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The Janus Kinase 1 Is Critical For Pancreatic Cancer Initiation And Progression, Hridaya Shrestha, Patrick Rädler, Rayane Dennaoui, Madison Wicker, Nirakar Rajbhandari, Yunguang Sun, Amy Peck, Kerry Vistisen, Aleata Triplett, Rafic Beydoun, Esta Sterneck, Dieter Saur, Hallgeir Rui, Kay-Uwe Wagner
The Janus Kinase 1 Is Critical For Pancreatic Cancer Initiation And Progression, Hridaya Shrestha, Patrick Rädler, Rayane Dennaoui, Madison Wicker, Nirakar Rajbhandari, Yunguang Sun, Amy Peck, Kerry Vistisen, Aleata Triplett, Rafic Beydoun, Esta Sterneck, Dieter Saur, Hallgeir Rui, Kay-Uwe Wagner
Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers
Interleukin-6 (IL-6)-class inflammatory cytokines signal through the Janus tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT) pathway and promote the development of pancreatic ductal adenocarcinoma (PDAC); however, the functions of specific intracellular signaling mediators in this process are less well defined. Using a ligand-controlled and pancreas-specific knockout in adult mice, we demonstrate in this study that JAK1 deficiency prevents the formation of KRASG12D-induced pancreatic tumors, and we establish that JAK1 is essential for the constitutive activation of STAT3, whose activation is a prominent characteristic of PDAC. We identify CCAAT/enhancer binding protein δ (C/EBPδ) as a biologically relevant …
T-Cell Redirecting Bispecific Antibodies: A Review Of A Novel Class Of Immuno-Oncology For Advanced Prostate Cancer, Julia Palecki, Amman Bhasin, Andrew Bernstein, Patrick Mille, William Tester, William Kelly, Kevin Zarrabi
T-Cell Redirecting Bispecific Antibodies: A Review Of A Novel Class Of Immuno-Oncology For Advanced Prostate Cancer, Julia Palecki, Amman Bhasin, Andrew Bernstein, Patrick Mille, William Tester, William Kelly, Kevin Zarrabi
Kimmel Cancer Center Faculty Papers
Novel T-cell immunotherapies such as bispecific T-cell engagers (BiTEs) are emerging as promising therapeutic strategies for prostate cancer. BiTEs are engineered bispecific antibodies containing two distinct binding domains that allow for concurrent binding to tumor-associated antigens (TAAs) as well as immune effector cells, thus promoting an immune response against cancer cells. Prostate cancer is rich in tumor associated antigens such as, but not limited to, PSMA, PSCA, hK2, and STEAP1 and there is strong biologic rationale for employment of T-cell redirecting BiTEs within the prostate cancer disease space. Early generation BiTE constructs employed in clinical study have demonstrated meaningful antitumor …
Operation Shark: Addressing The Negative Portrayal Of Sharks In Media, Michael R. O'Shea
Operation Shark: Addressing The Negative Portrayal Of Sharks In Media, Michael R. O'Shea
Masters Theses
Sharks are some of the most well adapted and effective animals in the animal kingdom. Unfortunately, they are also some of the most feared. For many people the word shark evokes images of vicious attacks like those seen in movies such as Jaws. Sharks have also been negatively portrayed in the media. This negative portrayal of sharks has led to misconceptions about sharks that have damaged their populations. Efforts have been made to raise awareness and fight common misconceptions of sharks. However, many people still hold on to the incorrect ideas they have about sharks. This thesis will examine the …
Chronic Stress-Induced Neuroinflammation: Relevance Of Rodent Models To Human Disease., Abigail G White, Elias Elias, Andrea Orozco, Shivon A Robinson, Melissa T Manners
Chronic Stress-Induced Neuroinflammation: Relevance Of Rodent Models To Human Disease., Abigail G White, Elias Elias, Andrea Orozco, Shivon A Robinson, Melissa T Manners
Faculty Scholarship for the College of Science & Mathematics
The brain is the central organ of adaptation to stress because it perceives and determines threats that induce behavioral, physiological, and molecular responses. In humans, chronic stress manifests as an enduring consistent feeling of pressure and being overwhelmed for an extended duration. This can result in a persistent proinflammatory response in the peripheral and central nervous system (CNS), resulting in cellular, physiological, and behavioral effects. Compounding stressors may increase the risk of chronic-stress-induced inflammation, which can yield serious health consequences, including mental health disorders. This review summarizes the current knowledge surrounding the neuroinflammatory response in rodent models of chronic stress-a …
