Publications by authors named "Amanda Burton"

40 Publications

Comparing telehealth to traditional office visits for patient management in the COVID-19 pandemic: A cross-sectional study in a respiratory assessment clinic.

J Telemed Telecare 2021 Feb 1:1357633X21990197. Epub 2021 Feb 1.

Wake Forest School of Medicine, Wake Forest Baptist Health, USA.

Introduction: The aim of this study was to examine whether telehealth is as safe and effective as traditional office visits in assessing and treating patients with symptoms consistent with COVID-19.

Methods: In this retrospective cross-sectional study, the primary outcome was any 14-day related healthcare follow-up event(s). Secondary outcomes were the type of 14-day related follow-up event including hospital admission, emergency department visit, office visit, telehealth visit and/or multiple follow-up visits. Individual visit types were identified due to the significant difference between a hospital admission and an office visit. Logistic regressions were done using the predictors of visit type, age, gender and comorbidities and the primary outcome variable of a related follow-up visit and then by follow-up type: hospital admission, emergency department visit or office visit.

Results: Of 1305 visits, median age was 42.3 years and 65.8% were female. Traditional office visits accounted for 741 (56.8%) of initial visits, while 564 (43.2%) visits occurred via telehealth. One hundred and forty-six (25.9%) of the telehealth visits resulted in a 14-day related healthcare follow-up visit versus 161 (21.7%) of the office visits (adjusted odds ratio (OR) 1.22, 95% CI 0.94-1.58).

Discussion: There was no significant difference in related follow-ups of initial telehealth visits compared to initial office visits including no significant difference in hospital admission or emergency department visits. These findings suggest that based on follow up healthcare utilization, telehealth may be a safe and effective option in assessing and treating patients with respiratory symptoms as the COVID-19 pandemic continues.
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http://dx.doi.org/10.1177/1357633X21990197DOI Listing
February 2021

Regulatory T Cell-Derived TRAIL Is Not Required for Peripheral Tolerance.

Immunohorizons 2021 Jan 22;5(1):48-58. Epub 2021 Jan 22.

Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;

TRAIL (/TRAIL/CD253/Apo2L) is an important immune molecule that mediates apoptosis. TRAIL can play key roles in regulating cell death in the tumor and autoimmune microenvironments. However, dissecting TRAIL function remains difficult because of the lack of optimal models. We have now generated a conditional knockout () for cell type-specific analysis of TRAIL function on C57BL/6, BALB/c, and NOD backgrounds. Previous studies have suggested a role for TRAIL in regulatory T cell (T)-mediated suppression. We generated mice with a T-restricted deletion and surprisingly found no impact on tumor growth in C57BL/6 and BALB/c tumor models. Furthermore, we found no difference in the suppressive capacity of -deficient T and no change in function or proliferation of T cells in tumors. We also assessed the role of TRAIL on T in two autoimmune mouse models: the NOD mouse model of autoimmune diabetes and the myelin oligodendrocyte glycoprotein (MOG) C57BL/6 model of experimental autoimmune encephalomyelitis. We found that deletion of on T had no effect on disease progression in either model. We conclude that T do not appear to be dependent on TRAIL exclusively as a mechanism of suppression in both the tumor and autoimmune microenvironments, although it remains possible that TRAIL may contribute in combination with other mechanisms and/or in different disease settings. Our conditional knockout mouse should prove to be a useful tool for the dissection of TRAIL function on different cell populations in multiple mouse models of human disease.
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http://dx.doi.org/10.4049/immunohorizons.2000098DOI Listing
January 2021

RIPK1 Distinctly Regulates -Induced Inflammatory Cell Death, PANoptosis.

Immunohorizons 2020 Dec 11;4(12):789-796. Epub 2020 Dec 11.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105

Bacterial pathogens from the genus cause fatal sepsis and gastritis in humans. Innate immune signaling and inflammatory cell death (pyroptosis, apoptosis, and necroptosis [PANoptosis]) serve as a first line of antimicrobial host defense. The receptor-interacting protein kinase 1 (RIPK1) is essential for -induced pyroptosis and apoptosis and an effective host response. However, it is not clear whether RIPK1 assembles a multifaceted cell death complex capable of regulating caspase-dependent pyroptosis and apoptosis or whether there is cross-talk with necroptosis under these conditions. In this study, we report that activates PANoptosis, as evidenced by the concerted activation of proteins involved in PANoptosis. Genetic deletion of RIPK1 abrogated the -induced activation of the inflammasome/pyroptosis and apoptosis but enhanced necroptosis. We also found that induced assembly of a RIPK1 PANoptosome complex capable of regulating all three branches of PANoptosis. Overall, our results demonstrate a role for the RIPK1 PANoptosome in -induced inflammatory cell death and host defense.
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http://dx.doi.org/10.4049/immunohorizons.2000097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906112PMC
December 2020

ZBP1 promotes fungi-induced inflammasome activation and pyroptosis, apoptosis, and necroptosis (PANoptosis).

J Biol Chem 2020 Dec 27;295(52):18276-18283. Epub 2020 Oct 27.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

are dangerous fungal pathogens with high morbidity and mortality, particularly in immunocompromised patients. Innate immune-mediated programmed cell death (pyroptosis, apoptosis, necroptosis) is an integral part of host defense against pathogens. Inflammasomes, which are canonically formed upstream of pyroptosis, have been characterized as key mediators of fungal sensing and drivers of proinflammatory responses. However, the specific cell death pathways and key upstream sensors activated in the context of and infections are unknown. Here, we report that and infection induced inflammatory programmed cell death in the form of pyroptosis, apoptosis, and necroptosis (PANoptosis). Further, we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as the apical sensor of fungal infection responsible for activating the inflammasome/pyroptosis, apoptosis, and necroptosis. The Zα2 domain of ZBP1 was required to promote this inflammasome activation and PANoptosis. Overall, our results demonstrate that and induce PANoptosis and that ZBP1 plays a vital role in inflammasome activation and PANoptosis in response to fungal pathogens.
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http://dx.doi.org/10.1074/jbc.RA120.015924DOI Listing
December 2020

Impaired NLRP3 inflammasome activation/pyroptosis leads to robust inflammatory cell death via caspase-8/RIPK3 during coronavirus infection.

