Knocking on closed doors: Host interferons dynamically regulate blood-brain barrier function during viral infections of the central nervous system

The central nervous system (CNS) is among the most important organ systems, integrating information inputs and coordinating the activity of all other body systems. Like many organ systems, the CNS is susceptible to infection by pathogenic microorganisms, including many arboviruses that are considered neurotropic because they are able to achieve robust replicatio

The Role of Written and Verbal Expression in Improving Communication Skills for Students in an Undergraduate Chemistry Program

Proofreading, editing, and critique, the customary assessment tools scientists use to evaluate professional journal articles, grant applications, and any other writing, can be applied equally well in introductory science instruction. Such feedback is, in fact, crucial to growth and development. When learning anything new, students and faculty alike rely heavily on sources other than themselves (‘external editors’) to assess their understanding as they develop self-assessment skills (or ‘internal editors’). Although they rarely describe it in these terms, faculty nonetheless assume that students have developed and refined their internal skills by the time they take examinations and write term papers. Unfortunately, science instructors traditionally provide little meaningful assistance or rationale for students to get to that point. This is in part because we faculty have already developed and deploy our professional skills so tacitly. To a degree, individuals who become faculty members probably follow paths of least resistance, the ones along which they were successful by virtue of their ‘natural aptitude’. What some instructors intend to be their best advice to students can be wholly inadequate if it only reflects on the surface aspects of what they did as students: “do lots of problems,” “write lots of prose,” “sit alone and wrestle with the ideas.” One of the things we faculty do quite naturally in our professional lives is to rely on external input. Having developed any idea to whatever limit we are able to achieve sitting alone in our workplaces with our internal editors and our reference sources, we next try out the ideas on our colleagues. Expressing our understanding to others is always a teaching activity since we are revealing our interpretation of some aspect of the world to another individual, testing the interpretation against another’s point-of-view. Faculty share a common experience that they describe in familiar terms: “I never really learned it until I had to teach it.” Perhaps what we also mean is that we actually think about our ideas in new ways when we are consciously aware of the fact that we need to describe them to someone else. In writing as well as speaking, attention to the needs of the audience is critical to clarity in the expression of meaning through the use of information (1). Learners learn differently, perhaps even more effectively, when they anticipate the need to express their understanding to someone else. For students, the most common example of this type of anticipation is in preparation for a written or oral examination. This perspective is not at all limited to expository writing and speaking, the usual modes of expression in the physical sciences; revealing internal perspectives represents +expression+ regardless of its modality, and does not favor writers and orators over thespians, pianists, painters, ballerinas or chanteurs

Inflation and Expectations in Experimental Markets

A total of nine experimental markets were studied. Seven of these involved eleven to twelve periods of inflation at a constant percentage and then two or three periods of no inflation. Two experiments involved no inflation for twelve periods and then inflation at a constant rate for three periods. In all but three markets, participants were asked to guess the mean price of the upcoming market period before they had any information about the parameters for that period. The subject with the best guess was given a financial reward in addition to any profit earned in the market. Convergence properties are compared. Rational expectations models are tested and the structure of forecasts are studied. In general the rational expectations models capture much of what is observed but paradoxes exist in the data and in the application of the models

CCR5 limits cortical viral loads during West Nile virus infection of the central nervous system