Decorin Suppresses Tumor Lymphangiogenesis: A Mechanism To Curtail Cancer Progression, Dipon K. Mondal, Christopher Xie, Gabriel J. Pascal, Simone Buraschi, Renato V. Iozzo
Decorin Suppresses Tumor Lymphangiogenesis: A Mechanism To Curtail Cancer Progression, Dipon K. Mondal, Christopher Xie, Gabriel J. Pascal, Simone Buraschi, Renato V. Iozzo
Kimmel Cancer Center Faculty Papers
The complex interplay between malignant cells and the cellular and molecular components of the tumor stroma is a key aspect of cancer growth and development. These tumor-host interactions are often affected by soluble bioactive molecules such as proteoglycans. Decorin, an archetypical small leucine-rich proteoglycan primarily expressed by stromal cells, affects cancer growth in its soluble form by interacting with several receptor tyrosine kinases (RTK). Overall, decorin leads to a context-dependent and protracted cessation of oncogenic RTK activity by attenuating their ability to drive a prosurvival program and to sustain a proangiogenic network. Through an unbiased transcriptomic analysis using deep RNAseq, …
Monophosphoryl Lipid A-Based Adjuvant To Promote The Immunogenicity Of Multivalent Meningococcal Polysaccharide Conjugate Vaccines, Kishore Alugupalli
Monophosphoryl Lipid A-Based Adjuvant To Promote The Immunogenicity Of Multivalent Meningococcal Polysaccharide Conjugate Vaccines, Kishore Alugupalli
Department of Microbiology and Immunology Faculty Papers
Activation of the adaptive immune system requires the engagement of costimulatory pathways in addition to B and T cell Ag receptor signaling, and adjuvants play a central role in this process. Many Gram-negative bacterial polysaccharide vaccines, including the tetravalent meningococcal conjugate vaccines (MCV4) and typhoid Vi polysaccharide vaccines, do not incorporate adjuvants. The immunogenicity of typhoid vaccines is due to the presence of associated TLR4 ligands in these vaccines. Because the immunogenicity of MCV4 is poor and requires boosters, I hypothesized that TLR4 ligands are absent in MCV4 and that incorporation of a TLR4 ligand-based adjuvant would improve their immunogenicity. …
Biomarkers For Managing Neurodegenerative Diseases, Lara Cheslow, Adam E. Snook, Scott A. Waldman
Biomarkers For Managing Neurodegenerative Diseases, Lara Cheslow, Adam E. Snook, Scott A. Waldman
Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers
Neurological disorders are the leading cause of cognitive and physical disability worldwide, affecting 15% of the global population. Due to the demographics of aging, the prevalence of neurological disorders, including neurodegenerative diseases, will double over the next two decades. Unfortunately, while available therapies provide symptomatic relief for cognitive and motor impairment, there is an urgent unmet need to develop disease-modifying therapies that slow the rate of pathological progression. In that context, biomarkers could identify at-risk and prodromal patients, monitor disease progression, track responses to therapy, and parse the causality of molecular events to identify novel targets for further clinical investigation. …
Soil Nutrient Redistribution Pattern About The Tree In A Silvopastoral System, L C. Nwaigbo, H G. Miller, A R. Sibbald, G Hudson
Soil Nutrient Redistribution Pattern About The Tree In A Silvopastoral System, L C. Nwaigbo, H G. Miller, A R. Sibbald, G Hudson
IGC Proceedings (1997-2023)
The objective of this paper is to report the effect of animal-tree interactions on soil nutrient redistribution pattern in a grazed silvopastoral experiment site at Glensaugh, in NE Scotland. Scots pine (Pinus sylvestris L) tree species were planted in square lattice arrangements at 5 m x 5 m, spacing (400 stems/ha) on plots replicated over three blocks in Randomized Complete Block design on a predominantly rye grass (Lolium perenne L) pasture which was grazed by sheep yearly from April to October. Included in the design were grazed pasture plots without trees (Control). Soil samples were collected from around …
Trees For Shelter: The Implications In Agroforestry System, L C. Nwaigbo, A R. Sibbald, G Hudson
Trees For Shelter: The Implications In Agroforestry System, L C. Nwaigbo, A R. Sibbald, G Hudson
