NLRP3-inflammasome activating DAMPs stimulate an inflammatory response in glia in the absence of priming which contributes to brain inflammation after injury

Inflammation in the absence of infection (sterile inflammation) contributes to acute injury and chronic disease. Cerebral ischemia is a devastating condition in which the primary injury is caused by reduced blood supply and is therefore sterile. The cytokine interleukin-1β (IL-1β) is a key contributor to ischemic brain injury and central inflammatory responses. The release of IL-1β is regulated by the protease caspase-1, and its activating complex, the inflammasome. Of the known inflammasomes the best characterized, and one that is perceived to sense sterile injury is formed by a pattern recognition receptor called NOD-like receptor pyrin domain containing three (NLRP3). A key feature of NLRP3-inflammasome dependent responses in vitro in macrophages is the requirement of an initial priming stimulus by a pathogen (PAMP), or damage associated molecular pattern (DAMP) respectively. We sought to determine the inflammatory responses of NLRP3-activating DAMPs on brain derived mixed glial cells in the absence of an initial priming stimulus in vitro. In cultured mouse mixed glia the DAMPs ATP, monosodium urate, and calcium pyrophosphate dehydrate crystals had no effect on the expression of IL-1α or IL-1β and induced release only when the cells were primed with a PAMP. In the absence of priming, these DAMPs did however induce inflammation via the production of IL-6 and CXCL1, and the release of the lysosomal protease cathepsin B. Furthermore, the acute phase protein serum amyloid A (SAA) acted as a priming stimulus on glial cells resulting in levels of IL-1 expression comparable to those induced by the PAMP lipopolysaccharide. In vivo, after cerebral ischemia, IL-1 production contributed to increased IL-6 and CXCL1 since these cytokines were profoundly reduced in the ischemic hemispheres from IL-1α/β double KO mice, although injury-induced cytokine responses were not abolished. Thus, DAMPs augment brain inflammation by directly stimulating production of glial derived inflammatory mediators. This is markedly enhanced by DAMP-induced IL-1-release-dependent responses that require a sterile endogenous priming stimulus such as SAA

A Study of ELL Adult’s Use of Mobile Communication Applications: an Examination of Tie Strength

This study begins to examine the problems that surround the usability and design of mobile communication applications for E.L.L (English Language Learner) immigrant adults in the United States by looking at the intent of this population when using phones. A user study was conducted where ELL immigrant adults answered questions about their mobile phone use. The results show that ELL immigrant adults use their smart phones daily and communicate with their friends and family, showing that maintenance of strong ties is important to this community. We hope this study moves towards an inclusive application that takes into account the relationship maintenance needs of this community

Astrocyte Ca2+-evoked ATP release regulates myelinated axon excitability and conduction speed*

INTRODUCTION: Astrocytes support neuronal function throughout the central nervous system. In the gray matter, they regulate synapse number during development, remove synaptically released neurotransmitters to terminate their action and prevent excitotoxicity, control the extracellular potassium concentration to prevent hyperexcitability, regulate blood flow to ensure an adequate energy supply, provide lactate to neurons for energy, and respond to rises of intracellular calcium concentration ([Ca2+]i) by releasing adenosine triphosphate (ATP) and other gliotransmitters that act on neuronal receptors to modulate information processing. However, their role is unclear in the white matter, which transmits information rapidly between gray matter areas using axons wrapped with capacitance-reducing myelin (although they have been suggested to regulate myelination during development and during normal function). RATIONALE: Recently, it has been suggested that learning and memory may reflect not only changes in synaptic function in the gray matter, but also changes in white matter function. In particular, neural circuit function might be regulated by changes in the conduction speed of myelinated axons that result in an altered arrival time of action potentials at a distant neuron. These speed changes might be brought about by alterations of the properties of the passively conducting myelinated internodes or of the intervening excitable nodes of Ranvier, where the action potential is generated. We applied immunohistochemistry to assess how astrocytes interact with myelinated axons, neuronal stimulation and light-evoked calcium uncaging in astrocytes to evoke Ca2+-dependent release of gliotransmitters, and electrophysiology and pharmacology to characterize how astrocyte-released substances might affect the axon initial segment (AIS) and nodes of Ranvier of myelinated neurons. Measurements of conduction velocity and computer modeling allowed us to interpret the results. RESULTS: Astrocytes closely approach the axons of myelinated neurons in layer V of the cerebral cortex that enter the corpus callosum. Uncaging Ca2+ within astrocytes or stimulating spike trains in neurons evoked a rise of astrocyte [Ca2+]i that triggered the release of ATP-containing vesicles from these cells. This evoked an inward current in the AIS and nodes of Ranvier of the pyramidal neurons. Pharmacology showed that this was mediated by the activation of Gs-linked adenosine A2a receptors (A2aRs), implying that the released ATP was converted to adenosine by extracellular enzymes. The A2aRs raise the intracellular concentration of cyclic AMP, which activates hyperpolarization-activated cyclic nucleotide–gated (HCN) channels mediating the inward hyperpolarization-activated current (Ih) and thus depolarizes the cell. In the AIS, the activation of A2aRs alters excitability and hence action potential generation, whereas in the nodes of Ranvier, it decreases the conduction speed of the action potential along the axon. CONCLUSION: As in the gray matter, astrocyte [Ca2+]i regulates the release of ATP into the extracellular space in the white matter. After conversion to adenosine, this regulates the excitability and conduction speed of myelinated axons. The changes in excitability at the AIS will lead to changes in the relationship between the synaptic input and action potential output of the cell. The altered conduction speed of the myelinated axon may change neural circuit function by changing the action potential arrival time at the cell’s output synapses, thus altering the integration of signals in postsynaptic neurons. Variations in astrocyte-derived adenosine level can occur between wake and sleep states, and the extracellular adenosine concentration rises during energy deprivation conditions. These changes in adenosine level could thus control white matter information flow and neural circuit function