J Biol Chem 2020 10 6;295(41):14040-14052. Epub 2020 Aug 6.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

Coronaviruses have caused several zoonotic infections in the past two decades, leading to significant morbidity and mortality globally. Balanced regulation of cell death and inflammatory immune responses is essential to promote protection against coronavirus infection; however, the underlying mechanisms that control these processes remain to be resolved. Here we demonstrate that infection with the murine coronavirus mouse hepatitis virus (MHV) activated the NLRP3 inflammasome and inflammatory cell death in the form of PANoptosis. Deleting NLRP3 inflammasome components or the downstream cell death executioner gasdermin D (GSDMD) led to an initial reduction in cell death followed by a robust increase in the incidence of caspase-8- and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated inflammatory cell deathafter coronavirus infection. Additionally, loss of GSDMD promoted robust NLRP3 inflammasome activation. Moreover, the amounts of some cytokines released during coronavirus infection were significantly altered in the absence of GSDMD. Altogether, our findings show that inflammatory cell death, PANoptosis, is induced by coronavirus infection and that impaired NLRP3 inflammasome function or pyroptosis can lead to negative consequences for the host. These findings may have important implications for studies of coronavirus-induced disease.
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http://dx.doi.org/10.1074/jbc.RA120.015036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549031PMC
October 2020

Interferon regulatory factor 1 regulates PANoptosis to prevent colorectal cancer.

JCI Insight 2020 06 18;5(12). Epub 2020 Jun 18.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Interferon regulatory factor 1 (IRF1) regulates diverse biological functions, including modulation of cellular responses involved in tumorigenesis. Genetic mutations and altered IRF1 function are associated with several cancers. Although the function of IRF1 in the immunobiology of cancer is emerging, IRF1-specific mechanisms regulating tumorigenesis and tissue homeostasis in vivo are not clear. Here, we found that mice lacking IRF1 were hypersusceptible to colorectal tumorigenesis. IRF1 functions in both the myeloid and epithelial compartments to confer protection against AOM/DSS-induced colorectal tumorigenesis. We further found that IRF1 also prevents tumorigenesis in a spontaneous mouse model of colorectal cancer. The attenuated cell death in the colons of Irf1-/- mice was due to defective pyroptosis, apoptosis, and necroptosis (PANoptosis). IRF1 does not regulate inflammation and the inflammasome in the colon. Overall, our study identified IRF1 as an upstream regulator of PANoptosis to induce cell death during colitis-associated tumorigenesis.
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http://dx.doi.org/10.1172/jci.insight.136720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406299PMC
June 2020

Identification of the PANoptosome: A Molecular Platform Triggering Pyroptosis, Apoptosis, and Necroptosis (PANoptosis).

Front Cell Infect Microbiol 2020 29;10:237. Epub 2020 May 29.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, United States.

Programmed cell death plays crucial roles in organismal development and host defense. Recent studies have highlighted mechanistic overlaps and extensive, multifaceted crosstalk between pyroptosis, apoptosis, and necroptosis, three programmed cell death pathways traditionally considered autonomous. The growing body of evidence, in conjunction with the identification of molecules controlling the concomitant activation of all three pathways by pathological triggers, has led to the development of the concept of PANoptosis. During PANoptosis, inflammatory cell death occurs through the collective activation of pyroptosis, apoptosis, and necroptosis, which can circumvent pathogen-mediated inhibition of individual death pathways. Many of the molecular details of this emerging pathway are unclear. Here, we describe the activation of PANoptosis by bacterial and viral triggers and report protein interactions that reveal the formation of a PANoptosome complex. Infection of macrophages with influenza A virus, vesicular stomatitis virus, , or serovar Typhimurium resulted in robust cell death and the hallmarks of PANoptosis activation. Combined deletion of the PANoptotic components caspase-1 (CASP1), CASP11, receptor-interacting serine/threonine-protein kinase 3 (RIPK3), and CASP8 largely protected macrophages from cell death induced by these pathogens, while deletion of individual components provided reduced or no protection. Further, molecules from the pyroptotic, apoptotic, and necroptotic cell death pathways interacted to form a single molecular complex that we have termed the PANoptosome. Overall, our study identifies pathogens capable of activating PANoptosis and the formation of a PANoptosome complex.
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http://dx.doi.org/10.3389/fcimb.2020.00237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274033PMC
May 2020

The Zα2 domain of ZBP1 is a molecular switch regulating influenza-induced PANoptosis and perinatal lethality during development.

J Biol Chem 2020 06 29;295(24):8325-8330. Epub 2020 Apr 29.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

Z-DNA-binding protein 1 (ZBP1) is an innate immune sensor of nucleic acids that regulates host defense responses and development. ZBP1 activation triggers inflammation and pyroptosis, necroptosis, and apoptosis (PANoptosis) by activating receptor-interacting Ser/Thr kinase 3 (RIPK3), caspase-8, and the NLRP3 inflammasome. ZBP1 is unique among innate immune sensors because of its N-terminal Zα1 and Zα2 domains, which bind to nucleic acids in the Z-conformation. However, the specific role of these Zα domains in orchestrating ZBP1 activation and subsequent inflammation and cell death is not clear. Here we generated mice that express ZBP1 lacking the Zα2 domain and demonstrate that this domain is critical for influenza A virus-induced PANoptosis and underlies perinatal lethality in mice in which the RIP homotypic interaction motif domain of RIPK1 has been mutated (). Deletion of the Zα2 domain in ZBP1 abolished influenza A virus-induced PANoptosis and NLRP3 inflammasome activation. Furthermore, deletion of the Zα2 domain of ZBP1 was sufficient to rescue mice from perinatal lethality caused by ZBP1-driven cell death and inflammation. Our findings identify the essential role of the Zα2 domain of ZBP1 in several physiological functions and establish a link between Z-RNA sensing via the Zα2 domain and promotion of influenza-induced PANoptosis and perinatal lethality.
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http://dx.doi.org/10.1074/jbc.RA120.013752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294087PMC
June 2020

Ets-2 deletion in myeloid cells attenuates IL-1α-mediated inflammatory disease caused by a Ptpn6 point mutation.