IGC Proceedings (1997-2023)
The objective of this study was to determine the horizontal and vertical variations in soil penetration resistance (PR) observed at tree-scale in silvopastoral plots that were grazed by sheep with and without trees. Sycamore trees (Acer pseudoplatanus L) were planted in the spring of 1988 at 10 m x 10 m spacing (100 stems/ha) at Glensaugh NE of Scotland on plots replicated over three blocks in Randomized Complete Block design on a predominantly rye grass (Lolium perenne L) pasture. Included in the design were pasture plots without trees (Control). The experiment is grazed by sheep yearly from April to …
Species Delimitation, Discovery And Conservation In A Tiger Beetle Species Complex Despite Discordant Genetic Data., Daniel P. Duran, Robert A Laroche, Stephen J Roman, William Godwin, David P Herrmann, Ethan Bull, Scott P Egan
Species Delimitation, Discovery And Conservation In A Tiger Beetle Species Complex Despite Discordant Genetic Data., Daniel P. Duran, Robert A Laroche, Stephen J Roman, William Godwin, David P Herrmann, Ethan Bull, Scott P Egan
School of Earth & Environment Faculty Scholarship
In an age of species declines, delineating and discovering biodiversity is critical for both taxonomic accuracy and conservation. In recent years, there has been a movement away from using exclusively morphological characters to delineate and describe taxa and an increase in the use of molecular markers to describe diversity or through integrative taxonomy, which employs traditional morphological characters, as well as genetic or other data. Tiger beetles are charismatic, of conservation concern, and much work has been done on the morphological delineation of species and subspecies, but few of these taxa have been tested with genetic analyses. In this study, …
Differentially Disrupted Spinal Cord And Muscle Energy Metabolism In Spinal And Bulbar Muscular Atrophy, Danielle Debartolo, Frederick Arnold, Y Liu, Elana Molotsky, Hsin-Yao Tang, Diane Merry
Differentially Disrupted Spinal Cord And Muscle Energy Metabolism In Spinal And Bulbar Muscular Atrophy, Danielle Debartolo, Frederick Arnold, Y Liu, Elana Molotsky, Hsin-Yao Tang, Diane Merry
Department of Biochemistry and Molecular Biology Faculty Papers
Prior studies showed that polyglutamine-expanded androgen receptor (AR) is aberrantly acetylated and that deacetylation of the mutant AR by overexpression of nicotinamide adenine dinucleotide-dependent (NAD+-dependent) sirtuin 1 is protective in cell models of spinal and bulbar muscular atrophy (SBMA). Based on these observations and reduced NAD+ in muscles of SBMA mouse models, we tested the therapeutic potential of NAD+ restoration in vivo by treating postsymptomatic transgenic SBMA mice with the NAD+ precursor nicotinamide riboside (NR). NR supplementation failed to alter disease progression and had no effect on increasing NAD+ or ATP content in muscle, despite producing a modest increase of …
Current Strategies For Increasing Knock-In Efficiency In Crispr/Cas9-Based Approaches, Andrés Felipe Leal, Angelica María Herreno-Pachón, Eliana Benincore-Flórez, Amali Karunathilaka, Shunji Tomatsu
Current Strategies For Increasing Knock-In Efficiency In Crispr/Cas9-Based Approaches, Andrés Felipe Leal, Angelica María Herreno-Pachón, Eliana Benincore-Flórez, Amali Karunathilaka, Shunji Tomatsu
Department of Pediatrics Faculty Papers
Since its discovery in 2012, the clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) system has supposed a promising panorama for developing novel and highly precise genome editing-based gene therapy (GT) alternatives, leading to overcoming the challenges associated with classical GT. Classical GT aims to deliver transgenes to the cells via their random integration in the genome or episomal persistence into the nucleus through lentivirus (LV) or adeno-associated virus (AAV), respectively. Although high transgene expression efficiency is achieved by using either LV or AAV, their nature can result in severe side effects in humans. For instance, …
Protecting Human And Animal Health: The Road From Animal Models To New Approach Methods, Barbara L F Kaplan, Alan M Hoberman, William Slikker, Mary Alice Smith, Emanuela Corsini, Thomas B Knudsen, M Sue Marty, Sonya K Sobrian, Suzanne C Fitzpatrick, Marcia H Ratner, Donna L Mendrick
