Digital Commons Network^™

Conditional Ablation Of Hdac3 In Islet Beta Cells Results In Glucose Intolerance And Enhanced Susceptibility To Stz-Induced Diabetes, Wen-Bin Chen, Ling Gao, Jie Wang, Yan-Gang Wang, Zheng Dong, Jiajun Zhao, Qing-Sheng Mi, Li Zhou

Dermatology Articles

Histone deacetylases (HDACs) are enzymes that regulate gene expression by modifying chromatin structure through removal of acetyl groups from target histones or non-histone proteins. Previous in vitro studies suggest that HDACs may be novel pharmacological targets in immune-mediated islet β-cell destruction. However, the role of specific HDAC in islet β-cell development and function remain unclear. Here, we generated a conditional islet β-cells specific HDAC3 deletion mouse model to determine the consequences of HDAC3 depletion on islet β-cell differentiation, maintenance and function. Islet morphology, insulin secretion, glucose tolerance, and multiple low-dose streptozotocin (STZ)-induced diabetes incidence were evaluated and compared between HDAC3 …

Design, Development And Evaluation Of A Compact Telerobotic Catheter Navigation System., Mohammad Ali Tavallaei, Daniel Gelman, Michael Konstantine Lavdas, Allan C Skanes, Douglas L Jones, Jeffrey S Bax, Maria Drangova

Medical Biophysics Publications

BACKGROUND: Remote catheter navigation systems protect interventionalists from scattered ionizing radiation. However, these systems typically require specialized catheters and extensive operator training.

METHODS: A new compact and sterilizable telerobotic system is described, which allows remote navigation of conventional tip-steerable catheters, with three degrees of freedom, using an interface that takes advantage of the interventionalist's existing dexterity skills. The performance of the system is evaluated ex vivo and in vivo for remote catheter navigation and ablation delivery.

RESULTS: The system has absolute errors of 0.1 ± 0.1 mm and 7 ± 6° over 100 mm of axial motion and 360° of …

A Quantitative Comparison Of The Hemispheric, Areal, And Laminar Origins Of Sensory And Motor Cortical Projections To The Superior Colliculus Of The Cat., Blake E Butler, Nicole Chabot, Stephen G Lomber

Brain and Mind Institute Researchers' Publications

The superior colliculus (SC) is a midbrain structure central to orienting behaviors. The organization of descending projections from sensory cortices to the SC has garnered much attention; however, rarely have projections from multiple modalities been quantified and contrasted, allowing for meaningful conclusions within a single species. Here, we examine corticotectal projections from visual, auditory, somatosensory, motor, and limbic cortices via retrograde pathway tracers injected throughout the superficial and deep layers of the cat SC. As anticipated, the majority of cortical inputs to the SC originate in the visual cortex. In fact, each field implicated in visual orienting behavior makes a …

Chemical Modification Of Extracellular Matrix By Cold Atmospheric Plasma-Generated Reactive Species Affects Chondrogenesis And Bone Formation., Peter Eisenhauer, Natalie Chernets, You Song, Danil Dobrynin, Nancy Pleshko, Marla J Steinbeck, Theresa A. Freeman

Department of Orthopaedic Surgery Faculty Papers

The goal of this study was to investigate whether cold plasma generated by dielectric barrier discharge (DBD) modifies extracellular matrices (ECM) to influence chondrogenesis and endochondral ossification. Replacement of cartilage by bone during endochondral ossification is essential in fetal skeletal development, bone growth and fracture healing. Regulation of this process by the ECM occurs through matrix remodelling, involving a variety of cell attachment molecules and growth factors, which influence cell morphology and protein expression. The commercially available ECM, Matrigel, was treated with microsecond or nanosecond pulsed (μsp or nsp, respectively) DBD frequencies conditions at the equivalent frequencies (1 kHz) or …

Adam17 Substrate Release In Proximal Tubule Drives Kidney Fibrosis, Eirini Kefaloyianni, Muthu Lakshmi Muthu, Jakob Kaeppler, Xiaoming Sun, Venkata Sabbisetti, Athena Chalaris, Stefan Rose-John, Eitan Wong, Irit Sagi, Sushrut S. Waikar, Helmut Rennke, Benjamin D. Humphreys, Joseph V. Bonventre, Andreas Herrlich

