Learning the language of school history: the role of linguistics in mapping the writing demands of the secondary school curriculum

This paper reports on a research study which used the tools of functional linguistics to illuminate the writing requirements of the history curriculum in the context of Australian secondary schools. It shows how the resulting linguistic description was integrated into a sequence of teaching and learning activities through collaboration between linguist specialists and content/pedagogic specialists. These activities were designed to facilitate students’ writing skills whilst simultaneously developing their historical knowledge. An independent evaluation of the approach pointed to positive changes in teachers’ attitudes and behaviours regarding the role of language in learning history. Equally, students’ writing improved, particularly in terms of its organisation and structure

A test of the cognitive model of negative symptoms: Associations between defeatist performance beliefs, self-efficacy beliefs, and negative symptoms in a non-clinical sample

The cognitive model of negative symptoms posits that defeatist performance beliefs—overgeneralized negative beliefs about one's ability to successfully perform tasks—contribute to the development and maintenance of negative symptoms. However, a conceptually similar construct, reduced generalized self-efficacy—diminished confidence in one's ability to effectively complete or respond to new or challenging tasks and situations—has also been linked to negative symptoms. To identify which beliefs might be most important to target to reduce negative symptoms, we examined: 1) the association between defeatist performance and self-efficacy beliefs and 2) which beliefs are more strongly associated with negative symptoms in a non-clinical sample of young adults (N = 941). Analyses revealed a significant, medium-sized correlation between defeatist performance and self-efficacy beliefs. Both beliefs types were significantly associated with negative symptoms, but defeatist performance beliefs were more strongly related to negative symptoms than self-efficacy beliefs. Defeatist performance and self-efficacy beliefs appear to be distinct yet overlapping constructs. Findings support the cognitive model and indicate that defeatist performance beliefs may have a greater role in the manifestation of negative symptoms than self-efficacy beliefs. Thus, defeatist performance beliefs may be a uniquely promising treatment target for reducing or preventing negative symptoms

Development of a new fusion-enhanced oncolytic immunotherapy platform based on herpes simplex virus type 1.

BackgroundOncolytic viruses preferentially replicate in tumors as compared to normal tissue and promote immunogenic cell death and induction of host systemic anti-tumor immunity. HSV-1 was chosen for further development as an oncolytic immunotherapy in this study as it is highly lytic, infects human tumor cells broadly, kills mainly by necrosis and is a potent activator of both innate and adaptive immunity. HSV-1 also has a large capacity for the insertion of additional, potentially therapeutic, exogenous genes. Finally, HSV-1 has a proven safety and efficacy profile in patients with cancer, talimogene laherparepvec (T-VEC), an oncolytic HSV-1 which expresses GM-CSF, being the only oncolytic immunotherapy approach that has received FDA approval. As the clinical efficacy of oncolytic immunotherapy has been shown to be further enhanced by combination with immune checkpoint inhibitors, developing improved oncolytic platforms which can synergize with other existing immunotherapies is a high priority. In this study we sought to further optimize HSV-1 based oncolytic immunotherapy through multiple approaches to maximize: (i) the extent of tumor cell killing, augmenting the release of tumor antigens and danger-associated molecular pattern (DAMP) factors; (ii) the immunogenicity of tumor cell death; and (iii) the resulting systemic anti-tumor immune response.MethodsTo sample the wide diversity amongst clinical strains of HSV-1, twenty nine new clinical strains isolated from cold sores from otherwise healthy volunteers were screened across a panel of human tumor cell lines to identify the strain with the most potent tumor cell killing ability, which was then used for further development. Following deletion of the genes encoding ICP34.5 and ICP47 to provide tumor selectivity, the extent of cell killing and the immunogenicity of cell death was enhanced through insertion of a gene encoding a truncated, constitutively highly fusogenic form of the envelope glycoprotein of gibbon ape leukemia virus (GALV-GP-R-). A number of further armed derivatives of this virus were then constructed intended to further enhance the anti-tumor immune response which was generated following fusion-enhanced, oncolytic virus replication-mediated cell death. These viruses expressed GMCSF, an anti-CTLA-4 antibody-like molecule, CD40L, OX40L and/or 4-1BB, each of which is expected to act predominantly at the site and time of immune response initiation. Expression of these proteins was confirmed by ELISA and/or western blotting. Immunogenic cell death was assessed by measuring the levels of HMGB1 and ATP from cell free supernatants from treated cells, and by measuring the surface expression of calreticulin. GALV-GP-R- mediated cell to cell fusion and killing was tested in a range of tumor cell lines in vitro. Finally, the in vivo therapeutic potential of these viruses was tested using human A549 (lung cancer) and MDA-MB-231(breast cancer) tumor nude mouse xenograft models and systemic anti-tumor effects tested using dual flank syngeneic 4434 (melanoma), A20 (lymphoma) mouse tumor models alone and in combination with a murine anti-PD1 antibody, and 9 L (gliosarcoma) tumors in rats.ResultsThe twenty nine clinical strains of HSV-1 isolated and tested demonstrated a broad range of tumor cell killing abilities allowing the most potent strain to be identified which was then used for further development. Oncolytic ability was demonstrated to be further augmented by the expression of GALV-GP-R- in a range of tumor cell lines in vitro and in mouse xenograft models in nude mice. The expression of GALV-GP-R- was also demonstrated to lead to enhanced immunogenic cell death in vitro as confirmed by the increased release of HMGB1 and ATP and increased levels of calreticulin on the cell surface. Experiments using the rat 9 L syngeneic tumor model demonstrated that GALV-GP-R- expression increased abscopal uninjected (anenestic) tumor responses and data using mouse 4434 tumors demonstrated that virus treatment increased CD8+ T cell levels both in the injected and uninjected tumor, and also led to increased expression of PD-L1. A combination study using varying doses of a virus expressing GALV-GP-R- and mGM-CSF and an anti-murine PD1 antibody showed enhanced anti-tumor effects with the combination which was most evident at low virus doses, and also lead to immunological memory. Finally, treatment of mice with derivatives of this virus which additionally expressed anti-mCTLA-4, mCD40L, m4-1BBL, or mOX40L demonstrated enhanced activity, particularly in uninjected tumors.ConclusionThe new HSV-1 based platform described provides a potent and versatile approach to developing new oncolytic immunotherapies for clinical use. Each of the modifications employed was demonstrated to aid in optimizing the potential of the virus to both directly kill tumors and to lead to systemic therapeutic benefit. For clinical use, these viruses are expected to be most effective in combination with other anti-cancer agents, in particular PD1/L1-targeted immune checkpoint blockade. The first virus from this program (expressing GALV-GP-R- and hGM-CSF) has entered clinical development alone and in combination with anti-PD1 therapy in a number of tumor types (NCT03767348)