Cell Mol Immunol 2020 Mar 19. Epub 2020 Mar 19.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.

The SHP-1 protein encoded by the Ptpn6 gene has been extensively studied in hematopoietic cells in the context of inflammation. A point mutation in this gene (Ptpn6) causes spontaneous inflammation in mice, which has a striking similarity to neutrophilic dermatoses in humans. Recent findings highlighted the role of signaling adapters and kinases in promoting inflammation in Ptpn6 mice; however, the underlying transcriptional regulation is poorly understood. Here, we report that SYK is important for driving neutrophil infiltration and initiating wound healing responses in Ptpn6 mice. Moreover, we found that deletion of the transcription factor Ets2 in myeloid cells ameliorates cutaneous inflammatory disease in Ptpn6 mice through transcriptional regulation of its target inflammatory genes. Furthermore, Ets-2 drives IL-1α-mediated inflammatory signaling in neutrophils of Ptpn6 mice. Overall, in addition to its well-known role in driving inflammation in cancer, Ets-2 plays a major role in regulating IL-1α-driven Ptpn6-mediated neutrophilic dermatoses. Model for the role of ETS-2 in neutrophilic inflammation in Ptpn6 mice. Mutation of the Ptpn6 gene results in SYK phosphorylation which then sequentially activates MAPK signaling pathways and activation of ETS-2. This leads to activation of ETS-2 target genes that contribute to neutrophil migration and inflammation. When Ets2 is deleted in Ptpn6 mice, the expression of these target genes is reduced, leading to the reduced pathology in neutrophilic dermatoses.
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http://dx.doi.org/10.1038/s41423-020-0398-7DOI Listing
March 2020

Innate immune priming in the absence of TAK1 drives RIPK1 kinase activity-independent pyroptosis, apoptosis, necroptosis, and inflammatory disease.

J Exp Med 2020 03;217(3)

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN.

RIPK1 kinase activity has been shown to be essential to driving pyroptosis, apoptosis, and necroptosis. However, here we show a kinase activity-independent role for RIPK1 in these processes using a model of TLR priming in a TAK1-deficient setting to mimic pathogen-induced priming and inhibition. TLR priming of TAK1-deficient macrophages triggered inflammasome activation, including the activation of caspase-8 and gasdermin D, and the recruitment of NLRP3 and ASC into a novel RIPK1 kinase activity-independent cell death complex to drive pyroptosis and apoptosis. Furthermore, we found fully functional RIPK1 kinase activity-independent necroptosis driven by the RIPK3-MLKL pathway in TAK1-deficient macrophages. In vivo, TAK1 inactivation resulted in RIPK3-caspase-8 signaling axis-driven myeloid proliferation and a severe sepsis-like syndrome. Overall, our study highlights a previously unknown mechanism for RIPK1 kinase activity-independent inflammasome activation and pyroptosis, apoptosis, and necroptosis (PANoptosis) that could be targeted for treatment of TAK1-associated myeloid proliferation and sepsis.
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http://dx.doi.org/10.1084/jem.20191644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062518PMC
March 2020

Prior cocaine self-administration impairs attention signals in anterior cingulate cortex.

Neuropsychopharmacology 2020 04 27;45(5):833-841. Epub 2019 Nov 27.

Department of Psychology, University of Maryland, College Park, MD, 20742, USA.

Although maladaptive decision-making is a defining feature of drug abuse and addiction, we have yet to ascertain how cocaine self-administration disrupts neural signals in anterior cingulate cortex (ACC), a brain region thought to contribute to attentional control. To address this issue, rats were trained on a reward-guided decision-making task; reward value was manipulated by independently varying the size of or the delay to reward over several trial blocks. Subsequently, rats self-administered either a cocaine (experimental group) or sucrose (control) during 12 consecutive days, after which they underwent a 1-month withdrawal period. Upon completion of this period, rats performed the previously learned reward-guided decision-making task while we recorded from single neurons in ACC. We demonstrate that prior cocaine self-administration attenuates attention and attention-related ACC signals in an intake-dependent manner, and that changes in attention are decoupled from ACC firing. These effects likely contribute to the impaired decision-making-typified by chronic substance abuse and relapse-observed after drug use.
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http://dx.doi.org/10.1038/s41386-019-0578-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075947PMC
April 2020

The nonreceptor tyrosine kinase SYK drives caspase-8/NLRP3 inflammasome-mediated autoinflammatory osteomyelitis.