Protecting Human And Animal Health: The Road From Animal Models To New Approach Methods, Barbara L F Kaplan, Alan M Hoberman, William Slikker, Mary Alice Smith, Emanuela Corsini, Thomas B Knudsen, M Sue Marty, Sonya K Sobrian, Suzanne C Fitzpatrick, Marcia H Ratner, Donna L Mendrick
Journal Articles
Animals and animal models have been invaluable for our current understanding of human and animal biology, including physiology, pharmacology, biochemistry, and disease pathology. However, there are increasing concerns with continued use of animals in basic biomedical, pharmacological, and regulatory research to provide safety assessments for drugs and chemicals. There are concerns that animals do not provide sufficient information on toxicity and/or efficacy to protect the target population, so scientists are utilizing the principles of replacement, reduction, and refinement (the 3Rs) and increasing the development and application of new approach methods (NAMs). NAMs are any technology, methodology, approach, or assay used …
Birds, Bats And Minds. Tales Of A Revolutionary Scientist: Donald R. Griffin. Volume One, Carolyn A. Ristau
Birds, Bats And Minds. Tales Of A Revolutionary Scientist: Donald R. Griffin. Volume One, Carolyn A. Ristau
eBooks
In this three-volume biography, we revisit the life and accomplishments of the revolutionary scientist, Donald R. Griffin. He encountered a lifetime of initial hostile resistance to his ideas and studies; now they are largely accepted. He and a colleague discovered the phenomenon of echolocation used by bats to navigate and capture insects, proposed that birds navigate guided by such cues as the sun and stars, and suggested that animals are likely aware, thinking and feeling beings. Forty interviews with his colleagues and friends help us understand the young emerging scientist and the mature researcher. We learn about his and others’ …
Comparative Animal Mucomics, Antonio R. Cerullo
Comparative Animal Mucomics, Antonio R. Cerullo
Dissertations, Theses, and Capstone Projects
Mucus is one of Nature’s most abundant and versatile biomaterials. These secretions are present in all animals, from the lowly garden snail to the great blue whale, and fulfill a multitude of functions, acting as antimicrobial barriers, moisturizers, adhesive glues, surface lubricants, and mineralizing agents. Despite their importance, very little is known about mucus compositions or properties. The largest challenge precluding the greater understanding of mucus function is its complexity; a single mucus contains complex mixtures of proteins, glycans, and ions that all have important roles in function. Therefore, understanding mucus function necessitates analysis that compares different mucus from one …
Secreted Igm Modulates Il-10 Expression In B Cells, Shannon Mcgettigan, Lazaro Aira, Gaurav Kumar, Romain Ballet, Eugene Butcher, Nicole Baumgarth, Gudrun Debes
Secreted Igm Modulates Il-10 Expression In B Cells, Shannon Mcgettigan, Lazaro Aira, Gaurav Kumar, Romain Ballet, Eugene Butcher, Nicole Baumgarth, Gudrun Debes
Department of Microbiology and Immunology Faculty Papers
IL-10+ B cells are critical for immune homeostasis and restraining immune responses in infection, cancer, and inflammation; however, the signals that govern IL-10+ B cell differentiation are ill-defined. Here we find that IL-10+ B cells expand in mice lacking secreted IgM ((s)IgM–/–) up to 10-fold relative to wildtype (WT) among all major B cell and regulatory B cell subsets. The IL-10+ B cell increase is polyclonal and presents within 24 hours of birth. In WT mice, sIgM is produced prenatally and limits the expansion of IL-10+ B cells. Lack of the high affinity …
Listeria Adhesion Protein Orchestrates Caveolae-Mediated Apical Junctional Remodeling Of Epithelial Barrier For Listeria Monocytogenes Translocation, Rishi Drolia, Donald B. Bryant, Shivendra Tenguria, Zuri A. Jules-Culver, Jessie Thind, Breanna Amelunke, Donqi Liu, Nicholas L. F. Gallina, Krishna K. Mishra, Manalee Samaddar, Manoj R. Sawale, Dharmendra K. Mishra, Abigail D. Cox, Arun K. Bhunia
Listeria Adhesion Protein Orchestrates Caveolae-Mediated Apical Junctional Remodeling Of Epithelial Barrier For Listeria Monocytogenes Translocation, Rishi Drolia, Donald B. Bryant, Shivendra Tenguria, Zuri A. Jules-Culver, Jessie Thind, Breanna Amelunke, Donqi Liu, Nicholas L. F. Gallina, Krishna K. Mishra, Manalee Samaddar, Manoj R. Sawale, Dharmendra K. Mishra, Abigail D. Cox, Arun K. Bhunia
Biological Sciences Faculty Publications
