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Necroptosis, Pyroptosis And Apoptosis: An Intricate Game Of Cell Death, Damien Bertheloot, Eicke Latz, Bernardo S. Franklin 2021 University of Bonn

Necroptosis, Pyroptosis And Apoptosis: An Intricate Game Of Cell Death, Damien Bertheloot, Eicke Latz, Bernardo S. Franklin

Open Access Publications by UMMS Authors

Cell death is a fundamental physiological process in all living organisms. Its roles extend from embryonic development, organ maintenance, and aging to the coordination of immune responses and autoimmunity. In recent years, our understanding of the mechanisms orchestrating cellular death and its consequences on immunity and homeostasis has increased substantially. Different modalities of what has become known as 'programmed cell death' have been described, and some key players in these processes have been identified. We have learned more about the intricacies that fine tune the activity of common players and ultimately shape the different types of cell death. These studies ...


Glial Cell Dysfunction In C9orf72-Related Amyotrophic Lateral Sclerosis And Frontotemporal Dementia, Mehdi Ghasemi, Kiandokht Keyhanian, Catherine Douthwright 2021 University of Massachusetts Medical School

Glial Cell Dysfunction In C9orf72-Related Amyotrophic Lateral Sclerosis And Frontotemporal Dementia, Mehdi Ghasemi, Kiandokht Keyhanian, Catherine Douthwright

Open Access Publications by UMMS Authors

Since the discovery of the chromosome 9 open reading frame 72 (C9orf72) repeat expansion mutation in 2011 as the most common genetic abnormality in amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease) and frontotemporal dementia (FTD), progress in understanding the signaling pathways related to this mutation can only be described as intriguing. Two major theories have been suggested-(i) loss of function or haploinsufficiency and (ii) toxic gain of function from either C9orf72 repeat RNA or dipeptide repeat proteins (DPRs) generated from repeat-associated non-ATG (RAN) translation. Each theory has provided various signaling pathways that potentially participate in ...


Examining Neuroanatomical Effects Of Prenatal Valproic Acid And Postnatal Testosterone In A Mouse Model Of Autism Spectrum Disorder, Bishakha Kumari, Elizabeth Ann Gordon, Cynthia Corbitt 2021 University of Louisville

Examining Neuroanatomical Effects Of Prenatal Valproic Acid And Postnatal Testosterone In A Mouse Model Of Autism Spectrum Disorder, Bishakha Kumari, Elizabeth Ann Gordon, Cynthia Corbitt

Undergraduate Arts and Research Showcase

Sex differences in Autism Spectrum Disorder (ASD) are well documented; males are diagnosed 4:1 over females. Testosterone (T) is one factor that differs by sex in humans and mice that could increase vulnerability to developing ASD in males. Valproic acid (VPA) is an anticonvulsant that has been found to increase the risk of autism in male offspring of pregnant women who take it to control seizures and is commonly used in mouse models of ASD. After prenatal VPA or vehicle on embryonic day 13, testosterone (T) or vehicle was administered to the mice on postnatal day 2 to investigate ...


Site Tolerance Of The Rada Intein, Chase Taul, Christopher Lennon Dr 2020 Murray State University

Site Tolerance Of The Rada Intein, Chase Taul, Christopher Lennon Dr

Honors College Theses

Inteins (intervening proteins) invade genes at the DNA level and splice out at the protein level. Once thought of as only a parasitic type of a mobile genetic element, recent work suggests a mutualistic relationship has formed in some cases within bacterial and archaeal hosts. After translation, a precursor protein is formed with the intein between two exteins. The intein is catalytic and can excise itself out through protein splicing. Intein insertion is biased towards the active site of the protein and is thought to cause inactivation of the host protein prior to splicing. Intein splicing is responsive to a ...