J Biol Chem 2020 03 12;295(11):3394-3400. Epub 2019 Nov 12.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

Chronic recurrent multifocal osteomyelitis (CRMO) in humans can be modeled in mice, which carry a missense mutation in the proline-serine-threonine phosphatase-interacting protein 2 () gene. As disease in mice, the experimental model analogous to human CRMO, is mediated specifically by IL-1β and not by IL-1α, delineating the molecular pathways contributing to pathogenic IL-1β production is crucial to developing targeted therapies. In particular, our earlier findings support redundant roles of NLR family pyrin domain-containing 3 (NLRP3) and caspase-1 with caspase-8 in instigating However, the signaling components upstream of caspase-8 and pro-IL-1β cleavage in mice are not well-understood. Therefore, here we investigated the signaling pathways in these mice and discovered a central role of a nonreceptor tyrosine kinase, spleen tyrosine kinase (SYK), in mediating osteomyelitis. Using several mutant mouse strains, immunoblotting, and microcomputed tomography, we demonstrate that absent in melanoma 2 (AIM2), receptor-interacting serine/ threonine protein kinase 3 (RIPK3), and caspase recruitment domain-containing protein 9 (CARD9) are each dispensable for osteomyelitis induction in mice, whereas genetic deletion of completely abrogates the disease phenotype. We further show that SYK centrally mediates signaling upstream of caspase-1 and caspase-8 activation and principally up-regulates NF-κB and IL-1β signaling in mice, thereby inducing These results provide a rationale for directly targeting SYK and its downstream signaling components in CRMO.
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http://dx.doi.org/10.1074/jbc.RA119.010623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076204PMC
March 2020

DDX3X acts as a live-or-die checkpoint in stressed cells by regulating NLRP3 inflammasome.

Nature 2019 09 11;573(7775):590-594. Epub 2019 Sep 11.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.

The cellular stress response has a vital role in regulating homeostasis by modulating cell survival and death. Stress granules are cytoplasmic compartments that enable cells to survive various stressors. Defects in the assembly and disassembly of stress granules are linked to neurodegenerative diseases, aberrant antiviral responses and cancer. Inflammasomes are multi-protein heteromeric complexes that sense molecular patterns that are associated with damage or intracellular pathogens, and assemble into cytosolic compartments known as ASC specks to facilitate the activation of caspase-1. Activation of inflammasomes induces the secretion of interleukin (IL)-1β and IL-18 and drives cell fate towards pyroptosis-a form of programmed inflammatory cell death that has major roles in health and disease. Although both stress granules and inflammasomes can be triggered by the sensing of cellular stress, they drive contrasting cell-fate decisions. The crosstalk between stress granules and inflammasomes and how this informs cell fate has not been well-studied. Here we show that the induction of stress granules specifically inhibits NLRP3 inflammasome activation, ASC speck formation and pyroptosis. The stress granule protein DDX3X interacts with NLRP3 to drive inflammasome activation. Assembly of stress granules leads to the sequestration of DDX3X, and thereby the inhibition of NLRP3 inflammasome activation. Stress granules and the NLRP3 inflammasome compete for DDX3X molecules to coordinate the activation of innate responses and subsequent cell-fate decisions under stress conditions. Induction of stress granules or loss of DDX3X in the myeloid compartment leads to a decrease in the production of inflammasome-dependent cytokines in vivo. Our findings suggest that macrophages use the availability of DDX3X to interpret stress signals and choose between pro-survival stress granules and pyroptotic ASC specks. Together, our data demonstrate the role of DDX3X in driving NLRP3 inflammasome and stress granule assembly, and suggest a rheostat-like mechanistic paradigm for regulating live-or-die cell-fate decisions under stress conditions.
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http://dx.doi.org/10.1038/s41586-019-1551-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980284PMC
September 2019

Cutting Edge: Dysregulated CARD9 Signaling in Neutrophils Drives Inflammation in a Mouse Model of Neutrophilic Dermatoses.

J Immunol 2018 09 6;201(6):1639-1644. Epub 2018 Aug 6.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105; and

Mice homozygous for the Y208N amino acid substitution in the carboxy terminus of SHP-1 (referred to as mice) spontaneously develop a severe inflammatory disease resembling neutrophilic dermatosis in humans. Disease in mice is characterized by persistent footpad swelling and suppurative inflammation. Recently, in addition to IL-1α and IL-1R signaling, we demonstrated a pivotal role for RIPK1, TAK1, and ASK1 in promoting inflammatory disease in mice. In the current study we have identified a previously unknown role for CARD9 signaling as a critical regulator for -mediated footpad inflammation. Genetic deletion of CARD9 significantly rescued the -mediated footpad inflammation. Mechanistically, enhanced IL-1α-mediated signaling in mice neutrophils was dampened in mice. Collectively, this study identifies SHP-1 and CARD9 cross-talk as a novel regulator of IL-1α-driven inflammation and opens future avenues for finding novel drug targets to treat neutrophilic dermatosis in humans.
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http://dx.doi.org/10.4049/jimmunol.1800760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483079PMC
September 2018

Previous cocaine self-administration disrupts reward expectancy encoding in ventral striatum.

Neuropsychopharmacology 2018 11 10;43(12):2350-2360. Epub 2018 Apr 10.

Department of Psychology, 1147 Biology-Psychology Building University of Maryland, College Park, MD, 20742, USA.

The nucleus accumbens core (NAc) is important for integrating and providing information to downstream areas about the timing and value of anticipated reward. Although NAc is one of the first brain regions to be affected by drugs of abuse, we still do not know how neural correlates related to reward expectancy are affected by previous cocaine self-administration. To address this issue, we recorded from single neurons in the NAc of rats that had previously self-administered cocaine or sucrose (control). Neural recordings were then taken while rats performed an odor-guided decision-making task in which we independently manipulated value of expected reward by changing the delay to or size of reward across a series of trial blocks. We found that previous cocaine self-administration made rats more impulsive, biasing choice behavior toward more immediate reward. Further, compared to controls, cocaine-exposed rats showed significantly fewer neurons in the NAc that were responsive during odor cues and reward delivery, and in the reward-responsive neurons that remained, diminished directional and value encoding was observed. Lastly, we found that after cocaine exposure, reward-related firing during longer delays was reduced compared to controls. These results demonstrate that prior cocaine self-administration alters reward-expectancy encoding in NAc, which could contribute to poor decision making observed after chronic cocaine use.
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http://dx.doi.org/10.1038/s41386-018-0058-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180050PMC
November 2018

ASK1/2 signaling promotes inflammation in a mouse model of neutrophilic dermatosis.