Open Access Publications

Kidney fibrosis following kidney injury is an unresolved health problem and causes significant morbidity and mortality worldwide. In a study into its molecular mechanism, we identified essential causative features. Acute or chronic kidney injury causes sustained elevation of a disintegrin and metalloprotease 17 (ADAM17); of its cleavage-activated proligand substrates, in particular of pro-TNFα and the EGFR ligand amphiregulin (pro-AREG); and of the substrates' receptors. As a consequence, EGFR is persistently activated and triggers the synthesis and release of proinflammatory and profibrotic factors, resulting in macrophage/neutrophil ingress and fibrosis. ADAM17 hypomorphic mice, specific ADAM17 inhibitor-treated WT mice, or mice with inducible …

Lipophosphoglycans From Leishmania Amazonensis Strains Display Immunomodulatory Properties Via Tlr4 And Do Not Affect Sand Fly Infection, Paula M. Nogueira, Rafael R. Assis, Ana C. Torrecilhas, Elvira M. Saraiva, Natália L. Pessoa, Marco A. Campos, Eric F. Marialva, Cláudia M. Ríos-Velasquez, Felipe A. Pessoa, Nágila F. Secundino, Jerônimo N. Rugani, Elsa Nieves, Salvatore J. Turco, Maria N. Melo, Rodrigo P. Soares

Molecular and Cellular Biochemistry Faculty Publications

The immunomodulatory properties of lipophosphoglycans (LPG) from New World species of Leishmania have been assessed in Leishmania infantum and Leishmania braziliensis, the causative agents of visceral and cutaneous leishmaniasis, respectively. This glycoconjugate is highly polymorphic among species with variation in sugars that branch off the conserved Gal(β1,4)Man(α1)-PO₄ backbone of repeat units. Here, the immunomodulatory activity of LPGs from Leishmania amazonensis, the causative agent of diffuse cutaneous leishmaniasis, was evaluated in two strains from Brazil. One strain (PH8) was originally isolated from the sand fly and the other (Josefa) was isolated from a human case. The ability of …

Mitochondrial Akt Regulation Of Hypoxic Tumor Reprogramming., Young Chan Chae, Valentina Vaira, M. Cecilia Caino, Hsin-Yao Tang, Jae Ho Seo, Andrew V. Kossenkov, Luisa Ottobrini, Cristina Martelli, Giovanni Lucignani, Irene Bertolini, Marco Locatelli, Kelly G. Bryant, Jagadish C. Ghosh, Sofia Lisanti, Bonsu Ku, Silvano Bosari, Lucia R. Languino, David W. Speicher, Dario C. Altieri

Department of Cancer Biology Faculty Papers

Hypoxia is a universal driver of aggressive tumor behavior, but the underlying mechanisms are not completely understood. Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex. In turn, this pathway switches tumor metabolism toward glycolysis, antagonizes apoptosis and autophagy, dampens oxidative stress, and maintains tumor cell proliferation in the face of severe hypoxia. Mitochondrial Akt-PDK1 signaling correlates with unfavorable prognostic markers and shorter survival in glioma patients and may provide an "actionable" therapeutic target in cancer.

Integrated Molecular Pathway Analysis Informs A Synergistic Combination Therapy Targeting Pten/Pi3k And Egfr Pathways For Basal-Like Breast Cancer, Qing-Bai She, Sofia K. Gruvberger-Saal, Matthew Maurer, Yilun Chen, Mervi Jumppanen, Tao Su, Meaghan Dendy, Ying-Ka Ingar Lau, Lorenzo Memeo, Hugo M. Horlings, Marc J. Van De Vijver, Jorma Isola, Hanina Hibshoosh, Neal Rosen, Ramon Parsons, Lao H. Saal

Markey Cancer Center Faculty Publications

Background: The basal-like breast cancer (BLBC) subtype is characterized by positive staining for basal mammary epithelial cytokeratin markers, lack of hormone receptor and HER2 expression, and poor prognosis with currently no approved molecularly-targeted therapies. The oncogenic signaling pathways driving basal-like tumorigenesis are not fully elucidated.