Sexually Dimorphic Oxytocin Receptor-Expressing Neurons In The Anteroventral Periventricular Nucleus Regulates Maternal Behavior, Kaustubh Sharma 2020 Louisiana State University and Agricultural and Mechanical College

Sexually Dimorphic Oxytocin Receptor-Expressing Neurons In The Anteroventral Periventricular Nucleus Regulates Maternal Behavior, Kaustubh Sharma

LSU Doctoral Dissertations

The neurohypophysial hormone oxytocin is involved in the regulation of social behaviors, including social recognition, pair bonding, and sex-specific parental behaviors in a variety of species. Oxytocin triggers these social behaviors by binding to oxytocin receptors (OXTR) in various parts of the brain. Oxytocin-induced sex-typical behavior, therefore, suggests a sexual dimorphic distribution of OXTR in the brain. In recent years, the oxytocin system in the brain received tremendous attention as a potential pharmacological target for treatment of many psychiatric disorders, such as anxiety, autism spectrum disorders, and even sex-specific psychiatric disorder like postpartum depression (PPD). An important problem and a ...


The Lipid Handling Capacity Of Subcutaneous Fat Is Programmed By Mtorc2 During Development, Wen-Yu Hsiao, Su Myung Jung, Yuefeng Tang, John A. Haley, Rui Li, Huawei Li, Camila Martinez Calejman, Joan Sanchez-Gurmaches, Chien-Min Hung, Amelia K. Luciano, Victoria DeMambro, Kathryn E. Wellen, Clifford J. Rosen, Lihua Julie Zhu, David A. Guertin 2020 University of Massachusetts Medical School

The Lipid Handling Capacity Of Subcutaneous Fat Is Programmed By Mtorc2 During Development, Wen-Yu Hsiao, Su Myung Jung, Yuefeng Tang, John A. Haley, Rui Li, Huawei Li, Camila Martinez Calejman, Joan Sanchez-Gurmaches, Chien-Min Hung, Amelia K. Luciano, Victoria Demambro, Kathryn E. Wellen, Clifford J. Rosen, Lihua Julie Zhu, David A. Guertin

Open Access Publications by UMMS Authors

Overweight and obesity are associated with type 2 diabetes, non-alcoholic fatty liver disease, cardiovascular disease and cancer, but all fat is not equal, as storing excess lipid in subcutaneous white adipose tissue (SWAT) is more metabolically favorable than in visceral fat. Here, we uncover a critical role for mTORC2 in setting SWAT lipid handling capacity. We find that subcutaneous white preadipocytes differentiating without the essential mTORC2 subunit Rictor upregulate mature adipocyte markers but develop a striking lipid storage defect resulting in smaller adipocytes, reduced tissue size, lipid re-distribution to visceral and brown fat, and sex-distinct effects on systemic metabolic fitness ...


On The Expanding Roles Of Trna Fragments In Modulating Cell Behavior, Rogan Magee, Isidore Rigoutsos 2020 Thomas Jefferson University

On The Expanding Roles Of Trna Fragments In Modulating Cell Behavior, Rogan Magee, Isidore Rigoutsos

Computational Medicine Center Faculty Papers

The fragments that derive from transfer RNAs (tRNAs) are an emerging category of regulatory RNAs. Known as tRFs, these fragments were reported for the first time only a decade ago, making them a relatively recent addition to the ever-expanding pantheon of non-coding RNAs. tRFs are short, 16-35 nucleotides (nts) in length, and produced through cleavage of mature and precursor tRNAs at various positions. Both cleavage positions and relative tRF abundance depend strongly on context, including the tissue type, tissue state, and disease, as well as the sex, population of origin, and race/ethnicity of an individual. These dependencies increase the ...


Astrocyte- And Neuron-Derived Cxcl1 Drives Neutrophil Transmigration And Blood-Brain Barrier Permeability In Viral Encephalitis, Benedict D. Michael, Laura Bricio-Moreno, Elizabeth W. Sorensen, Yoshishige Miyabe, Jeffrey Lian, Tom Solomon, Evelyn A. Kurt-Jones, Andrew D. Luster 2020 Harvard Medical School

Astrocyte- And Neuron-Derived Cxcl1 Drives Neutrophil Transmigration And Blood-Brain Barrier Permeability In Viral Encephalitis, Benedict D. Michael, Laura Bricio-Moreno, Elizabeth W. Sorensen, Yoshishige Miyabe, Jeffrey Lian, Tom Solomon, Evelyn A. Kurt-Jones, Andrew D. Luster