The cellular junctional architecture remodeling by Listeria adhesion protein-heat shock protein 60 (LAP-Hsp60) interaction for Listeria monocytogenes (Lm) passage through the epithelial barrier is incompletely understood. Here, using the gerbil model, permissive to internalin (Inl) A/B-mediated pathways like in humans, we demonstrate that Lm crosses the intestinal villi at 48 h post-infection. In contrast, the single isogenic (lap− or ΔinlA) or double (lap−ΔinlA) mutant strains show significant defects. LAP promotes Lm translocation via endocytosis of cell-cell junctional complex in enterocytes that do not display luminal E-cadherin. In comparison, InlA facilitates …
Fused In Sarcoma Regulates Glutamate Signaling And Oxidative Stress Response, Chiong-Hee Wong, Abu Rahat, Howard C Chang
Fused In Sarcoma Regulates Glutamate Signaling And Oxidative Stress Response, Chiong-Hee Wong, Abu Rahat, Howard C Chang
Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship
Mutations in fused in sarcoma (fust-1) are linked to ALS. However, how these ALS causative mutations alter physiological processes and lead to the onset of ALS remains largely unknown. By obtaining humanized fust-1 ALS mutations via CRISPR-CAS9, we generated a C. elegans ALS model. Homozygous fust-1 ALS mutant and fust-1 deletion animals are viable in C. elegans. This allows us to better characterize the molecular mechanisms of fust-1-dependent responses. We found FUST-1 plays a role in regulating superoxide dismutase, glutamate signaling, and oxidative stress. FUST-1 suppresses SOD-1 and VGLUT/EAT-4 in the nervous system. FUST-1 also regulates synaptic AMPA-type glutamate receptor …
Needle Biopsy Accelerates Pro-Metastatic Changes And Systemic Dissemination In Breast Cancer: Implications For Mortality By Surgery Delay, Hiroyasu Kameyama, Priya Dondapati, Reese Simmons, Macall Leslie, John Langenheim, Yunguang Sun, Misung Yi, Aubrey Rottschaefer, Rashmi Pathak, Shreya Nuguri, Kar-Ming Fung, Shirng-Wern Tsaih, Inna Chervoneva, Hallgeir Rui, Takemi Tanaka
Needle Biopsy Accelerates Pro-Metastatic Changes And Systemic Dissemination In Breast Cancer: Implications For Mortality By Surgery Delay, Hiroyasu Kameyama, Priya Dondapati, Reese Simmons, Macall Leslie, John Langenheim, Yunguang Sun, Misung Yi, Aubrey Rottschaefer, Rashmi Pathak, Shreya Nuguri, Kar-Ming Fung, Shirng-Wern Tsaih, Inna Chervoneva, Hallgeir Rui, Takemi Tanaka
Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers
ncreased breast cancer (BC) mortality risk posed by delayed surgical resection of tumor after diagnosis is a growing concern, yet the underlying mechanisms remain unknown. Our cohort analyses of early-stage BC patients reveal the emergence of a significantly rising mortality risk when the biopsy-to-surgery interval was extended beyond 53 days. Additionally, histology of post-biopsy tumors shows prolonged retention of a metastasis-permissive wound stroma dominated by M2-like macrophages capable of promoting cancer cell epithelial-to-mesenchymal transition and angiogenesis. We show that needle biopsy promotes systemic dissemination of cancer cells through a mechanism of sustained activation of the COX-2/PGE2/EP2 feedforward loop, …
Nucleus Accumbens Core Single Cell Ensembles Bidirectionally Respond To Experienced Versus Observed Aversive Events, Oyku Dinckol, Noah Harris Wenger, Jennifer E Zachry, Munir Gunes Kutlu
Nucleus Accumbens Core Single Cell Ensembles Bidirectionally Respond To Experienced Versus Observed Aversive Events, Oyku Dinckol, Noah Harris Wenger, Jennifer E Zachry, Munir Gunes Kutlu
Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship
Fear learning is a critical feature of survival skills among mammals. In rodents, fear learning manifests itself through direct experience of the aversive event or social transmission of aversive stimuli such as observing and acting on conspecifics' distress. The neuronal network underlying the social transmission of information largely overlaps with the brain regions that mediate behavioral responses to aversive and rewarding stimuli. In this study, we recorded single cell activity patterns of nucleus accumbens (NAc) core neurons using in vivo optical imaging of calcium transients via miniature scopes. This cutting-edge imaging methodology not only allows us to record activity patterns …
