige" thermogenic adipocytes reveals mechanisms for ...


The Central Role Of The Tail In Switching Off 10s Myosin Ii Activity, Shixin Yang, Kyounghwan Lee, John L. Woodhead, Osamu Sato, Mitsuo Ikebe, Roger Craig Sep 2019

The Central Role Of The Tail In Switching Off 10s Myosin Ii Activity, Shixin Yang, Kyounghwan Lee, John L. Woodhead, Osamu Sato, Mitsuo Ikebe, Roger Craig

Radiology Publications and Presentations

Myosin II is a motor protein with two heads and an extended tail that plays an essential role in cell motility. Its active form is a polymer (myosin filament) that pulls on actin to generate motion. Its inactive form is a monomer with a compact structure (10S sedimentation coefficient), in which the tail is folded and the two heads interact with each other, inhibiting activity. This conformation is thought to function in cells as an energy-conserving form of the molecule suitable for storage as well as transport to sites of filament assembly. The mechanism of inhibition of the compact molecule ...


Atf6alpha Impacts Cell Number By Influencing Survival, Death And Proliferation, Rohit B. Sharma, Jarin T. Snyder, Laura C. Alonso Sep 2019

Atf6alpha Impacts Cell Number By Influencing Survival, Death And Proliferation, Rohit B. Sharma, Jarin T. Snyder, Laura C. Alonso

Open Access Articles

BACKGROUND: A growing body of literature suggests the cell-intrinsic activity of Atf6alpha during ER stress responses has implications for tissue cell number during growth and development, as well as in adult biology and tumorigenesis [1]. This concept is important, linking the cellular processes of secretory protein synthesis and endoplasmic reticulum stress response with functional tissue capacity and organ size. However, the field contains conflicting observations, especially notable in secretory cell types like the pancreatic beta cell.

SCOPE OF REVIEW: Here we summarize current knowledge of the basic biology of Atf6alpha, along with the pleiotropic roles Atf6alpha plays in cell life ...


Modeling Of Cisplatin-Induced Signaling Dynamics In Triple-Negative Breast Cancer Cells Reveals Mediators Of Sensitivity, Anne Margriet Heijink, Marieke Everts, Megan E. Honeywell, Ryan Richards, Yannick P. Kok, Elisabeth G. E. De Vries, Michael J. Lee, Marcel A T M Van Vugt Aug 2019

Modeling Of Cisplatin-Induced Signaling Dynamics In Triple-Negative Breast Cancer Cells Reveals Mediators Of Sensitivity, Anne Margriet Heijink, Marieke Everts, Megan E. Honeywell, Ryan Richards, Yannick P. Kok, Elisabeth G. E. De Vries, Michael J. Lee, Marcel A T M Van Vugt

Open Access Articles

Triple-negative breast cancers (TNBCs) display great diversity in cisplatin sensitivity that cannot be explained solely by cancer-associated DNA repair defects. Differential activation of the DNA damage response (DDR) to cisplatin has been proposed to underlie the observed differential sensitivity, but it has not been investigated systematically. Systems-level analysis-using quantitative time-resolved signaling data and phenotypic responses, in combination with mathematical modeling-identifies that the activation status of cell-cycle checkpoints determines cisplatin sensitivity in TNBC cell lines. Specifically, inactivation of the cell-cycle checkpoint regulator MK2 or G3BP2 sensitizes cisplatin-resistant TNBC cell lines to cisplatin. Dynamic signaling data of five cell cycle-related signals predicts ...