Open Access Publications by UMMS Authors

Herpes simplex virus (HSV)-1 encephalitis has significant morbidity partly because of an over-exuberant immune response characterized by leukocyte infiltration into the brain and increased blood-brain barrier (BBB) permeability. Determining the role of specific leukocyte subsets and the factors that mediate their recruitment into the brain is critical to developing targeted immune therapies. In a murine model, we find that the chemokines CXCL1 and CCL2 are induced in the brain following HSV-1 infection. Ccr2 (CCL2 receptor)-deficient mice have reduced monocyte recruitment, uncontrolled viral replication, and increased morbidity. Contrastingly, Cxcr2 (CXCL1 receptor)-deficient mice exhibit markedly reduced neutrophil recruitment, BBB ...


Osteoblast-Osteoclast Communication And Bone Homeostasis, Jung-Min Kim, Chujiao Lin, Zheni Stavre, Matthew B. Greenblatt, Jae-Hyuck Shim 2020 University of Massachusetts Medical School

Osteoblast-Osteoclast Communication And Bone Homeostasis, Jung-Min Kim, Chujiao Lin, Zheni Stavre, Matthew B. Greenblatt, Jae-Hyuck Shim

Open Access Publications by UMMS Authors

Bone remodeling is tightly regulated by a cross-talk between bone-forming osteoblasts and bone-resorbing osteoclasts. Osteoblasts and osteoclasts communicate with each other to regulate cellular behavior, survival and differentiation through direct cell-to-cell contact or through secretory proteins. A direct interaction between osteoblasts and osteoclasts allows bidirectional transduction of activation signals through EFNB2-EPHB4, FASL-FAS or SEMA3A-NRP1, regulating differentiation and survival of osteoblasts or osteoclasts. Alternatively, osteoblasts produce a range of different secretory molecules, including M-CSF, RANKL/OPG, WNT5A, and WNT16, that promote or suppress osteoclast differentiation and development. Osteoclasts also influence osteoblast formation and differentiation through secretion of soluble factors, including S1P ...


Single-Stranded Phosphorothioated Regions Enhance Cellular Uptake Of Cholesterol-Conjugated Sirna But Not Silencing Efficacy, Socheata Ly, Dimas Echeverria, Jacquelyn Sousa, Anastasia Khvorova 2020 University of Massachusetts Medical School

Single-Stranded Phosphorothioated Regions Enhance Cellular Uptake Of Cholesterol-Conjugated Sirna But Not Silencing Efficacy, Socheata Ly, Dimas Echeverria, Jacquelyn Sousa, Anastasia Khvorova

Open Access Publications by UMMS Authors

Small interfering RNAs (siRNAs) have potential to silence virtually any disease-causing gene but require chemical modifications for delivery to the tissue and cell of interest. Previously, we demonstrated that asymmetric, phosphorothioate (PS)-modified, chemically stabilized, cholesterol-conjugated siRNAs, called hsiRNAs, support rapid cellular uptake and efficient mRNA silencing both in cultured cells and in vivo. Here, we systematically evaluated the impact of number, structure, and sequence context of PS-modified backbones on cellular uptake and RNAi-mediated silencing efficacy. We find that PS enhances cellular internalization in a sequence-dependent manner but only when present in a single-stranded but not double-stranded region. Furthermore, the ...


Cell Type Impacts Accessibility Of Mrna To Silencing By Rna Interference, Chantal M. Ferguson, Dimas Echeverria, Matthew R. Hassler, Socheata Ly, Anastasia Khvorova 2020 University of Massachusetts Medical School

Cell Type Impacts Accessibility Of Mrna To Silencing By Rna Interference, Chantal M. Ferguson, Dimas Echeverria, Matthew R. Hassler, Socheata Ly, Anastasia Khvorova

Open Access Publications by UMMS Authors

RNA interference (RNAi) is a potent mechanism that silences mRNA and protein expression in all cells and tissue types. RNAi is known to exert many of its functional effects in the cytoplasm, and thus, the cellular localization of target mRNA may impact observed potency. Here, we demonstrate that cell identity has a profound impact on accessibility of apolipoprotein E (ApoE) mRNA to RNAi. We show that, whereas both neuronal and glial cell lines express detectable ApoE mRNA, in neuronal cells, ApoE mRNA is not targetable by RNAi. Screening of a panel of thirty-five chemically modified small interfering RNAs (siRNAs) did ...