Dna Barcoding Indicates Multiple Invasions Of The Freshwater Snail Melanoides Tuberculata Sensu Lato In Florida, Lori Tolley-Jordan, Michael A. Chadwick, Jimmy K. Triplett
Dna Barcoding Indicates Multiple Invasions Of The Freshwater Snail Melanoides Tuberculata Sensu Lato In Florida, Lori Tolley-Jordan, Michael A. Chadwick, Jimmy K. Triplett
Research, Publications & Creative Work
Melanoides tuberculata sensu lato (Thiaridae) are polymorphic female-clonal snails of Asian and African origins that have invaded freshwaters worldwide, including those in Florida. Although the snails have been documented in Florida for at least 70 years, no studies have investigated whether the observed distribution is due to a single introduction or multiple independent invasions. Here, cytochrome oxidase I was used to measure genetic diversity within and among sites in Florida and compare genetic diversity between Florida and other regions of the world. We also examined the relationship between shell morphology and haplotype diversity to determine if shell morphs can serve …
Neutralizing Antibodies Against Ebv Gp42 Show Potent In Vivo Protection And Define Novel Epitopes, Qian Wu, Ling Zhong, Dongmei Wei, Wanlin Zhang, Junping Hong, Yinfeng Kang, Kaiyun Chen, Yang Huang, Qingbing Zheng, Miao Xu, Mu-Sheng Zeng, Yi-Xin Zeng, Ningshao Xia, Qinjian Zhao, Claude Krummenacher, Yixin Chen, Xiao Zhang
Neutralizing Antibodies Against Ebv Gp42 Show Potent In Vivo Protection And Define Novel Epitopes, Qian Wu, Ling Zhong, Dongmei Wei, Wanlin Zhang, Junping Hong, Yinfeng Kang, Kaiyun Chen, Yang Huang, Qingbing Zheng, Miao Xu, Mu-Sheng Zeng, Yi-Xin Zeng, Ningshao Xia, Qinjian Zhao, Claude Krummenacher, Yixin Chen, Xiao Zhang
Faculty Scholarship for the College of Science & Mathematics
Epstein-Barr virus (EBV) is the first reported human oncogenic virus and infects more than 95% of the human population worldwide. EBV latent infection in B lymphocytes is essential for viral persistence. Glycoprotein gp42 is an indispensable member of the triggering complex for EBV entry into B cells. The C-type lectin domain (CTLD) of gp42 plays a key role in receptor binding and is the major target of neutralizing antibodies. Here, we isolated two rabbit antibodies, 1A7 and 6G7, targeting gp42 CTLD with potent neutralizing activity against B cell infection. Antibody 6G7 efficiently protects humanized mice from lethal EBV challenge and …
Trehalose Enhances Mitochondria Deficits In Human Npc1 Mutant Fibroblasts But Disrupts Mouse Purkinje Cell Dendritic Growth Ex Vivo., Collin M Macleod, Fawad A K Yousufzai, Liam T Spencer, Sarah Kim, Lucianne A Rivera-Rosario, Zerian D Barrera, Lindsay Walsh, Claude Krummenacher, Benjamin Carone, Ileana Soto
Trehalose Enhances Mitochondria Deficits In Human Npc1 Mutant Fibroblasts But Disrupts Mouse Purkinje Cell Dendritic Growth Ex Vivo., Collin M Macleod, Fawad A K Yousufzai, Liam T Spencer, Sarah Kim, Lucianne A Rivera-Rosario, Zerian D Barrera, Lindsay Walsh, Claude Krummenacher, Benjamin Carone, Ileana Soto
Faculty Scholarship for the College of Science & Mathematics
Lysosomes play important roles in catabolism, nutrient sensing, metabolic signaling, and homeostasis. NPC1 deficiency disrupts lysosomal function by inducing cholesterol accumulation that leads to early neurodegeneration in Niemann-Pick type C (NPC) disease. Mitochondria pathology and deficits in NPC1 deficient cells are associated with impaired lysosomal proteolysis and metabolic signaling. It is thought that activation of the transcription factor TFEB, an inducer of lysosome biogenesis, restores lysosomal-autophagy activity in lysosomal storage disorders. Here, we investigated the effect of trehalose, a TFEB activator, in the mitochondria pathology of NPC1 mutant fibroblasts in vitro and in mouse developmental Purkinje cells ex vivo. We …
Dietary L-Tryptophan Consumption Determines The Number Of Colonic Regulatory T Cells And Susceptibility To Colitis Via Gpr15, Nguyen Van, Karen Zhang, Rachel Wigmore, Anne Kennedy, Carolina Dasilva, Jialing Huang, Manju Ambelil, Jose Villagomez, Gerald O'Connor, Randy Longman, Miao Cao, Adam Snook, Michael Platten, Gerard Kasenty, Luis Sigal, George C Prendergast, Sangwon Kim
Dietary L-Tryptophan Consumption Determines The Number Of Colonic Regulatory T Cells And Susceptibility To Colitis Via Gpr15, Nguyen Van, Karen Zhang, Rachel Wigmore, Anne Kennedy, Carolina Dasilva, Jialing Huang, Manju Ambelil, Jose Villagomez, Gerald O'Connor, Randy Longman, Miao Cao, Adam Snook, Michael Platten, Gerard Kasenty, Luis Sigal, George C Prendergast, Sangwon Kim
