T-cell production of matrix metalloproteinases and inhibition of parasite clearance by TIMP-1 during chronic Toxoplasma infection in the brain

Chronic infection with the intracellular protozoan parasite Toxoplasma gondii leads to tissue remodelling in the brain and a continuous requirement for peripheral leucocyte migration within the CNS (central nervous system). In the present study, we investigate the role of MMPs (matrix metalloproteinases) and their inhibitors in T-cell migration into the infected brain. Increased expression of two key molecules, MMP-8 and MMP-10, along with their inhibitor, TIMP-1 (tissue inhibitor of metalloproteinases-1), was observed in the CNS following infection. Analysis of infiltrating lymphocytes demonstrated MMP-8 and -10 production by CD4+ and CD8+ T-cells. In addition, infiltrating T-cells and CNS resident astrocytes increased their expression of TIMP-1 following infection. TIMP-1-deficient mice had a decrease in perivascular accumulation of lymphocyte populations, yet an increase in the proportion of CD4+ T-cells that had trafficked into the CNS. This was accompanied by a reduction in parasite burden in the brain. Taken together, these findings demonstrate a role for MMPs and TIMP-1 in the trafficking of lymphocytes into the CNS during chronic infection in the brain

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

A History of Discrete Event Simulation Programming Languages

The history of simulation programming languages is organized as a progression in periods of similar developments. The five periods, spanning 1955-1986, are labeled: The Period of Search (1955-1960); The Advent (1961-1965); The Formative Period (1966-1970); The Expansional Period (1971-1978); and The Period of Consolidation and Regeneration (1979-1986). The focus is on recognizing the people and places that have made important contributions in addition to the nature of the contribution. A balance between comprehensive and in-depth treatment has been reached by providing more detailed description of those languages which have or have had major use. Over 30 languages are mentioned, and numerous variations are described in the major contributors. A concluding summary notes the concepts and techniques either originating with simulation programming languages or given significant visibility by them

Pannotia's mantle signature: the quest for supercontinent identification

A supercontinent is generally considered to reflect the assembly of all, or most, of the Earth's continental lithosphere. Previous studies have used geological, atmospheric and biogenic ‘geomarkers’ to supplement supercontinent identification. However, there is no formal definition of how much continental material is required to be assembled, or indeed which geomarkers need to be present. Pannotia is a hypothesized landmass that existed in the interval c. 0.65–0.54 Ga and was comprised of Gondwana, Laurentia, Baltica and possibly Siberia. Although Pannotia was considerably smaller than Pangaea (and also fleeting in its existence), the presence of geomarkers in the geological record support its identification as a supercontinent. Using 3D mantle convection models, we simulate the evolution of the mantle in response to the convergence leading to amalgamation of Rodinia and Pangaea. We then compare this supercontinent ‘fingerprint’ to Pannotian activity. For the first time, we show that Pannotian continental convergence could have generated a mantle signature in keeping with that of a simulated supercontinent. As a result, we posit that any formal identification of a supercontinent must take into consideration the thermal evolution of the mantle associated with convergence leading to continental amalgamation, rather than simply the size of the connected continental landmass

T-cell production of matrix metalloproteinases and inhibition of parasite clearance by TIMP-1 during chronic Toxoplasma infection in the brain.

Chronic infection with the intracellular protozoan parasite Toxoplasma gondii leads to tissue remodelling in the brain and a continuous requirement for peripheral leucocyte migration within the CNS (central nervous system). In the present study, we investigate the role of MMPs (matrix metalloproteinases) and their inhibitors in T-cell migration into the infected brain. Increased expression of two key molecules, MMP-8 and MMP-10, along with their inhibitor, TIMP-1 (tissue inhibitor of metalloproteinases-1), was observed in the CNS following infection. Analysis of infiltrating lymphocytes demonstrated MMP-8 and -10 production by CD4+ and CD8+ T-cells. In addition, infiltrating T-cells and CNS resident astrocytes increased their expression of TIMP-1 following infection. TIMP-1-deficient mice had a decrease in perivascular accumulation of lymphocyte populations, yet an increase in the proportion of CD4+ T-cells that had trafficked into the CNS. This was accompanied by a reduction in parasite burden in the brain. Taken together, these findings demonstrate a role for MMPs and TIMP-1 in the trafficking of lymphocytes into the CNS during chronic infection in the brain

SPARC coordinates extracellular matrix remodeling and efficient recruitment to and migration of antigen-specific T cells in the brain following infection.