J Clin Invest 2018 05 9;128(5):2042-2047. Epub 2018 Apr 9.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Mice homozygous for the Tyr208Asn amino acid substitution in the carboxy terminus of Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1) (referred to as Ptpn6spin mice) spontaneously develop a severe inflammatory disease resembling neutrophilic dermatosis in humans. Disease in Ptpn6spin mice is characterized by persistent footpad swelling and suppurative inflammation. Recently, in addition to IL-1α and IL-1R signaling, we demonstrated a pivotal role for several kinases such as SYK, RIPK1, and TAK1 in promoting inflammatory disease in Ptpn6spin mice. In order to identify new kinases involved in SHP-1-mediated inflammation, we took a genetic approach and discovered apoptosis signal-regulating kinases 1 and 2 (ASK1 and ASK2) as novel kinases regulating Ptpn6-mediated footpad inflammation. Double deletion of ASK1 and ASK2 abrogated cutaneous inflammatory disease in Ptpn6spin mice. This double deletion further rescued the splenomegaly and lymphomegaly caused by excessive neutrophil infiltration in Ptpn6spin mice. Mechanistically, ASK regulates Ptpn6spin-mediated disease by controlling proinflammatory signaling in the neutrophils. Collectively, the present study identifies SHP-1 and ASK signaling crosstalk as a critical regulator of IL-1α-driven inflammation and opens future avenues for finding novel drug targets to treat neutrophilic dermatosis in humans.
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http://dx.doi.org/10.1172/JCI98446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919885PMC
May 2018

Guanylate Binding Proteins Regulate Inflammasome Activation in Response to Hyperinjected Yersinia Translocon Components.

Infect Immun 2017 10 20;85(10). Epub 2017 Sep 20.

Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Gram-negative bacterial pathogens utilize virulence-associated secretion systems to inject, or translocate, effector proteins into host cells to manipulate cellular processes and promote bacterial replication. However, translocated bacterial products are sensed by ucleotide binding domain and eucine-rich epeat-containing proteins (NLRs), which trigger the formation of a multiprotein complex called the inflammasome, leading to secretion of interleukin-1 (IL-1) family cytokines, pyroptosis, and control of pathogen replication. Pathogenic bacteria inject effector proteins termed Yops, as well as pore-forming proteins that comprise the translocon itself, into target cells. The translocation regulatory protein YopK promotes bacterial virulence by limiting hyperinjection of the translocon proteins YopD and YopB into cells, thereby limiting cellular detection of virulence activity. How hyperinjection of translocon proteins leads to inflammasome activation is currently unknown. We found that translocated YopB and YopD colocalized with the late endosomal/lysosomal protein LAMP1 and that the frequency of YopD and LAMP1 association correlated with the level of caspase-1 activation in individual cells. We also observed colocalization between YopD and Galectin-3, an indicator of endosomal membrane damage. Intriguingly, YopK limited the colocalization of Galectin-3 with YopD, suggesting that YopK limits the induction or sensing of endosomal membrane damage by components of the type III secretion system (T3SS) translocon. Furthermore, guanylate binding proteins (GBPs) encoded on chromosome 3 ( ), which respond to pathogen-induced damage or alteration of host membranes, were necessary for inflammasome activation in response to hyperinjected YopB/-D. Our findings indicate that lysosomal damage by translocon proteins promotes inflammasome activation and implicate GBPs as key regulators of this process.
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http://dx.doi.org/10.1128/IAI.00778-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607426PMC
October 2017

Prior Cocaine Self-Administration Increases Response-Outcome Encoding That Is Divorced from Actions Selected in Dorsal Lateral Striatum.

J Neurosci 2017 08 10;37(32):7737-7747. Epub 2017 Jul 10.

Department of Psychology and

Dorsal lateral striatum (DLS) is a highly associative structure that encodes relationships among environmental stimuli, behavioral responses, and predicted outcomes. DLS is known to be disrupted after chronic drug abuse; however, it remains unclear what neural signals in DLS are altered. Current theory suggests that drug use enhances stimulus-response processing at the expense of response-outcome encoding, but this has mostly been tested in simple behavioral tasks. Here, we investigated what neural correlates in DLS are affected by previous cocaine exposure as rats performed a complex reward-guided decision-making task in which predicted reward value was independently manipulated by changing the delay to or size of reward associated with a response direction across a series of trial blocks. After cocaine self-administration, rats exhibited stronger biases toward higher-value reward and firing in DLS more strongly represented action-outcome contingencies independent from actions subsequently taken rather than outcomes predicted by selected actions (chosen-outcome contingencies) and associations between stimuli and actions (stimulus-response contingencies). These results suggest that cocaine self-administration strengthens action-outcome encoding in rats (as opposed to chosen-outcome or stimulus-response encoding), which abnormally biases behavior toward valued reward when there is a choice between two options during reward-guided decision-making. Current theories suggest that the impaired decision-making observed in individuals who chronically abuse drugs reflects a decrease in goal-directed behaviors and an increase in habitual behaviors governed by neural representations of response-outcome (R-O) and stimulus-response associations, respectively. We examined the impact that prior cocaine self-administration had on firing in dorsal lateral striatum (DLS), a brain area known to be involved in habit formation and affected by drugs of abuse, during performance of a complex reward-guided decision-making task. Surprisingly, we found that previous cocaine exposure enhanced R-O associations in DLS. This suggests that there may be more complex consequences of drug abuse than current theories have explored, especially when examining brain and behavior in the context of a complex two-choice decision-making task.
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http://dx.doi.org/10.1523/JNEUROSCI.0897-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551065PMC
August 2017

Evaluation of the Effectiveness of Two Morphine Protocols to Treat Neonatal Abstinence Syndrome in a Level II Nursery in a Community Hospital.

Pharmacotherapy 2017 Jul 6;37(7):856-860. Epub 2017 Jul 6.

Inpatient Pharmacy Department, Ephraim McDowell Regional Medical Center, Danville, Kentucky.