The Figure in Art: Selections from the Gettysburg College Collection

The Figure in Art: Selections from the Gettysburg College Collection is the second annual exhibition curated by students enrolled in the Art History Methods class. This exhibition is an exciting academic endeavor and provides an incredible opportunity for engaged learning, research, and curatorial experience. The eleven student curators are Diane Brennan, Rebecca Duffy, Kristy Garcia, Megan Haugh, Dakota Homsey, Molly Lindberg, Kathya Lopez, Kelly Maguire, Kylie McBride, Carolyn McBrady and Erica Schaumberg. Their research presents a multifaceted view of the representation of figures in various art forms from different periods and cultures.https://cupola.gettysburg.edu/artcatalogs/1017/thumbnail.jp

A Medical/Legal Teaching and Assessment Collaboration on Domestic Violence: Assessment Using Standardized Patients/Standardized Clients

Assessment of skills is an important, emerging topic in law school education. Two recent and influential books, Educating Lawyers published by the Carnegie Foundation and Best Practices in Legal Education, published by the Clinical Legal Education Association have both suggested dramatic reform of legal education. Among other reforms, these studies urge law schools to use “outcome-based” assessments, i.e., using learning objectives  and assessing knowledge and skills in standardized situations based on specific criteria, rather than simply comparing students’ performances to each other.

Critical Roles for Interleukin 1 and Tumor Necrosis Factor α in Antibody-induced Arthritis

In spontaneous inflammatory arthritis of K/BxN T cell receptor transgenic mice, the effector phase of the disease is provoked by binding of immunoglobulins (Igs) to joint surfaces. Inflammatory cytokines are known to be involved in human inflammatory arthritis, in particular rheumatoid arthritis, although, overall, the pathogenetic mechanisms of the human affliction remain unclear. To explore the analogy between the K/BxN model and human patients, we assessed the role and relative importance of inflammatory cytokines in K/BxN joint inflammation by transferring arthritogenic serum into a panel of genetically deficient recipients. Interleukin (IL)-1 proved absolutely necessary. Tumor necrosis factor (TNF)–α was also required, although seemingly less critically than IL-1, because a proportion of TNF-α–deficient mice developed robust disease. There was no evidence for an important role for IL-6. Bone destruction and reconstruction were also examined. We found that all mice with strong inflammation exhibited the bone erosion and reconstruction phenomena typical of K/BxN arthritis, with no evidence of any particular requirement for TNFα for bone destruction. The variability in the requirement for TNF-α, reminiscent of that observed in treated rheumatoid arthritis patients, did not appear genetically programmed but related instead to subtle environmental changes

Complementary network-based approaches for exploring genetic structure and functional connectivity in two vulnerable, endemic ground squirrels

The persistence of small populations is influenced by genetic structure and functional connectivity. We used two network-based approaches to understand the persistence of the northern Idaho ground squirrel (Urocitellus brunneus) and the southern Idaho ground squirrel (U. endemicus), two congeners of conservation concern. These graph theoretic approaches are conventionally applied to social or transportation networks, but here are used to study population persistence and connectivity. Population graph analyses revealed that local extinction rapidly reduced connectivity for the southern species, while connectivity for the northern species could be maintained following local extinction. Results from gravity models complemented those of population graph analyses, and indicated that potential vegetation productivity and topography drove connectivity in the northern species. For the southern species, development (roads) and small-scale topography reduced connectivity, while greater potential vegetation productivity increased connectivity. Taken together, the results of the two network-based methods (population graph analyses and gravity models) suggest the need for increased conservation action for the southern species, and that management efforts have been effective at maintaining habitat quality throughout the current range of the northern species. To prevent further declines, we encourage the continuation of management efforts for the northern species, whereas conservation of the southern species requires active management and additional measures to curtail habitat fragmentation. Our combination of population graph analyses and gravity models can inform conservation strategies of other species exhibiting patchy distributions

A Medical/Legal Teaching and Assessment Collaboration on Domestic Violence: Assessment Using Standardized Patients/Standardized Clients

Assessment of skills is an important, emerging topic in law school education. Two recent and influential books, Educating Lawyers published by the Carnegie Foundation and Best Practices in Legal Education, published by the Clinical Legal Education Association have both suggested dramatic reform of legal education. Among other reforms, these studies urge law schools to use outcome-based\u27 assessments, i.e., using learning objectives and assessing knowledge and skills in standardized situations based on specific criteria, rather than simply comparing students\u27 performances to each other