Methods: One hundred sixteen unselected breast tumors were subjected to integrated analysis of phosphoinositide 3-kinase (PI3K) pathway related molecular aberrations by immunohistochemistry, mutation analysis, and gene expression profiling. Incidence and relationships between molecular biomarkers were characterized. Findings for select biomarkers were validated in an independent series. Synergistic cell killing in vitro and in vivo tumor …

Simultaneous Quantitation Of Oxidized And Reduced Glutathione Via Lc-Ms/Ms: An Insight Into The Redox State Of Hematopoietic Stem Cells, Dustin W. Carroll, Diana Howard, Haining Zhu, Christian M. Paumi, Mary Vore, Subbarao Bondada, Ying Liang, Chi Wang, Daret K. St. Clair

Toxicology and Cancer Biology Faculty Publications

Cellular redox balance plays a significant role in the regulation of hematopoietic stem-progenitor cell (HSC/MPP) self-renewal and differentiation. Unregulated changes in cellular redox homeostasis are associated with the onset of most hematological disorders. However, accurate measurement of the redox state in stem cells is difficult because of the scarcity of HSC/MPPs. Glutathione (GSH) constitutes the most abundant pool of cellular antioxidants. Thus, GSH metabolism may play a critical role in hematological disease onset and progression. A major limitation to studying GSH metabolism in HSC/MPPs has been the inability to measure quantitatively GSH concentrations in small numbers of HSC/MPPs. Current methods …

Multiple Mechanisms For Processing Reward Uncertainty In The Primate Basal Forebrain, Noah M. Ledbetter, Charles D. Chen, Ilya E. Monosov

Open Access Publications

UNLABELLED: The ability to use information about the uncertainty of future outcomes is critical for adaptive behavior in an uncertain world. We show that the basal forebrain (BF) contains at least two distinct neural-coding strategies to support this capacity. The dorsal-lateral BF, including the ventral pallidum (VP), contains reward-sensitive neurons, some of which are selectively suppressed by uncertain-reward predictions (U(-)). In contrast, the medial BF (mBF) contains reward-sensitive neurons, some of which are selectively enhanced (U(+)) by uncertain-reward predictions. In a two-alternative choice-task, U(-) neurons were selectively suppressed while monkeys chose uncertain options over certain options. During the same choice-epoch, …

Phenotypes Associated With Knockouts Of Eight Dense Granule Gene Loci (Gra2-9) In Virulent Toxoplasma Gondii, Leah M. Rommereim, Valeria Bellini, Barbara A. Fox, Graciane Pètre, Camille Rak, Bastien Touquet, Delphine Aldebert, Jean-François Dubremetz, Marie-France Cesbron-Delauw, Corinne Mercier, David J. Bzik

Dartmouth Scholarship

Toxoplasma gondii actively invades host cells and establishes a parasitophorous vacuole (PV) that accumulates many proteins secreted by the dense granules (GRA proteins). To date, at least 23 GRA proteins have been reported, though the function(s) of most of these proteins still remains unknown. We targeted gene knockouts at ten GRA gene loci (GRA1-10) to investigate the cellular roles and essentiality of these classical GRA proteins during acute infection in the virulent type I RH strain. While eight of these genes (GRA2-9) were successfully knocked out, targeted knockouts at the GRA1 and GRA10 loci were not …

Secretion Of Rhoptry And Dense Granule Effector Proteins By Nonreplicating Toxoplasma Gondii Uracil Auxotrophs Controls The Development Of Antitumor Immunity, Barbara A. Fox, Kiah L. Sanders, Leah M. Rommereim, Rebekah B. Guevara, David J. Bzik

Dartmouth Scholarship

Nonreplicating type I uracil auxotrophic mutants of Toxoplasma gondii possess a potent ability to activate therapeutic immunity to established solid tumors by reversing immune suppression in the tumor microenvironment. Here we engineered targeted deletions of parasite secreted effector proteins using a genetically tractable Δku80 vaccine strain to show that the secretion of specific rhoptry (ROP) and dense granule (GRA) proteins by uracil auxotrophic mutants of T. gondii in conjunction with host cell invasion activates antitumor immunity through host responses involving CD8α⁺ dendritic cells, the IL-12/interferon-gamma (IFN-γ) T_H1 axis, as well as CD4⁺ and CD8 …

Suboptimal Choice In Pigeons: Stimulus Value Predicts Choice Over Frequencies, Aaron P. Smith, Alexandria R. Bailey, Jonathan J. Chow, Joshua S. Beckmann, Thomas R. Zentall