Central nervous system (CNS) injury and infection can result in profound tissue remodeling in the brain, the mechanism and purpose of which is poorly understood. Infection with the protozoan parasite Toxoplasma gondii causes chronic infection and inflammation in the brain parenchyma. Control of parasite replication requires the continuous presence of IFNγ-producing T cells to keep T. gondii in its slowly replicating cyst form. During infection, a network of extracellular matrix fibers, revealed using multiphoton microscopy, forms in the brain. The origin and composition of these structures are unknown but the fibers have been observed to act as a substrate for migrating T cells. In this study, we show a critical regulator of extracellular matrix (ECM) remodeling, Secreted Protein, Acidic, Rich in Cysteine (SPARC), is upregulated in the brain during the early phases of infection in the frontal cortex. In the absence of SPARC, a reduced and disordered fibrous network, increased parasite burden, and reduced antigen-specific T cell entry into the brain points to a role for SPARC in T cell recruitment to and migration within the brain. We also report SPARC can directly bind to CCR7 ligands CCL19 and CCL21 but not CXCL10, and enhance migration toward a chemokine gradient. Measurement of T cell behavior points to tissue remodeling being important for access of immune cells to the brain and facilitating cellular locomotion. Together, these data identify SPARC as an important regulatory component of immune cell trafficking and access to the inflamed CNS

Speculations on the Paleozoic legacy of Gondwana amalgamation

Using Gondwana as an example, we show how the geological record can be interrogated to detect significant changes in mantle convection patterns at critical junctures in Earth’s evolution. Evidence of major changes in mantle circulation in the aftermath of late Neoproterozoic-early Paleozoic Gondwana assembly is provided by widespread (i) plume-related magmatism around Gondwana’s periphery, (ii) ironstone deposits related to mantle plume-ocean ridge interaction and enhanced hydrothermal activity, and (iii) super-mature clastic deposits that reflect epeirogenic uplift triggered by mantle upwelling beneath Gondwana combined with deep tropical weathering. In our model, Gondwana assembled above a region of mantle downwelling in which subducted slabs between the converging Gondwanan continents descended to the core-mantle boundary. Renewed subduction along Gondwana’s periphery yielded early arc magmas. But as downwelling beneath Gondwana evolved into upwelling as a result of the ponding of subducted slabs at the base of the mantle, mantle plumes rose from the margins of the nascent upwelling to interact with the edges of Gondwana, where they penetrated the peripheral subduction zones via slab windows, tears and transform faults to generate voluminous calc-alkalic crustal melts in hydrated arc regions and A-type magmas in dry back-arc regions. The plumes also underplated oceanic lithosphere and interacted with adjacent ocean ridges, thereby enhancing hydrothermal activity and the flux of bioessential nutrients, leading to the recurrence of marine iron-rich sedimentary rocks in the geological record. At the same time, upwelling beneath a tropical to equatorial Gondwana led to epeirogenic uplift, deep weathering and erosion, resulting in the production of widespread super-mature clastic deposits. We contend that major changes in mantle convection patterns were encoded into the geological record of Gondwana assembly, influenced global-scale mantle convection patterns, and should be incorporated into geodynamic models for the assembly of Pangea.NSERCAustralian Research CouncilCzech Operational Programme ResearchMinisterio de Ciencia, Innovación y Universidades/Agencia Estatal de Investigación/Fondo Europeo de Desarrollo RegionalSt. Francis Xavier UniversityNSERC CanadaDepto. de Geodinámica, Estratigrafía y PaleontologíaInstituto de Geociencias (IGEO)TRUEpu