The Osmium Isotope Signature of Phanerozoic Large Igneous Provinces

The emplacement of Large Igneous Provinces (LIPs) throughout the Phanerozoic Eon introduced vast quantities of mafic rocks to the Earth's surface, which were subsequently weathered into the oceans. Osmium isotope data can be used to track these LIP-related weathering fluxes, providing a global fingerprint of the timing and magnitude of LIP emplacement, and guiding assessments of the impact of these events on ocean biogeochemistry and the regulation of the global climate system. Sedimentary Os isotope records spanning late Phanerozoic LIP events are reviewed herein and new observations from Eocene hyperthermal event ETM-2 are presented. While Os isotope stratigraphy can provide major constraints on LIP activity in the geological record, it cannot always distinguish whether the extrusive activity was subaerial or submarine. The utility of osmium isotopes as a global tracer of past volcanism may be enhanced when used alongside proxies such as mercury concentrations, which may be more diagnostic of the style of individual episodes of LIP emplacement. Hitherto, only a few high-resolution Os-isotope records across Phanerozoic LIPs have effectively exploited the short oceanic residence time of Os. Future high-resolution studies across suitable, well-preserved stratigraphic records will significantly improve our understanding of the nature, progression, and consequences of LIP emplacement

Underground railroads: citizen entitlements and unauthorized mobility in the antebellum period and today

In recent years, some scholars and prominent political figures have advocated the deepening of North American integration on roughly the European Union model, including the creation of new political institutions and the free movement of workers across borders. The construction of such a North American Union, if it included even a very thin trans-state citizenship regime, could represent the most significant expansion of individual entitlements in the region since citizenship was extended to former slaves in the United States. With such a possibility as its starting point, this article explores some striking parallels between the mass, legally prohibited movement across boundaries by fugitive slaves in the pre-Civil War period, and that by current unauthorized migrants to the United States. Both were, or are, met on their journeys by historically parallel groups of would-be helpers and hinderers. Their unauthorized movements in both periods serve as important signals of incomplete entitlements or institutional protections. Most crucially, moral arguments for extending fuller entitlements to both groups are shown here to be less distinct than may be prima facie evident, reinforcing the case for expanding and deepening the regional membership regime

Single Cell Analysis of Lymph Node Tissue from HIV-1 Infected Patients Reveals that the Majority of CD4⁺ T-cells Contain One HIV-1 DNA Molecule