Regulation Of Microrna-497-Targeting Akt2 Influences Tumor Growth And Chemoresistance To Cisplatin In Lung Cancer., Lin Wang, Xiang-Bo Ji, Li-Hong Wang, Jian-Ge Qiu, Feng-Mei Zhou, Wen-Jing Liu, Di-di Wan, Marie Chai-Mi Lin, Ling-Zhi Liu, Jian-Ying Zhang, Bing-Hua Jiang 2020 Zhengzhou University

Regulation Of Microrna-497-Targeting Akt2 Influences Tumor Growth And Chemoresistance To Cisplatin In Lung Cancer., Lin Wang, Xiang-Bo Ji, Li-Hong Wang, Jian-Ge Qiu, Feng-Mei Zhou, Wen-Jing Liu, Di-Di Wan, Marie Chai-Mi Lin, Ling-Zhi Liu, Jian-Ying Zhang, Bing-Hua Jiang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background: MicroRNA-497 (miR-497) has been implicated in several cancers. Increasing studies demonstrate the role of AKT2 in cancers as an oncogene which is closely associated with tumor aggressiveness by enhancing cancer cell survival, migration and invasion However, miR-497/AKT2 axis in non-small cell lung cancer (NSCLC) remains unclear.

Methods: Quantitative real-time PCR (qRT-PCR) was used to quantify the expression of miR-497 and its target gene. The function of miR-497 in lung cancer was investigated through in vitro and in vivo assays (cell proliferation assay, cell migration assay, colony formation assay, flow cytometry assay, immunoblotting and tumorigenesis assay). Luciferase reporter assay ...


Quantification Of Lactoyl-Coa (Lactyl-Coa) By Liquid Chromatography Mass Spectrometry In Mammalian Cells And Tissues., Erika L Varner, Sophie Trefely, David Bartee, Eliana von Krusenstiern, Luke Izzo, Carmen Bekeova, Roddy S O'Connor, Erin L Seifert, Kathryn E Wellen, Jordan L Meier, Nathaniel W Snyder 2020 Temple University

Quantification Of Lactoyl-Coa (Lactyl-Coa) By Liquid Chromatography Mass Spectrometry In Mammalian Cells And Tissues., Erika L Varner, Sophie Trefely, David Bartee, Eliana Von Krusenstiern, Luke Izzo, Carmen Bekeova, Roddy S O'Connor, Erin L Seifert, Kathryn E Wellen, Jordan L Meier, Nathaniel W Snyder

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Lysine lactoylation is a recently described protein post-translational modification (PTM). However, the biochemical pathways responsible for this acylation remain unclear. Two metabolite-dependent mechanisms have been proposed: enzymatic histone lysine lactoylation derived from lactoyl-coenzyme A (lactoyl-CoA, also termed lactyl-CoA), and non-enzymatic lysine lactoylation resulting from acyl-transfer via lactoyl-glutathione. While the former has precedent in the form of enzyme-catalysed lysine acylation, the lactoyl-CoA metabolite has not been previously quantified in mammalian systems. Here, we use liquid chromatography-high-resolution mass spectrometry (LC-HRMS) together with a synthetic standard to detect and validate the presence of lactoyl-CoA in cell and tissue samples. Conducting a retrospective analysis ...