BACKGROUND: Cell-mediated immunity is critical for clearance of central nervous system (CNS) infection with the encephalitic flavivirus, West Nile virus (WNV). Prior studies from our laboratory have shown that WNV-infected neurons express chemoattractants that mediate recruitment of antiviral leukocytes into the CNS. Although the chemokine receptor, CCR5, has been shown to play an important role in CNS host defense during WNV infection, regional effects of its activity within the infected brain have not been defined. METHODS: We used CCR5-deficient mice and an established murine model of WNV encephalitis to determine whether CCR5 activity impacts on WNV levels within the CNS in a region-specific fashion. Statistical comparisons between groups were made with one- or two-way analysis of variance; Bonferroni’s post hoc test was subsequently used to compare individual means. Survival was analyzed by the log-rank test. Analyses were conducted using Prism software (GraphPad Prism). All data were expressed as means ± SEM. Differences were considered significant if P ≤ 0.05. RESULTS: As previously shown, lack of CCR5 activity led to increased symptomatic disease and mortality in mice after subcutaneous infection with WNV. Evaluation of viral burden in the footpad, draining lymph nodes, spleen, olfactory bulb, and cerebellum derived from WNV-infected wild-type, and CCR5(−/−) mice showed no differences between the genotypes. In contrast, WNV-infected, CCR5(−/−) mice exhibited significantly increased viral burden in cortical tissues, including the hippocampus, at day 8 post-infection. CNS regional studies of chemokine expression via luminex analysis revealed significantly increased expression of CCR5 ligands, CCL4 and CCL5, within the cortices of WNV-infected, CCR5(−/−) mice compared with those of similarly infected WT animals. Cortical elevations in viral loads and CCR5 ligands in WNV-infected, CCR5(−/−) mice, however, were associated with decreased numbers of infiltrating mononuclear cells and increased permeability of the blood-brain barrier. CONCLUSIONS: These data indicate that regional differences in chemokine expression occur in response to WNV infection of the CNS, and that cortical neurons require CCR5 activity to limit viral burden in this brain region

Antioxidant enzymes in the developing lungs of egg-laying and metamorphosing vertebrates

© The Company of BiologistsThe activities of the pulmonary antioxidant enzymes (AOE), superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase, increase in the final 10–20 % of gestation in the mammalian lung, to protect the lung from attack by increasing levels of reactive oxygen species at birth. Whether the increase occurs as a normal ‘preparation for birth’, i.e. by a genetically determined mechanism, or in response to increased levels of oxygen, i.e. in response to the environment, is not completely understood. We examined the activities of catalase, SOD and GPx in the developing lungs of two oviparous vertebrate species, the chicken (Gallus gallus) and an agamid lizard (Pogona vitticeps), and in a metamorphosing vertebrate, the anuran Limnodynastes terraereginae. During in ovo development embryos come into contact with higher levels of environmental oxygen, and at a much earlier stage of development, compared with the intrauterine development of mammals. Furthermore, in metamorphosing frogs, the lungs are inflated at an early stage to aid in buoyancy, although the gas-exchange function only develops much later upon final metamorphosis. Here, we hypothesise that the activity of the AOE will be elevated relatively much earlier during development in both oviparous and metamorphosing vertebrates. We also examined the effect of mild hypoxia (17 % oxygen) on the development of the pulmonary AOE in the chicken, to test the hypothesis that these enzymes are responsive to environmental oxygen. In the normoxic lung of both Gallus gallus and Pogona vitticeps, catalase and GPx activities were significantly increased in late incubation, whereas SOD activity decreased in late incubation. Catalase and SOD activities were virtually identical in hypoxic and normoxic embryos of the chicken, but GPx activity was significantly affected by hypoxia. In the developing frog, the activities of all enzymes were high at stage 30, demonstrating that the system is active before the lung displays any significant gas-exchange function. SOD and GPx activity did not increase further with development. Catalase activity increased after stage 40, presumably correlating with an increase in air-breathing. In summary, catalase expression in the two oviparous vertebrates appears to be completely under genetic control as the activity of this enzyme does not change in response to changes in oxygen tension. However, in tadpoles, catalase may be responsive to environmental oxygen. SOD also appears to follow a largely genetically determined program in all species. Under normoxic conditions, GPx appears to follow a genetically determined developmental pattern, but this enzyme demonstrated the largest capacity to respond to environmental oxygen fluctuations. In conclusion, it appears that the AOE are differentially regulated. Furthermore, the AOE in the different species appear to have evolved different levels of dependency on environmental variables. Finally, the late developmental increase in AOE activity seen in mammals is not as pronounced in oviparous and metamorphosing vertebrates.Adam P. Starrs, Sandra Orgeig, Christopher B. Daniels, Margaret Davies and Olga V. Lopatk