Psychology Faculty Publications

Pigeons have shown suboptimal gambling-like behavior when preferring a stimulus that infrequently signals reliable reinforcement over alternatives that provide greater reinforcement overall. As a mechanism for this behavior, recent research proposed that the stimulus value of alternatives with more reliable signals for reinforcement will be preferred relatively independently of their frequencies. The present study tested this hypothesis using a simplified design of a Discriminative alternative that, 50% of the time, led to either a signal for 100% reinforcement or a blackout period indicative of 0% reinforcement against a Nondiscriminative alternative that always led to a signal that predicted 50% reinforcement. …

Repeated Closed Head Injury In Mice Results In Sustained Motor And Memory Deficits And Chronic Cellular Changes, Amanda Nicholle Bolton Hall, Binoy Joseph, Jennifer M. Brelsfoard, Kathryn E. Saatman

Spinal Cord and Brain Injury Research Center Faculty Publications

Millions of mild traumatic brain injuries (TBIs) occur every year in the United States, with many people subject to multiple head injuries that can lead to chronic behavioral dysfunction. We previously reported that mild TBI induced using closed head injuries (CHI) repeated at 24h intervals produced more acute neuron death and glial reactivity than a single CHI, and increasing the length of time between injuries to 48h reduced the cumulative acute effects of repeated CHI. To determine whether repeated CHI is associated with behavioral dysfunction or persistent cellular damage, mice receiving either five CHI at 24h intervals, five CHI at …

Detection Of Zoonotic Enteropathogens In Children And Domestic Animals In A Semirural Community In Ecuador., Karla Vasco, Jay P Graham, Gabriel Trueba

Environmental and Occupational Health Faculty Publications

UNLABELLED: Animals are important reservoirs of zoonotic enteropathogens, and transmission to humans occurs more frequently in low- and middle-income countries (LMICs), where small-scale livestock production is common. In this study, we investigated the presence of zoonotic enteropathogens in stool samples from 64 asymptomatic children and 203 domestic animals of 62 households in a semirural community in Ecuador between June and August 2014. Multilocus sequence typing (MLST) was used to assess zoonotic transmission of Campylobacter jejuni and atypical enteropathogenic Escherichia coli (aEPEC), which were the most prevalent bacterial pathogens in children and domestic animals (30.7% and 10.5%, respectively). Four sequence types …

Are Animals Persons?, Mark Rowlands

Animal Sentience

It is orthodox to suppose that very few, if any, nonhuman animals are persons. The category “person” is restricted to self-aware creatures: humans (above a certain age) and possibly some of the great apes and cetaceans. I argue that this orthodoxy should be rejected, because it rests on a mistaken conception of the kind of self-awareness relevant to personhood. Replacing this with a sense of self-awareness that is relevant requires us to accept that personhood is much more widely distributed through the animal kingdom.

Bioturbation By The Fungus-Gardening Ant, Trachymyrmex Septentrionalis, Walter R. Tschinkel, Jon N. Seal

Biology Faculty Publications and Presentations

Soil invertebrates such as ants are thought to be important manipulators of soils in temperate and tropical ecosystems. The fungus gardening ant, Trachymyrmex septentrionalis, is an important agent of biomantling, that is, of depositing soil excavated from below onto the surface, and has been suggested as an agent of bioturbation (moving soil below ground) as well. The amount of bioturbation by this ant was quantified by planting queenright colonies in sand columns consisting of 5 layers of different colored sand. The amount of each color of sand deposited on the surface was determined from April to November 2015. In November, …

Honey, Wax, And The Dead Bee, Keith Botelho

Early Modern Culture

No abstract provided.

Red-Shifted Aequorin Variants Incorporating Non-Canonical Amino Acids: Applications In In Vivo Imaging, Kristen M. Grinstead, Laura Rowe, Mark Ensor, Smita Joel, Pirouz Daftarian, Emre Dikici, Jean-Marc Zingg, Sylvia Daunert

Pharmaceutical Sciences Faculty Publications

The increased importance of in vivo diagnostics has posed new demands for imaging technologies. In that regard, there is a need for imaging molecules capable of expanding the applications of current state-of-the-art imaging in vivo diagnostics. To that end, there is a desire for new reporter molecules capable of providing strong signals, are non-toxic, and can be tailored to diagnose or monitor the progression of a number of diseases. Aequorin is a non-toxic photoprotein that can be used as a sensitive marker for bioluminescence in vivo imaging. The sensitivity of aequorin is due to the fact that bioluminescence is a …

Structure And Functions Of Angiotensinogen, Hong Lu, Lisa A. Cassis, Craig W. Vander Kooi, Alan Daugherty