Department of Microbiology and Immunology Faculty Papers
Environmental factors are the major contributor to the onset of immunological disorders such as ulcerative colitis. However, their identities remain unclear. Here, we discover that the amount of consumed L-Tryptophan (L-Trp), a ubiquitous dietary component, determines the transcription level of the colonic T cell homing receptor, GPR15, hence affecting the number of colonic FOXP3+ regulatory T (Treg) cells and local immune homeostasis. Ingested L-Trp is converted by host IDO1/2 enzymes, but not by gut microbiota, to compounds that induce GPR15 transcription preferentially in Treg cells via the aryl hydrocarbon receptor. Consequently, two weeks of dietary L-Trp supplementation nearly double …
Novel Treatments For Pxe: Targeting The Systemic And Local Drivers Of Ectopic Calcification, Ida Joely Jacobs, Qiaoli Li
Novel Treatments For Pxe: Targeting The Systemic And Local Drivers Of Ectopic Calcification, Ida Joely Jacobs, Qiaoli Li
Department of Biochemistry and Molecular Biology Faculty Papers
Pseudoxanthoma elasticum (PXE) is a heritable multisystem ectopic calcification disorder. The gene responsible for PXE, ABCC6, encodes ABCC6, a hepatic efflux transporter regulating extracellular inorganic pyrophosphate (PPi), a potent endogenous calcification inhibitor. Recent studies demonstrated that in addition to the deficiency of plasma PPi, the activated DDR/PARP signaling in calcified tissues provides an additional possible mechanism of ectopic calcification in PXE. This study examined the effects of etidronate (ETD), a stable PPi analog, and its combination with minocycline (Mino), a potent inhibitor of DDR/PARP, on ectopic calcification in an Abcc6-/- mouse model of PXE. Abcc6-/- mice, at 4 weeks of …
Tmem27 Suppresses Tumor Development By Promoting Ret Ubiquitination, Positioning, And Degradation, Qianjin Guo, Zi-Ming Cheng, Hector Gonzalez-Cantú, Matthew Rotondi, Gabriela Huelgas-Morales, Purushoth Ethiraj, Zhijun Qiu, Jonathan Lefkowitz, Wan Song, Bethany N Landry, Hector Lopez, Cynthia M Estrada-Zuniga, Shivi Goyal, Mohammad Aasif Khan, Timothy J Walker, Exing Wang, Faqian Li, Yanli Ding, Lois M Mulligan, Ricardo C T Aguiar, Patricia L M Dahia
Tmem27 Suppresses Tumor Development By Promoting Ret Ubiquitination, Positioning, And Degradation, Qianjin Guo, Zi-Ming Cheng, Hector Gonzalez-Cantú, Matthew Rotondi, Gabriela Huelgas-Morales, Purushoth Ethiraj, Zhijun Qiu, Jonathan Lefkowitz, Wan Song, Bethany N Landry, Hector Lopez, Cynthia M Estrada-Zuniga, Shivi Goyal, Mohammad Aasif Khan, Timothy J Walker, Exing Wang, Faqian Li, Yanli Ding, Lois M Mulligan, Ricardo C T Aguiar, Patricia L M Dahia
Journal Articles
The TMEM127 gene encodes a transmembrane protein of poorly known function that is mutated in pheochromocytomas, neural crest-derived tumors of adrenomedullary cells. Here, we report that, at single-nucleus resolution, TMEM127-mutant tumors share precursor cells and transcription regulatory elements with pheochromocytomas carrying mutations of the tyrosine kinase receptor RET. Additionally, TMEM127-mutant pheochromocytomas, human cells, and mouse knockout models of TMEM127 accumulate RET and increase its signaling. TMEM127 contributes to RET cellular positioning, trafficking, and lysosome-mediated degradation. Mechanistically, TMEM127 binds to RET and recruits the NEDD4 E3 ubiquitin ligase for RET ubiquitination and degradation via TMEM127 C-terminal PxxY motifs. Lastly, increased cell …
Illegal Shooting Is Now A Leading Cause Of Death Of Birds Along Power Lines In The Western Usa, Eve C. Thomason, Natalie J. S. Turley, James R. Belthoff, Tara J. Conkling, Todd E. Katzner
Illegal Shooting Is Now A Leading Cause Of Death Of Birds Along Power Lines In The Western Usa, Eve C. Thomason, Natalie J. S. Turley, James R. Belthoff, Tara J. Conkling, Todd E. Katzner
Biology Faculty Publications and Presentations
Human actions, both legal and illegal, affect wildlife in many ways. Inaccurate diagnosis of cause of death undermines law enforcement, management, threat assessment, and mitigation. We found 410 dead birds collected along 196 km of power lines in four western USA states during 2019–2022. We necropsied these carcasses to test conventional wisdom suggesting that electrocution is the leading cause of death of birds at electrical infrastructure. Of 175 birds with a known cause of death, 66% died from gunshot. Both raptors and corvids were more likely to die from gunshot than from other causes, along both transmission and distribution lines. …