Nano-Vesicle (Mis)Communication In Senescence-Related Pathologies, Sherin Saheera, Ajay Godwin Potnuri, Prasanna Krishnamurthy 2020 University of Massachusetts Medical School

Nano-Vesicle (Mis)Communication In Senescence-Related Pathologies, Sherin Saheera, Ajay Godwin Potnuri, Prasanna Krishnamurthy

COVID-19 Publications by UMMS Authors

Extracellular vesicles are a heterogeneous group of cell-derived membranous structures comprising of exosomes, apoptotic bodies, and microvesicles. Of the extracellular vesicles, exosomes are the most widely sorted and extensively explored for their contents and function. The size of the nanovesicular structures (exosomes) range from 30 to 140 nm and are present in various biological fluids such as saliva, plasma, urine etc. These cargo-laden extracellular vesicles arise from endosome-derived multivesicular bodies and are known to carry proteins and nucleic acids. Exosomes are involved in multiple physiological and pathological processes, including cellular senescence. Exosomes mediate signaling crosstalk and play a critical role ...


Single-Cell Rna Profiling Reveals Adipocyte To Macrophage Signaling Sufficient To Enhance Thermogenesis, Felipe Henriques, Alexander H. Bedard, Adilson L. Guilherme, Mark Kelly, Lawrence M. Lifshitz, Karl D. Bellve, Leslie A. Rowland, Batuhan Yenilmez, Shreya Kumar, Yetao Wang, Jeremy Luban, Michael P. Czech 2020 University of Massachusetts Medical School

Single-Cell Rna Profiling Reveals Adipocyte To Macrophage Signaling Sufficient To Enhance Thermogenesis, Felipe Henriques, Alexander H. Bedard, Adilson L. Guilherme, Mark Kelly, Lawrence M. Lifshitz, Karl D. Bellve, Leslie A. Rowland, Batuhan Yenilmez, Shreya Kumar, Yetao Wang, Jeremy Luban, Michael P. Czech

Open Access Publications by UMMS Authors

Adipocytes deficient in fatty acid synthase (iAdFASNKO) emit signals that mimic cold exposure to enhance the appearance of thermogenic beige adipocytes in mouse inguinal white adipose tissues (iWATs). Both cold exposure and iAdFASNKO upregulate the sympathetic nerve fiber (SNF) modulator Neuregulin 4 (Nrg4), activate SNFs, and require adipocyte cyclic AMP/protein kinase A (cAMP/PKA) signaling for beige adipocyte appearance, as it is blocked by adipocyte Gsalpha deficiency. Surprisingly, however, in contrast to cold-exposed mice, neither iWAT denervation nor Nrg4 loss attenuated adipocyte browning in iAdFASNKO mice. Single-cell transcriptomic analysis of iWAT stromal cells revealed increased macrophages displaying gene expression ...


An Atlas Of Cell Types In The Mouse Epididymis And Vas Deferens, Vera D. Rinaldi, Elisa Donnard, Kyle Gellatly, Morten Rasmussen, Alper Kucukural, Onur Yukselen, Manuel Garber, Upasna Sharma, Oliver J. Rando 2020 University of Massachusetts Medical School

An Atlas Of Cell Types In The Mouse Epididymis And Vas Deferens, Vera D. Rinaldi, Elisa Donnard, Kyle Gellatly, Morten Rasmussen, Alper Kucukural, Onur Yukselen, Manuel Garber, Upasna Sharma, Oliver J. Rando

University of Massachusetts Medical School Faculty Publications

Following testicular spermatogenesis, mammalian sperm continue to mature in a long epithelial tube known as the epididymis, which plays key roles in remodeling sperm protein, lipid, and RNA composition. To understand the roles for the epididymis in reproductive biology, we generated a single-cell atlas of the murine epididymis and vas deferens. We recovered key epithelial cell types including principal cells, clear cells, and basal cells, along with associated support cells that include fibroblasts, smooth muscle, macrophages and other immune cells. Moreover, our data illuminate extensive regional specialization of principal cell populations across the length of the epididymis. In addition to ...