Saha Cardiovascular Research Center Faculty Publications

Angiotensinogen (AGT) is the sole precursor of all angiotensin peptides. Although AGT is generally considered as a passive substrate of the renin–angiotensin system, there is accumulating evidence that the regulation and functions of AGT are intricate. Understanding the diversity of AGT properties has been enhanced by protein structural analysis and animal studies. In addition to whole-body genetic deletion, AGT can be regulated in vivo by cell-specific procedures, adeno-associated viral approaches and antisense oligonucleotides. Indeed, the availability of these multiple manipulations of AGT in vivo has provided new insights into the multifaceted roles of AGT. In this review, the combination of …

The Salicylic Acid-Mediated Release Of Plant Volatiles Affects The Host Choice Of Bemisia Tabaci, Xiaobin Shi, Gong Chen, Lixia Tian, Zhengke Peng, Wen Xie, Qingjun Wu, Shaoli Wang, Xuguo Zhou, Youjun Zhang

Entomology Faculty Publications

The whitefly Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) causes serious crop losses worldwide by transmitting viruses. We have previously shown that salicylic acid (SA)-related plant defenses directly affect whiteflies. In this study, we applied exogenous SA to tomato plants in order to investigate the interaction between SA-induced plant volatiles and nonviruliferous B. tabaci B and Q or B- and Q-carrying tomato yellow leaf curl virus (TYLCV). The results showed that exogenous SA caused plants to repel nonviruliferous whiteflies, but the effect was reduced when the SA concentration was low and when the whiteflies were viruliferous. Exogenous SA increased the number and …

20-Hydroxyecdysone (20e) Primary Response Gene E75 Isoforms Mediate Steroidogenesis Autoregulation And Regulate Developmental Timing In Bombyx, Kang Li, Ling Tian, Zhongjian Guo, Sanyou Guo, Jianzhen Zhang, Shi-Hong Gu, Subba Reddy Palli, Yang Cao, Sheng Li

Entomology Faculty Publications

The temporal control mechanisms that precisely control animal development remain largely elusive. The timing of major developmental transitions in insects, including molting and metamorphosis, is coordinated by the steroid hormone 20-hydroxyecdysone (20E). 20E involves feedback loops to maintain pulses of ecdysteroid biosynthesis leading to its upsurge, whereas the underpinning molecular mechanisms are not well understood. Using the silkworm Bombyx mori as a model, we demonstrated that E75, the 20E primary response gene, mediates a regulatory loop between ecdysteroid biosynthesis and 20E signaling. E75 isoforms A and C directly bind to retinoic acid receptor-related response elements in Halloween gene promoter …

Introduction: Fabulous Animals, Holly Dugan, Karl Steel

Early Modern Culture

No abstract provided.

Enter The Dragon: Desire And Meaning In A True And Wonderfull Encounter, Jan Stirm

Early Modern Culture

No abstract provided.

Cellular And Molecular Features Of Developmentally Programmed Genome Rearrangement In A Vertebrate (Sea Lamprey: Petromyzon Marinus), Vladimir A. Timoshevskiy, Joseph R. Herdy, Melissa C. Keinath, Jeramiah J. Smith

Biology Faculty Publications

The sea lamprey (Petromyzon marinus) represents one of the few vertebrate species known to undergo large-scale programmatic elimination of genomic DNA over the course of its normal development. Programmed genome rearrangements (PGRs) result in the reproducible loss of ~20% of the genome from somatic cell lineages during early embryogenesis. Studies of PGR hold the potential to provide novel insights related to the maintenance of genome stability during the cell cycle and coordination between mechanisms responsible for the accurate distribution of chromosomes into daughter cells, yet little is known regarding the mechanistic basis or cellular context of PGR in …

Age- And Sex-Related Changes In Fasting Plasma Glucose And Lipoprotein In Cynomolgus Monkeys, Feng Yue, Guodong Zhang, Rongping Tang, Zhouquan Zhang, Liqiong Teng, Zhiming Zhang

Neuroscience Faculty Publications

Background: The age-related dysfunction of glucose and lipid metabolism has a long-standing relationship with cardiovascular and neurodegenerative disease. However, the effects of metabolic dysfunction on men and women are different. Reasons for these sex differences remains unclear. Cynomolgus monkeys have been used, in the past, for the study of human metabolic diseases due to their biologically proximity to humans. Nevertheless, few studies to date have focused on both age- and sex-related differences in glucose and lipid metabolism. The present study was designed to specifically address these questions by using a large cohort of cynomolgus monkeys (N = 1,399) including …