Promotion Of Adipogenesis By Jmjd6 Requires The At Hook-Like Domain And Is Independent Of Its Catalytic Function, Pablo Reyes-Gutierrez, Jake W. Carrasquillo-Rodriguez, Anthony N. Imbalzano Aug 2019

Promotion Of Adipogenesis By Jmjd6 Requires The At Hook-Like Domain And Is Independent Of Its Catalytic Function, Pablo Reyes-Gutierrez, Jake W. Carrasquillo-Rodriguez, Anthony N. Imbalzano

Open Access Articles

JMJD6 is a member of the Jumonji C domain containing enzymes that demethylate and/or hydroxylate substrate proteins. It is a multi-functional protein that has been implicated in disparate aspects of transcriptional and post-transcriptional control of gene expression, including but not limited to enhancer and promoter binding, release of paused RNA polymerase II, control of splicing, and interaction with the translation machinery. JMJD6 contributes to multiple aspects of animal development, including adipogenesis modeled in culture. We mutated proposed or characterized domains in the JMJD6 protein to better understand the requirement for JMJD6 in adipogenic differentiation. Mutation of JMJD6 amino acids ...


Assessing The Structure-Function Relationships Of The Apolipoprotein(A) Kringle Iv Sub-Type 10 Domain, Matthew J. Borrelli Aug 2019

Assessing The Structure-Function Relationships Of The Apolipoprotein(A) Kringle Iv Sub-Type 10 Domain, Matthew J. Borrelli

Electronic Thesis and Dissertation Repository

Elevated plasma lipoprotein(a) (Lp(a)) is the most prevalent heritable risk factor in the development of cardiovascular disease. The apolipoprotein(a) (apo(a)) component of Lp(a) is strongly implicated in the pathogenicity of Lp(a). It is hypothesized that the inflammatory potential of Lp(a)/apo(a) is mediated by the lysine binding ability of the apo(a) kringle IV10 (KIV10) domain, along with its covalently bound oxidized phospholipid (oxPL). Using targeted mutagenesis, two novel null alleles for the LPA gene that generate non-secretable apo(a) species have been identified, resulting from amino acid substitutions in the KIV10 ...


Mapping And Functional Characterization Of Proteolytic Cleavage Of Murine Kidney Injury Molecule-1, Saranga Sriranganathan Aug 2019

Mapping And Functional Characterization Of Proteolytic Cleavage Of Murine Kidney Injury Molecule-1, Saranga Sriranganathan

Electronic Thesis and Dissertation Repository

Kidney injury molecule-1 (KIM-1) is a transmembrane glycoprotein expressed apically on proximal tubule epithelia during acute kidney injury (AKI). KIM-1, as a phagocytic receptor, facilitates clearance of apoptotic cells (efferocytosis) from tubular lumen, thereby reducing inflammation and promoting repair. Human KIM-1 undergoes spontaneous and accelerated ectodomain shedding into urine and blood via metalloproteases; tumour necrosis factor-a converting enzyme (TACE/ADAM17) and a disintegrin and metalloprotease 10 (ADAM10). Blood and urine KIM-1 are clinical AKI biomarkers, however, biological significance of KIM-1 shedding is unknown. To study this in vivo in mice, I first aimed to identify murine KIM-1 cleavage site and ...


Leaky Gut’S Contribution To Inefficient Nutrient Utilization, S. K. Kvidera, E. A. Horst, M. Al-Qaisi, M. J. Dickson, R. P. Rhoads, A. F. Keating, L. H. Baumgard Aug 2019

Leaky Gut’S Contribution To Inefficient Nutrient Utilization, S. K. Kvidera, E. A. Horst, M. Al-Qaisi, M. J. Dickson, R. P. Rhoads, A. F. Keating, L. H. Baumgard

Aileen Keating

There are a variety of situations in an animal’s life when nutrient utilization is reprioritized from productive towards agriculturally unproductive purposes. Two well-known examples that markedly reduce production are heat stress and ketosis. Decreased feed intake, experienced during both disorders, is unable to fully explain production losses. Additionally, both disorders are characterized by negative energy balance, body weight loss, inflammation, and liver fat accumulation. While the metabolism of ketosis and heat stress has been thoroughly studied for the last 40 years, the initial insult in the cascade of events ultimately reducing productivity in both heat-stressed and ketotic cows has ...