The authors sought to evaluate the impact on length of hospital stay and treatment duration of morphine after implementation of a change in the institutional protocol for managing neonatal abstinence syndrome (NAS) in an effort to improve patient outcomes. A single-center, retrospective chart review was conducted at a Level II nursery in a community hospital in Kentucky. Fifty-nine neonates born between January 1, 2014, and December 31, 2015, who were diagnosed with NAS and received morphine for treatment were included. The protocol 1 group consisted of 33 neonates who received an initial dose of morphine 0.04 mg/kg/dose administered orally every 4 hours (January 1-December 31, 2014), and the protocol 2 group consisted of 26 neonates who received an initial dose of morphine 0.06 mg/kg/dose administered orally every 3 hours (January 1-November 30, 2015), after a change in the protocol for managing NAS was implemented on January 1, 2015. Data were reviewed and compared between the two protocol groups to determine the impact that the dosage change had on length of hospital stay and morphine treatment duration. The average length of stay decreased by 7 days in the protocol 2 group compared with the protocol 1 group (21 vs 28.65 days). The average duration of treatment decreased by 7 days in the protocol 2 group compared with the protocol 1 group (18.3 vs 25.4 days). These differences between groups were not statistically significant, however, because the population size was not large enough to achieve adequate power. These results indicate that protocol 2 displayed the potential to decrease length of stay and duration of treatment compared with protocol 1 at this facility; however, balancing higher starting doses with the risk of oversedation will continue to challenge the health care team. Concern for oversedation when using the higher starting dose in protocol 2 has prompted further research (e.g., protocol 3, initial morphine 0.05 mg/kg/dose every 3 hrs). Continued research is also necessary with larger patient populations to enable generalizability to other institutions.
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http://dx.doi.org/10.1002/phar.1966DOI Listing
July 2017

Differential roles of caspase-1 and caspase-11 in infection and inflammation.

Sci Rep 2017 03 27;7:45126. Epub 2017 Mar 27.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Caspase-1, also known as interleukin-1β (IL-1β)-converting enzyme (ICE), regulates antimicrobial host defense, tissue repair, tumorigenesis, metabolism and membrane biogenesis. On activation within an inflammasome complex, caspase-1 induces pyroptosis and converts pro-IL-1β and pro-IL-18 into their biologically active forms. "ICE" or "Casp1" mice generated using 129 embryonic stem cells carry a 129-associated inactivating passenger mutation on the caspase-11 locus, essentially making them deficient in both caspase-1 and caspase-11. The overlapping and unique functions of caspase-1 and caspase-11 are difficult to unravel without additional genetic tools. Here, we generated caspase-1-deficient mouse (Casp1) on the C57BL/6 J background that expressed caspase-11. Casp1 cells did not release IL-1β and IL-18 in response to NLRC4 activators Salmonella Typhimurium and flagellin, canonical or non-canonical NLRP3 activators LPS and ATP, Escherichia coli, Citrobacter rodentium and transfection of LPS, AIM2 activators Francisella novicida, mouse cytomegalovirus and DNA, and the infectious agents Listeria monocytogenes and Aspergillus fumigatus. We further demonstrated that caspase-1 and caspase-11 differentially contributed to the host defense against A. fumigatus infection and to endotoxemia.
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http://dx.doi.org/10.1038/srep45126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366862PMC
March 2017

NLRC3 is an inhibitory sensor of PI3K-mTOR pathways in cancer.

Nature 2016 Dec 12;540(7634):583-587. Epub 2016 Dec 12.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

NLRs (nucleotide-binding domain and leucine-rich repeats) belong to a large family of cytoplasmic sensors that regulate an extraordinarily diverse range of biological functions. One of these functions is to contribute to immunity against infectious diseases, but dysregulation of their functional activity leads to the development of inflammatory and autoimmune diseases. Cytoplasmic innate immune sensors, including NLRs, are central regulators of intestinal homeostasis. NLRC3 (also known as CLR16.2 or NOD3) is a poorly characterized member of the NLR family and was identified in a genomic screen for genes encoding proteins bearing leucine-rich repeats (LRRs) and nucleotide-binding domains. Expression of NLRC3 is drastically reduced in the tumour tissue of patients with colorectal cancer compared to healthy tissues, highlighting an undefined potential function for this sensor in the development of cancer. Here we show that mice lacking NLRC3 are hyper-susceptible to colitis and colorectal tumorigenesis. The effect of NLRC3 is most dominant in enterocytes, in which it suppresses activation of the mTOR signalling pathways and inhibits cellular proliferation and stem-cell-derived organoid formation. NLRC3 associates with PI3Ks and blocks activation of the PI3K-dependent kinase AKT following binding of growth factor receptors or Toll-like receptor 4. These findings reveal a key role for NLRC3 as an inhibitor of the mTOR pathways, mediating protection against colorectal cancer.
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http://dx.doi.org/10.1038/nature20597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5468516PMC
December 2016

NLRP3 inflammasome plays a redundant role with caspase 8 to promote IL-1β-mediated osteomyelitis.