Mutation Linked To Autosomal Dominant Nocturnal Frontal Lobe Epilepsy Reduces Low-Sensitivity Α4Β2, And Increases Α5Α4Β2, Nicotinic Receptor Surface Expression, Weston A. Nichols, Brandon J. Henderson, Christopher B. Marotta, Caroline Y. Yu, Chris Richards, Dennis A. Dougherty, Henry A. Lester, Bruce N. Cohen

Chemistry Faculty Publications

A number of mutations in α4β2-containing (α4β2*) nicotinic acetylcholine (ACh) receptors (nAChRs) are linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), including one in the β2 subunit called β2V287L. Two α4β2* subtypes with different subunit stoichiometries and ACh sensitivities co-exist in the brain, a high-sensitivity subtype with (α4)₂(β2)₃ subunit stoichiometry and a low-sensitivity subtype with (α4)₃(β2)₂ stoichiometry. The α5 nicotinic subunit also co-assembles with α4β2 to form a high-sensitivity α5α4β2 nAChR. Previous studies suggest that the β2V287L mutation suppresses low-sensitivity α4β2* nAChR expression in a knock-in mouse model and also that α5 co-expression …

Sine-Wave Electrical Stimulation Initiates A Voltage-Gated Potassium Channel-Dependent Soft Tissue Response Characterized By Induction Of Hemocyte Recruitment And Collagen Deposition, Brandon M. Franklin, Eleni Maroudas, Jeffrey L. Osborn

Biology Faculty Publications

Soft tissue repair is a complex process that requires specific communication between multiple cell types to orchestrate effective restoration of physiological functions. Macrophages play a critical role in this wound healing process beginning at the onset of tissue injury. Understanding the signaling mechanisms involved in macrophage recruitment to the wound site is an essential step for developing more effective clinical therapies. Macrophages are known to respond to electrical fields, but the underlying cellular mechanisms mediating this response is unknown. This study demonstrated that low‐amplitude sine‐wave electrical stimulation (ES) initiates a soft tissue response in the absence of injury in Procambarus …

Using Diffusion Tractography To Predict Cortical Connection Strength And Distance: A Quantitative Comparison With Tracers In The Monkey, Chad J. Donahue, Stamatios N. Sotiropoulos, Saad Jbabdi, Moises Hernandez-Fernandez, Timothy E. Behrens, Tim B. Dyrby, Timothy Coalson, Henry Kennedy, Kenneth Knoblauch, David C. Van Essen, Matthew F. Glasser

Open Access Publications

UNLABELLED: Tractography based on diffusion MRI offers the promise of characterizing many aspects of long-distance connectivity in the brain, but requires quantitative validation to assess its strengths and limitations. Here, we evaluate tractography's ability to estimate the presence and strength of connections between areas of macaque neocortex by comparing its results with published data from retrograde tracer injections. Probabilistic tractography was performed on high-quality postmortem diffusion imaging scans from two Old World monkey brains. Tractography connection weights were estimated using a fractional scaling method based on normalized streamline density. We found a correlation between log-transformed tractography and tracer connection weights …

Staphylococcus Aureus Coordinates Leukocidin Expression And Pathogenesis By Sensing Metabolic Fluxes Via Rpirc, Divya Balasubramanian, Elizabeth A Ohneck, Jessica Chapman, Andy Weiss, Min Kyung Kim, Tamara Reyes-Robles, Judy Zhong, Lindsey N. Shaw, Desmond S. Lun, Beatrix Ueberheide, Bo Shopsin, Victor J Torres

Molecular Biosciences Faculty Publications

Staphylococcus aureus is a formidable human pathogen that uses secreted cytolytic factors to injure immune cells and promote infection of its host. Of these proteins, the bicomponent family of pore-forming leukocidins play critical roles in S. aureus pathogenesis. The regulatory mechanisms governing the expression of these toxins are incompletely defined. In this work, we performed a screen to identify transcriptional regulators involved in leukocidin expression in S. aureus strain USA300. We discovered that a metabolic sensor-regulator, RpiRc, is a potent and selective repressor of two leukocidins, LukED and LukSF-PV. Whole-genome transcriptomics, S. aureus exoprotein proteomics, and metabolomic analyses revealed that …