The Impact Of Dietary Supplementation Of Arginine During Gestation In A Commercial Swine Herd: I. Gilt Reproductive Performance, Elizabeth A. Hines, Matthew R. Romoser, Zoë E. Kiefer, Aileen F. Keating, Lance H. Baumgard, Jarad Niemi, Nicholas K. Gabler, John F. Patience, Benjamin Haberl, Noel H. Williams, Brian J. Kerr, Kevin J. Touchette, Jason W. Ross Aug 2019

The Impact Of Dietary Supplementation Of Arginine During Gestation In A Commercial Swine Herd: I. Gilt Reproductive Performance, Elizabeth A. Hines, Matthew R. Romoser, Zoë E. Kiefer, Aileen F. Keating, Lance H. Baumgard, Jarad Niemi, Nicholas K. Gabler, John F. Patience, Benjamin Haberl, Noel H. Williams, Brian J. Kerr, Kevin J. Touchette, Jason W. Ross

Aileen Keating

Supplemental Arg during gestation purportedly benefits fetal development. However, the benefits of a gestational Arg dietary strategy in commercial production are unclear. Therefore, objectives of this study examined Arg supplementation during different gestational stages and the effects on gilt reproductive performance. Pubertal gilts (n = 548) were allocated into four treatment groups: Control (n = 143; 0% supplemental Arg) or one of three supplemental Arg (1% as fed) treatments: from 15 to 45 d of gestation (n = 138; Early-Arg); from 15 d of gestation until farrowing (n = 139; Full-Arg); or from 85 d of gestation until farrowing (n = 128; Late-Arg). At farrowing ...


The Effects Of Branched Chained Amino Acid Supplementation On Acute Markers Of Fatigue And Performance, Joseph Walters Aug 2019

The Effects Of Branched Chained Amino Acid Supplementation On Acute Markers Of Fatigue And Performance, Joseph Walters

Electronic Theses and Dissertations

The purposes of this dissertation were to investigate the acute effects of branched-chain amino acids on psychological, physiological, and subsequent performance changes following high volume resistance training. The rationale for this study design was based on abrupt or contiguous training/ competitions that specific athletes encounter in a competitive season. This study design also sought to fill some gaps in the scientific literature concerning the efficacy of BCAAs for subjective fatigue in a resistance training paradigm. To address the purposes of this dissertation, a one-week study was conducted on resistance trained males, in which half of the subjects were randomly selected ...


High-Fat Diet In A Mouse Insulin-Resistant Model Induces Widespread Rewiring Of The Phosphotyrosine Signaling Network, Antje Dittmann, Norman J. Kennedy, Nina L. Soltero, Nader Morshed, Miyeko D. Mana, Omer H. Yilmaz, Roger J. Davis, Forest M. White Aug 2019

High-Fat Diet In A Mouse Insulin-Resistant Model Induces Widespread Rewiring Of The Phosphotyrosine Signaling Network, Antje Dittmann, Norman J. Kennedy, Nina L. Soltero, Nader Morshed, Miyeko D. Mana, Omer H. Yilmaz, Roger J. Davis, Forest M. White

Open Access Articles

Obesity-associated type 2 diabetes and accompanying diseases have developed into a leading human health risk across industrialized and developing countries. The complex molecular underpinnings of how lipid overload and lipid metabolites lead to the deregulation of metabolic processes are incompletely understood. We assessed hepatic post-translational alterations in response to treatment of cells with saturated and unsaturated free fatty acids and the consumption of a high-fat diet by mice. These data revealed widespread tyrosine phosphorylation changes affecting a large number of enzymes involved in metabolic processes as well as canonical receptor-mediated signal transduction networks. Targeting two of the most prominently affected ...