Proc Natl Acad Sci U S A 2016 Apr 6;113(16):4452-7. Epub 2016 Apr 6.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105

Missense mutation in the proline-serine-threonine phosphatase-interacting protein 2 (Pstpip2) gene results in the development of spontaneous chronic bone disease characterized by bone deformity and inflammation that is reminiscent of patients with chronic multifocal osteomyelitis (cmo). Interestingly, this disease is specifically mediated by IL-1β but not IL-1α. The precise molecular pathways that promote pathogenic IL-1β production inPstpip2(cmo)mice remain unidentified. Furthermore, how IL-1β provokes inflammatory bone disease inPstpip2(cmo)mice is not known. Here, we demonstrate that double deficiency of Nod like receptor family, pyrin domain containing 3 (NLRP3) and caspase 8 inPstpip2(cmo)mice provides similar protection as observed in caspase-1 and caspase-8-deficientPstpip2(cmo)mice, demonstrating redundant roles for the NLRP3 inflammasome and caspase 8 in provoking osteomyelitic disease inPstpip2(cmo)mice. Consistently, immunofluorescence studies exhibited distinct caspase-1 and caspase-8 puncta in diseasedPtpn6(spin)neutrophils. Data from our chimera studies demonstrated that IL-1β produced by hematopoietic cells is sensed by the radioresistant compartment to promote bone disease. Furthermore, our results showed that the IL-1β signaling is unidirectional and feedback signaling of IL-1β onto the hematopoietic compartment is not important for disease induction. In conclusion, our studies have uncovered the combined actions of the NLRP3 inflammasome and caspase 8 leading to IL-1β maturation and the directionality of IL-1β in driving disease inPstpip2(cmo)mice.
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http://dx.doi.org/10.1073/pnas.1601636113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843439PMC
April 2016

Prenatal Nicotine Exposure Impairs Executive Control Signals in Medial Prefrontal Cortex.

Neuropsychopharmacology 2016 Feb 20;41(3):716-25. Epub 2015 Jul 20.

Department of Psychology, University of Maryland, College Park, MD, USA.

Prenatal nicotine exposure (PNE) is linked to numerous psychiatric disorders including attention deficit hyperactivity disorder (ADHD). Current literature suggests that core deficits observed in ADHD reflect abnormal inhibitory control governed by the prefrontal cortex. Yet, it is unclear how neural activity in the medial prefrontal cortex (mPFC) is modulated during tasks that assess response inhibition or if these neural correlates, along with behavior, are affected by PNE. To address this issue, we recorded from single mPFC neurons in control and PNE rats as they performed a stop-signal task. We found that PNE rats were faster for all trial-types, made more premature responses, and were less likely to inhibit behavior on 'STOP' trials during which rats had to inhibit an already initiated response. Activity in mPFC was modulated by response direction and was positively correlated with accuracy and movement time in control but not PNE rats. Although the number of single neurons correlated with response direction was significantly reduced by PNE, neural activity observed on general STOP trials was largely unaffected. However, dramatic behavioral deficits on STOP trials immediately following non-conflicting (GO) trials in the PNE group appear to be mediated by the loss of conflict monitoring signals in mPFC. We conclude that prenatal nicotine exposure makes rats impulsive and disrupts firing of mPFC neurons that carry signals related to response direction and conflict monitoring.
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http://dx.doi.org/10.1038/npp.2015.197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707818PMC
February 2016

Altered basolateral amygdala encoding in an animal model of schizophrenia.

J Neurosci 2015 Apr;35(16):6394-400

Department of Psychology and Program in Neuroscience and Cognitive Science, University of Maryland, College Park, Maryland 20742,

It has been proposed that schizophrenia results, in part, from the inappropriate or spurious attribution of salience to cues in the environment. We have recently reported neural correlates of salience in the basolateral amygdala (ABL) of rats during learning in an odor-guided discrimination task. Here we tested whether this dopamine-dependent salience signal is altered in rats with neonatal ventral hippocampal lesions (NVHLs), a rodent model of schizophrenia. We found that ABL signals related to violations in reward prediction were only mildly affected by NVHL; however, neurons in rats with NVHLs showed significantly stronger selectivity during odor sampling, particularly for the more salient large-reward cue. The elevated cue-evoked activity in NVHL rats was correlated with heightened orienting behavior and also with changes in firing to the shifts in reward, suggesting that it reflected abnormal signaling of the large reward-predicting cue's salience. These results are broadly consistent with the proposal that schizophrenics suffer from enhanced signaling of salience.
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http://dx.doi.org/10.1523/JNEUROSCI.5096-14.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405556PMC
April 2015

From ventral-medial to dorsal-lateral striatum: neural correlates of reward-guided decision-making.

Neurobiol Learn Mem 2015 Jan 21;117:51-9. Epub 2014 May 21.

Department of Psychology, University of Maryland, College Park, MD 20742, United States; Program in Neuroscience and Cognitive Science, University of Maryland, College Park, MD 20742, United States. Electronic address:

The striatum is critical for reward-guided and habitual behavior. Anatomical and interference studies suggest a functional heterogeneity within striatum. Medial regions, such as nucleus accumbens core and dorsal medial striatum play roles in goal-directed behavior, while dorsal lateral striatum is critical for control of habitual action. Subdivisions of striatum are topographically connected with different cortical and subcortical structures forming channels that carry information related to limbic, associative, and sensorimotor functions. Here, we describe data showing that as one progresses from ventral-medial to dorsal-lateral striatum, there is a shift from more prominent value encoding to activity more closely related to associative and motor aspects of decision-making. In addition, we will describe data suggesting that striatal circuits work in parallel to control behavior and that regions within striatum can compensate for each other when functions are disrupted.
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http://dx.doi.org/10.1016/j.nlm.2014.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240773PMC
January 2015

Increased firing to cues that predict low-value reward in the medial orbitofrontal cortex.

Cereb Cortex 2014 Dec 30;24(12):3310-21. Epub 2013 Jul 30.

Department of Psychology, Program in Neuroscience and Cognitive Science, University of Maryland, College Park, MD 20742, USA.

Anatomical, imaging, and lesion work have suggested that medial and lateral aspects of orbitofrontal cortex (OFC) play different roles in reward-guided decision-making, yet few single-neuron recording studies have examined activity in more medial parts of the OFC (mOFC) making it difficult to fully assess its involvement in motivated behavior. Previously, we have shown that neurons in lateral parts of the OFC (lOFC) selectively fire for rewards of different values. In that study, we trained rats to respond to different fluid wells for rewards of different sizes or delivered at different delays. Rats preferred large over small reward, and rewards delivered after short compared with long delays. Here, we recorded from single neurons in rat rostral mOFC as they performed the same task. Similar to the lOFC, activity was attenuated for rewards that were delivered after long delays and was enhanced for delivery of larger rewards. However, unlike lOFC, odor-responsive neurons in the mOFC were more active when cues predicted low-value outcomes. These data suggest that odor-responsive mOFC neurons signal the association between environmental cues and unfavorable outcomes during decision making.
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http://dx.doi.org/10.1093/cercor/bht189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224243PMC
December 2014

Ventral striatum lesions enhance stimulus and response encoding in dorsal striatum.