Regional astrocyte IFN signaling restricts pathogenesis during neurotropic viral infection

Type I IFNs promote cellular responses to viruses, and IFN receptor (IFNAR) signaling regulates the responses of endothelial cells of the blood-brain barrier (BBB) during neurotropic viral infection. However, the role of astrocytes in innate immune responses of the BBB during viral infection of the CNS remains to be fully elucidated. Here, we have demonstrated that type I IFNAR signaling in astrocytes regulates BBB permeability and protects the cerebellum from infection and immunopathology. Mice with astrocyte-specific loss of IFNAR signaling showed decreased survival after West Nile virus infection. Accelerated mortality was not due to expanded viral tropism or increased replication. Rather, viral entry increased specifically in the hindbrain of IFNAR-deficient mice, suggesting that IFNAR signaling critically regulates BBB permeability in this brain region. Pattern recognition receptors and IFN-stimulated genes had higher basal and IFN-induced expression in human and mouse cerebellar astrocytes than did cerebral cortical astrocytes, suggesting that IFNAR signaling has brain region–specific roles in CNS immune responses. Taken together, our data identify cerebellar astrocytes as key responders to viral infection and highlight the existence of distinct innate immune programs in astrocytes from evolutionarily disparate regions of the CNS

RIPK3 restricts viral pathogenesis via cell death-independent neuroinflammation

Receptor-interacting protein kinase-3 (RIPK3) is an activator of necroptotic cell death, but recent work has implicated additional roles for RIPK3 in inflammatory signaling independent of cell death. However, while necroptosis has been shown to contribute to antiviral immunity, death-independent roles for RIPK3 in host defense have not been demonstrated. Using a mouse model of West Nile virus (WNV) encephalitis, we show that RIPK3 restricts WNV pathogenesis independently of cell death. Ripk3(-/-) mice exhibited enhanced mortality compared to wild-type (WT) controls, while mice lacking the necroptotic effector MLKL, or both MLKL and caspase-8, were unaffected. The enhanced susceptibility of Ripk3(-/-) mice arose from suppressed neuronal chemokine expression and decreased central nervous system (CNS) recruitment of T lymphocytes and inflammatory myeloid cells, while peripheral immunity remained intact. These data identify pleiotropic functions for RIPK3 in the restriction of viral pathogenesis and implicate RIPK3 as a key coordinator of immune responses within the CNS

Plasmodium falciparum histidine-rich protein II compromises brain endothelial barriers and may promote cerebral malaria pathogenesis

Cerebral malaria (CM) is a disease of the vascular endothelium caused by Plasmodium falciparum. It is characterized by parasite sequestration, inflammatory cytokine production, and vascular leakage. A distinguishing feature of P. falciparum infection is parasite production and secretion of histidine-rich protein II (HRPII). Plasma HRPII is a diagnostic and prognostic marker for falciparum malaria. We demonstrate that disruption of a human cerebral microvascular endothelial barrier by P. falciparum-infected erythrocytes depends on expression of HRPII. Purified recombinant or native HRPII can recapitulate these effects. HRPII action occurs via activation of the inflammasome, resulting in decreased integrity of tight junctions and increased endothelial permeability. We propose that HRPII is a virulence factor that may contribute to cerebral malaria by compromising endothelial barrier integrity within the central nervous system

Comparative Effectiveness of Surfactant Preparations in Premature Infants

To compare effectiveness of three surfactant preparations (beractant, calfactant, and poractant alpha) in premature infants for preventing three outcomes: (1) air leak syndromes; (2) death; and (3) bronchopulmonary dysplasia (BPD) or death (composite outcomes)