The Gpcr-Gαs-Pka Signaling Axis Promotes T Cell Dysfunction And Cancer Immunotherapy Failure, Victoria H Wu, Bryan S Yung, Farhoud Faraji, Robert Saddawi-Konefka, Zhiyong Wang, Alexander T Wenzel, Miranda J Song, Meghana S Pagadala, Lauren M Clubb, Joshua Chiou, Sanju Sinha, Marin Matic, Francesco Raimondi, Thomas S Hoang, Rebecca Berdeaux, Dario A A Vignali, Ramiro Iglesias-Bartolome, Hannah Carter, Eytan Ruppin, Jill P Mesirov, J Silvio Gutkind
The Gpcr-Gαs-Pka Signaling Axis Promotes T Cell Dysfunction And Cancer Immunotherapy Failure, Victoria H Wu, Bryan S Yung, Farhoud Faraji, Robert Saddawi-Konefka, Zhiyong Wang, Alexander T Wenzel, Miranda J Song, Meghana S Pagadala, Lauren M Clubb, Joshua Chiou, Sanju Sinha, Marin Matic, Francesco Raimondi, Thomas S Hoang, Rebecca Berdeaux, Dario A A Vignali, Ramiro Iglesias-Bartolome, Hannah Carter, Eytan Ruppin, Jill P Mesirov, J Silvio Gutkind
Journal Articles
Immune checkpoint blockade (ICB) targeting PD-1 and CTLA-4 has revolutionized cancer treatment. However, many cancers do not respond to ICB, prompting the search for additional strategies to achieve durable responses. G-protein-coupled receptors (GPCRs) are the most intensively studied drug targets but are underexplored in immuno-oncology. Here, we cross-integrated large singe-cell RNA-sequencing datasets from CD8+ T cells covering 19 distinct cancer types and identified an enrichment of Gαs-coupled GPCRs on exhausted CD8+ T cells. These include EP2, EP4, A2AR, β1AR and β2AR, all of which promote T cell dysfunction. We also developed transgenic mice expressing a chemogenetic CD8-restricted Gαs–DREADD to activate …
Structures Of Channelrhodopsin Paralogs In Peptidiscs Explain Their Contrasting K+ And Na+ Selectivities, Takefumi Morizumi, Kyumhyuk Kim, Hai Li, Elena G Govorunova, Oleg A Sineshchekov, Yumei Wang, Lei Zheng, Éva Bertalan, Ana-Nicoleta Bondar, Azam Askari, Leonid S Brown, John L Spudich, Oliver P Ernst
Structures Of Channelrhodopsin Paralogs In Peptidiscs Explain Their Contrasting K+ And Na+ Selectivities, Takefumi Morizumi, Kyumhyuk Kim, Hai Li, Elena G Govorunova, Oleg A Sineshchekov, Yumei Wang, Lei Zheng, Éva Bertalan, Ana-Nicoleta Bondar, Azam Askari, Leonid S Brown, John L Spudich, Oliver P Ernst
Journal Articles
Kalium channelrhodopsin 1 from Hyphochytrium catenoides (HcKCR1) is a light-gated channel used for optogenetic silencing of mammalian neurons. It selects K+ over Na+ in the absence of the canonical tetrameric K+ selectivity filter found universally in voltage- and ligand-gated channels. The genome of H. catenoides also encodes a highly homologous cation channelrhodopsin (HcCCR), a Na+ channel with >100-fold larger Na+ to K+ permeability ratio. Here, we use cryo-electron microscopy to determine atomic structures of these two channels embedded in peptidiscs to elucidate structural foundations of their dramatically different cation selectivity. Together with structure-guided mutagenesis, we show that K+ versus Na+ …
Invited Review: Adrenocortical Function In Avian And Non-Avian Reptiles: Insights From Dispersed Adrenocortical Cells., Rocco V. Carsia, Patrick J. Mcilroy, Henry B John-Alder
Invited Review: Adrenocortical Function In Avian And Non-Avian Reptiles: Insights From Dispersed Adrenocortical Cells., Rocco V. Carsia, Patrick J. Mcilroy, Henry B John-Alder
Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship
Herein we review our work involving dispersed adrenocortical cells from several lizard species: the Eastern Fence Lizard (Sceloporus undulatus), Yarrow's Spiny Lizard (Sceloporus jarrovii), Striped Plateau Lizard (Sceloporus virgatus) and the Yucatán Banded Gecko (Coleonyx elegans). Early work demonstrated changes in steroidogenic function of adrenocortical cells derived from adult S. undulatus associated with seasonal interactions with sex. However, new information suggests that both sexes operate within the same steroidogenic budget over season. The observed sex effect was further explored in orchiectomized and ovariectomized lizards, some supported with exogenous testosterone. Overall, a suppressive effect of testosterone was evident, especially in cells …