Biol Psychiatry 2014 Jan 20;75(2):132-9. Epub 2013 Jun 20.

Department of Psychology, University of Maryland, College Park, Maryland; Program in Neuroscience and Cognitive Science, University of Maryland, College Park, Maryland. Electronic address:

Background: The development of addiction is thought to reflect a transition from goal-directed to stimulus-response driven behavior, functions attributed to ventral (VS) and dorsal striatum (DS), respectively. In line with this theory, neuroadaptations that occur during prolonged drug use progress from VS to DS. Here we ask if VS dysfunction alone, independent of drug use, can affect neural selectivity in DS.

Methods: To address this issue, we recorded from single neurons in DS while rats performed an odor-guided choice task for differently valued rewards in rats with and without unilateral VS lesions. In a separate group of animals, we used bilateral VS lesions to determine if VS was critical for performance on this task.

Results: We describe data showing that unilateral lesions of VS enhance neural representations in DS during performance of a task that is dependent on VS. Furthermore, we show that VS is critical for reward-guided decision-making initially, but that rats regain function after several days.

Conclusions: These results suggest that loss of VS function, independent of chronic drug use, can trigger stronger encoding in DS in a reward-guided decision-making task and that the transition from VS to DS governed behavior observed in addiction might be due, in part, to initial loss of VS function.
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http://dx.doi.org/10.1016/j.biopsych.2013.05.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3796031PMC
January 2014

Separate populations of neurons in ventral striatum encode value and motivation.

PLoS One 2013 28;8(5):e64673. Epub 2013 May 28.

Department of Psychology, University of Maryland, College Park, Maryland, United States of America.

Neurons in the ventral striatum (VS) fire to cues that predict differently valued rewards. It is unclear whether this activity represents the value associated with the expected reward or the level of motivation induced by reward anticipation. To distinguish between the two, we trained rats on a task in which we varied value independently from motivation by manipulating the size of the reward expected on correct trials and the threat of punishment expected upon errors. We found that separate populations of neurons in VS encode expected value and motivation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0064673PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665540PMC
January 2014

Response inhibition signals and miscoding of direction in dorsomedial striatum.

Front Integr Neurosci 2012 7;6:69. Epub 2012 Sep 7.

Department of Psychology, University of Maryland, College Park MD, USA.

The ability to inhibit action is critical for everyday behavior and is affected by a variety of disorders. Behavioral control and response inhibition is thought to depend on a neural circuit that includes the dorsal striatum, yet the neural signals that lead to response inhibition and its failure are unclear. To address this issue, we recorded from neurons in rat dorsomedial striatum (mDS) in a novel task in which rats responded to a spatial cue that signaled that reward would be delivered either to the left or to the right. On 80% of trials rats were instructed to respond in the direction cued by the light (GO). On 20% of trials a second light illuminated instructing the rat to refrain from making the cued movement and move in the opposite direction (STOP). Many neurons in mDS encoded direction, firing more or less strongly for GO movements made ipsilateral or contralateral to the recording electrode. Neurons that fired more strongly for contralateral GO responses were more active when rats were faster, showed reduced activity on STOP trials, and miscoded direction on errors, suggesting that when these neurons were overly active, response inhibition failed. Neurons that decreased firing for contralateral movement were excited during trials in which the rat was required to stop the ipsilateral movement. For these neurons activity was reduced when errors were made and was negatively correlated with movement time suggesting that when these neurons were less active on STOP trials, response inhibition failed. Finally, the activity of a significant number of neurons represented a global inhibitory signal, firing more strongly during response inhibition regardless of response direction. Breakdown by cell type suggests that putative medium spiny neurons (MSNs) tended to fire more strongly under STOP trials, whereas putative interneurons exhibited both activity patterns.
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http://dx.doi.org/10.3389/fnint.2012.00069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3435520PMC
October 2012

Prevention of autoimmune diabetes by ectopic pancreatic β-cell expression of interleukin-35.

Diabetes 2012 Jun 16;61(6):1519-26. Epub 2012 Mar 16.

Department of Immunology, St Jude Children’s Research Hospital, Memphis, Tennessee, USA.

Interleukin (IL)-35 is a newly identified inhibitory cytokine used by T regulatory cells to control T cell-driven immune responses. However, the therapeutic potential of native, biologically active IL-35 has not been fully examined. Expression of the heterodimeric IL-35 cytokine was targeted to β-cells via the rat insulin promoter (RIP) II. Autoimmune diabetes, insulitis, and the infiltrating cellular populations were analyzed. Ectopic expression of IL-35 by pancreatic β-cells led to substantial, long-term protection against autoimmune diabetes, despite limited intraislet IL-35 secretion. Nonobese diabetic RIP-IL35 transgenic mice exhibited decreased islet infiltration with substantial reductions in the number of CD4(+) and CD8(+) T cells, and frequency of glucose-6-phosphatase catalytic subunit-related protein-specific CD8(+) T cells. Although there were limited alterations in cytokine expression, the reduced T-cell numbers observed coincided with diminished T-cell proliferation and G1 arrest, hallmarks of IL-35 biological activity. These data present a proof of principle that IL-35 could be used as a potent inhibitor of autoimmune diabetes and implicate its potential therapeutic utility in the treatment of type 1 diabetes.
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http://dx.doi.org/10.2337/db11-0784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3357277PMC
June 2012