Distribution And Responsiveness Of Rat Anti-Müllerian Hormone During Ovarian Development And Vcd-Induced Ovotoxicity, Connie J. Mark-Kappeler, Nivedita Sen, Aileen F. Keating, I. Glenn Sipes, Patricia B. Hoyer Jul 2019

Distribution And Responsiveness Of Rat Anti-Müllerian Hormone During Ovarian Development And Vcd-Induced Ovotoxicity, Connie J. Mark-Kappeler, Nivedita Sen, Aileen F. Keating, I. Glenn Sipes, Patricia B. Hoyer

Aileen Keating

Anti-Müllerian hormone (AMH) is produced by granulosa cells in primary to small antral follicles of the adult ovary and helps maintain primordial follicles in a dormant state. The industrial chemical, 4-vinylcyclohexene diepoxide (VCD) causes specific ovotoxicity in primordial and small primary follicles of mice and rats. Previous studies suggest that this ovotoxicity involves acceleration of primordial to primary follicle recruitment via interactions with the Kit/Kit ligand signaling pathway. Because of its accepted role in inhibiting primordial follicle recruitment, the present study was designed to investigate a possible interaction between AMH and VCD-induced ovotoxicity. Protein distribution of AMH was compared ...


Dual Protective Role For Glutathione S-Transferase Class Pi Against Vcd-Induced Ovotoxicity In The Rat Ovary, Aileen F. Keating, Nivedita Sen, I. Glenn Sipes, Patricia B. Hoyer Jul 2019

Dual Protective Role For Glutathione S-Transferase Class Pi Against Vcd-Induced Ovotoxicity In The Rat Ovary, Aileen F. Keating, Nivedita Sen, I. Glenn Sipes, Patricia B. Hoyer

Aileen Keating

The occupational chemical 4-vinylcyclohexene diepoxide (VCD) selectively destroys ovarian small pre-antral follicles in rats and mice via apoptosis. Detoxification of VCD can occur through glutathione conjugation, catalyzed by glutathione S-transferase (GST) enzymes. Further, GST class pi (GSTp) can negatively regulate JNK activity through protein:protein interactions in extraovarian tissues. Dissociation of this protein complex in the face of chemical exposure releases the inhibition of pro-apoptotic JNK. Increased JNK activity during VCD-induced ovotoxicity has been shown in isolated ovarian small pre-antral follicles following in vivo dosing of rats (80mg/ Kg/d; 15d, i.p). The present study investigated the pattern of ...


Inhibition Of Pik3 Signaling Pathway Members By The Ovotoxicant 4-Vinylcyclohexene Diepoxide In Rats, Aileen F. Keating, Shannon M. Fernandez, Connie J. Mark-Kappeler, Nivedita Sen, I. Glenn Sipes, Patricia B. Hoyer Jul 2019

Inhibition Of Pik3 Signaling Pathway Members By The Ovotoxicant 4-Vinylcyclohexene Diepoxide In Rats, Aileen F. Keating, Shannon M. Fernandez, Connie J. Mark-Kappeler, Nivedita Sen, I. Glenn Sipes, Patricia B. Hoyer

Aileen Keating

4-Vinylcyclohexene diepoxide (VCD), an occupational chemical that specifically destroys primordial and small primary follicles in the ovaries of rats and mice, is thought to target an oocyte-expressed tyrosine kinase receptor, Kit. This study compared the temporal effect of VCD on protein distribution of KIT and its downstream PIK3-activated proteins, AKT and FOXO3. Postnatal Day 4 Fischer 344 rat ovaries were cultured in control media ± VCD (30 μM) for 2–8 days (d2–d8). KIT, AKT, phosphorylated AKT, FOXO3, and pFOXO3 protein levels were assessed by Western blotting and/or immunofluorescence staining with confocal microscopy. Phosphorylated AKT was decreased (P < 0.05) in oocyte nuclei in primordial (39% decrease) and small primary (37% decrease) follicles within 2 days of VCD exposure. After d4, VCD reduced (P ...