Regulation Of The Mammalian Swi/Snf Family Of Chromatin Remodeling Enzymes By Phosphorylation During Myogenesis, Teresita Padilla-Benavides, Pablo Reyes-Gutierrez, Anthony N. Imbalzano 2020 University of Massachusetts Medical School

Regulation Of The Mammalian Swi/Snf Family Of Chromatin Remodeling Enzymes By Phosphorylation During Myogenesis, Teresita Padilla-Benavides, Pablo Reyes-Gutierrez, Anthony N. Imbalzano

University of Massachusetts Medical School Faculty Publications

Myogenesis is the biological process by which skeletal muscle tissue forms. Regulation of myogenesis involves a variety of conventional, epigenetic, and epigenomic mechanisms that control chromatin remodeling, DNA methylation, histone modification, and activation of transcription factors. Chromatin remodeling enzymes utilize ATP hydrolysis to alter nucleosome structure and/or positioning. The mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) family of chromatin remodeling enzymes is essential for myogenesis. Here we review diverse and novel mechanisms of regulation of mSWI/SNF enzymes by kinases and phosphatases. The integration of classic signaling pathways with chromatin remodeling enzyme function impacts myoblast viability and proliferation as well ...


Cd4 Deficiency Causes Poliomyelitis And Axonal Blebbing In Murine Coronavirus-Induced Neuroinflammation., Debanjana Chakravarty, Fareeha Saadi, Soumya Kundu, Abhishek Bose, Reas Khan, Kimberly Dine, Lawrence C Kenyon, Kenneth S Shindler, Jayasri Das Sarma 2020 Indian Institute of Science Education and Research

Cd4 Deficiency Causes Poliomyelitis And Axonal Blebbing In Murine Coronavirus-Induced Neuroinflammation., Debanjana Chakravarty, Fareeha Saadi, Soumya Kundu, Abhishek Bose, Reas Khan, Kimberly Dine, Lawrence C Kenyon, Kenneth S Shindler, Jayasri Das Sarma

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Mouse hepatitis virus (MHV) is a murine betacoronavirus (m-CoV) that causes a wide range of diseases in mice and rats, including hepatitis, enteritis, respiratory diseases, and encephalomyelitis in the central nervous system (CNS). MHV infection in mice provides an efficient cause-effect experimental model to understand the mechanisms of direct virus-induced neural-cell damage leading to demyelination and axonal loss, which are pathological features of multiple sclerosis (MS), the most common disabling neurological disease in young adults. Infiltration of T lymphocytes, activation of microglia, and their interplay are the primary pathophysiological events leading to disruption of the myelin sheath in MS. However ...


Luteinizing Hormone Action In Human Oocyte Maturation And Quality: Signaling Pathways, Regulation, And Clinical Impact, Armando Arroyo, Beomsu Kim, John Yeh 2020 SUNY Upstate Medical University

Luteinizing Hormone Action In Human Oocyte Maturation And Quality: Signaling Pathways, Regulation, And Clinical Impact, Armando Arroyo, Beomsu Kim, John Yeh

Open Access Publications by UMMS Authors

The ovarian follicle luteinizing hormone (LH) signaling molecules that regulate oocyte meiotic maturation have recently been identified. The LH signal reduces preovulatory follicle cyclic nucleotide levels which releases oocytes from the first meiotic arrest. In the ovarian follicle, the LH signal reduces cyclic nucleotide levels via the CNP/NPR2 system, the EGF/EGF receptor network, and follicle/oocyte gap junctions. In the oocyte, reduced cyclic nucleotide levels activate the maturation promoting factor (MPF). The activated MPF induces chromosome segregation and completion of the first and second meiotic divisions. The purpose of this paper is to present an overview of the ...


The Current Neuroscientific Understanding Of Alzheimer's Disease, Rachel A. Brandes 2020 University of Tennessee, Knoxville

The Current Neuroscientific Understanding Of Alzheimer's Disease, Rachel A. Brandes

Pursuit - The Journal of Undergraduate Research at The University of Tennessee

Alzheimer’s disease is a degenerative neurological illness characterized by the deterioration of brain regions implicated in memory and cognitive function. While researchers have yet to find a cure or effective treatment, they have gained a better understanding of its pathology and development. Through years of neuroscience research, scientists have discovered much of what happens in the brain during Alzheimer’s disease onset and how this causes its symptoms; many hypotheses regarding this aspect of the illness involve temporal lobe atrophy, neurofibrillary tangles, and amyloid plaques. Although Alzheimer’s disease affects millions of people every day, it seems that most ...


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