Genetic recombination contributes to the diversity of human immunodeficiency virus (HIV-1). Productive HIV-1 recombination is, however, dependent on both the number of HIV-1 genomes per infected cell and the genetic relationship between these viral genomes. A detailed analysis of the number of proviruses and their genetic relationship in infected cells isolated from peripheral blood and tissue compartments is therefore important for understanding HIV-1 recombination, genetic diversity and the dynamics of HIV-1 infection. To address these issues, we used a previously developed single-cell sequencing technique to quantify and genetically characterize individual HIV-1 DNA molecules from single cells in lymph node tissue and peripheral blood. Analysis of memory and naïve CD4+ T cells from paired lymph node and peripheral blood samples from five untreated chronically infected patients revealed that the majority of these HIV-1-infected cells (>90%) contain only one copy of HIV-1 DNA, implying a limited potential for productive recombination in virus produced by these cells in these two compartments. Phylogenetic analysis revealed genetic similarity of HIV-1 DNA in memory and naïve CD4+ T-cells from lymph node, peripheral blood and HIV-1 RNA from plasma, implying exchange of virus and/or infected cells between these compartments in untreated chronic infection

Aneurysm permeability following coil embolization: packing density and coil distribution

BACKGROUND: Rates of durable aneurysm occlusion following coil embolization vary widely, and a better understanding of coil mass mechanics is desired. The goal of this study is to evaluate the impact of packing density and coil uniformity on aneurysm permeability. METHODS: Aneurysm models were coiled using either Guglielmi detachable coils or Target coils. The permeability was assessed by taking the ratio of microspheres passing through the coil mass to those in the working fluid. Aneurysms containing coil masses were sectioned for image analysis to determine surface area fraction and coil uniformity. RESULTS: All aneurysms were coiled to a packing density of at least 27%. Packing density, surface area fraction of the dome and neck, and uniformity of the dome were significantly correlated (p \u3c 0.05). Hence, multivariate principal components-based partial least squares regression models were used to predict permeability. Similar loading vectors were obtained for packing and uniformity measures. Coil mass permeability was modeled better with the inclusion of packing and uniformity measures of the dome (r(2)=0.73) than with packing density alone (r(2)=0.45). The analysis indicates the importance of including a uniformity measure for coil distribution in the dome along with packing measures. CONCLUSIONS: A densely packed aneurysm with a high degree of coil mass uniformity will reduce permeability

The STAR Silicon Strip Detector (SSD)

The STAR Silicon Strip Detector (SSD) completes the three layers of the Silicon Vertex Tracker (SVT) to make an inner tracking system located inside the Time Projection Chamber (TPC). This additional fourth layer provides two dimensional hit position and energy loss measurements for charged particles, improving the extrapolation of TPC tracks through SVT hits. To match the high multiplicity of central Au+Au collisions at RHIC the double sided silicon strip technology was chosen which makes the SSD a half million channels detector. Dedicated electronics have been designed for both readout and control. Also a novel technique of bonding, the Tape Automated Bonding (TAB), was used to fullfill the large number of bounds to be done. All aspects of the SSD are shortly described here and test performances of produced detection modules as well as simulated results on hit reconstruction are given.Comment: 11 pages, 8 figures, 1 tabl

Can Doubly Strange Dibaryon Resonances be Discovered at RHIC?

The baryon-baryon continuum invariant mass spectrum generated from relativistic nucleus + nucleus collision data may reveal the existence of doubly-strange dibaryons not stable against strong decay if they lie within a few MeV of threshold. Furthermore, since the dominant component of these states is a superposition of two color-octet clusters which can be produced intermediately in a color-deconfined quark-gluon plasma (QGP), an enhanced production of dibaryon resonances could be a signal of QGP formation. A total of eight, doubly-strange dibaryon states are considered for experimental search using the STAR detector (Solenoidal Tracker at RHIC) at the new Relativistic Heavy Ion Collider (RHIC). These states may decay to Lambda-Lambda and/or proton-Cascade-minus, depending on the resonance energy. STAR's large acceptance, precision tracking and vertex reconstruction capabilities, and large data volume capacity, make it an ideal instrument to use for such a search. Detector performance and analysis sensitivity are studied as a function of resonance production rate and width for one particular dibaryon which can directly strong decay to proton-Cascade-minus but not Lambda-Lambda. Results indicate that such resonances may be discovered using STAR if the resonance production rates are comparable to coalescence model predictions for dibaryon bound states.Comment: 28 pages, 5 figures, revised versio