In vitro and in vivo evaluation of human adenovirus type 49 as a vector for therapeutic applications

The human adenovirus phylogenetic tree is split across seven species (A–G). Species D adenoviruses offer potential advantages for gene therapy applications, with low rates of pre-exist-ing immunity detected across screened populations. However, many aspects of the basic virology of species D—such as their cellular tropism, receptor usage, and in vivo biodistribution profile— remain unknown. Here, we have characterized human adenovirus type 49 (HAdV-D49)—a rela-tively understudied species D member. We report that HAdV-D49 does not appear to use a single pathway to gain cell entry, but appears able to interact with various surface molecules for entry. As such, HAdV-D49 can transduce a broad range of cell types in vitro, with variable engagement of blood coagulation FX. Interestingly, when comparing in vivo biodistribution to adenovirus type 5, HAdV-D49 vectors show reduced liver targeting, whilst maintaining transduction of lung and spleen. Overall, this presents HAdV-D49 as a robust viral vector platform for ex vivo manipulation of human cells, and for in vivo applications where the therapeutic goal is to target the lung or gain access to immune cells in the spleen, whilst avoiding liver interactions, such as intravascular vaccine applications

Computers in Secondary Schools: Educational Games

This entry introduces educational games in secondary schools. Educational games include three main types of educational activities with a playful learning intention supported by digital technologies: educational serious games, educational gamification, and learning through game creation. Educational serious games are digital games that support learning objectives. Gamification is defined as the use of "game design elements and game thinking in a non-gaming context" (Deterding et al. 2011, p. 13). Educational gamification is not developed through a digital game but includes game elements for supporting the learning objectives. Learning through game creation is focused on the process of designing and creating a prototype of a game to support a learning process related to the game creation process or the knowledge mobilized through the game creation process. Four modalities of educational games in secondary education are introduced in this entry to describe educational games in secondary education: educational purpose of entertainment games, serious games, gamification, and game design

Destabilization of the thermohaline circulation by transient perturbations to the hydrological cycle

We reconsider the problem of the stability of the thermohaline circulation as described by a two-dimensional Boussinesq model with mixed boundary conditions. We determine how the stability properties of the system depend on the intensity of the hydrological cycle. We define a two-dimensional parameters' space descriptive of the hydrology of the system and determine, by considering suitable quasi-static perturbations, a bounded region where multiple equilibria of the system are realized. We then focus on how the response of the system to finite-amplitude surface freshwater forcings depends on their rate of increase. We show that it is possible to define a robust separation between slow and fast regimes of forcing. Such separation is obtained by singling out an estimate of the critical growth rate for the anomalous forcing, which can be related to the characteristic advective time scale of the system.Comment: 37 pages, 8 figures, submitted to Clim. Dy

30% land conservation and climate action reduces tropical extinction risk by more than 50%

Limiting climate change to less than 2°C is the focus of international policy under the climate convention (UNFCCC), and is essential to preventing extinctions, a focus of the Convention on Biological Diversity (CBD). The post‐2020 biodiversity framework drafted by the CBD proposes conserving 30% of both land and oceans by 2030. However, the combined impact on extinction risk of species from limiting climate change and increasing the extent of protected and conserved areas has not been assessed. Here we create conservation spatial plans to minimize extinction risk in the tropics using data on 289 219 species and modeling two future greenhouse gas concentration pathways (RCP2.6 and 8.5) while varying the extent of terrestrial protected land and conserved areas from <17% to 50%. We find that limiting climate change to 2°C and conserving 30% of terrestrial area could more than halve aggregate extinction risk compared with uncontrolled climate change and no increase in conserved area

Large-scale associations between the leukocyte transcriptome and BOLD responses to speech differ in autism early language outcome subtypes.

Heterogeneity in early language development in autism spectrum disorder (ASD) is clinically important and may reflect neurobiologically distinct subtypes. Here, we identified a large-scale association between multiple coordinated blood leukocyte gene coexpression modules and the multivariate functional neuroimaging (fMRI) response to speech. Gene coexpression modules associated with the multivariate fMRI response to speech were different for all pairwise comparisons between typically developing toddlers and toddlers with ASD and poor versus good early language outcome. Associated coexpression modules were enriched in genes that are broadly expressed in the brain and many other tissues. These coexpression modules were also enriched in ASD-associated, prenatal, human-specific, and language-relevant genes. This work highlights distinctive neurobiology in ASD subtypes with different early language outcomes that is present well before such outcomes are known. Associations between neuroimaging measures and gene expression levels in blood leukocytes may offer a unique in vivo window into identifying brain-relevant molecular mechanisms in ASD

IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection

Funding: This work was funded by a Career Development Fellowship (1028634) and a project grant (GRNT1028641) awarded to AHa by the Australian National Health & Medical Research Council (NHMRC). IS was supported by The University of Queensland Centennial and IPRS Scholarships. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Vaccines against toxoplasma gondii : challenges and opportunities

Development of vaccines against Toxoplasma gondii infection in humans is of high priority, given the high burden of disease in some areas of the world like South America, and the lack of effective drugs with few adverse effects. Rodent models have been used in research on vaccines against T. gondii over the past decades. However, regardless of the vaccine construct, the vaccines have not been able to induce protective immunity when the organism is challenged with T. gondii, either directly or via a vector. Only a few live, attenuated T. gondii strains used for immunization have been able to confer protective immunity, which is measured by a lack of tissue cysts after challenge. Furthermore, challenge with low virulence strains, especially strains with genotype II, will probably be insufficient to provide protection against the more virulent T. gondii strains, such as those with genotypes I or II, or those genotypes from South America not belonging to genotype I, II or III. Future studies should use animal models besides rodents, and challenges should be performed with at least one genotype II T. gondii and one of the more virulent genotypes. Endpoints like maternal-foetal transmission and prevention of eye disease are important in addition to the traditional endpoint of survival or reduction in numbers of brain cysts after challenge

Return of naturally sourced Pb to Atlantic surface waters

Anthropogenic emissions completely overwhelmed natural marine lead (Pb) sources during the past century, predominantly due to leaded petrol usage. Here, based on Pb isotope measurements, we reassess the importance of natural and anthropogenic Pb sources to the tropical North Atlantic following the nearly complete global cessation of leaded petrol use. Significant proportions of up to 30-50% of natural Pb, derived from mineral dust, are observed in Atlantic surface waters, reflecting the success of the global effort to reduce anthropogenic Pb emissions. The observation of mineral dust derived Pb in surface waters is governed by the elevated atmospheric mineral dust concentration of the North African dust plume and the dominance of dry deposition for the atmospheric aerosol flux to surface waters. Given these specific regional conditions, emissions from anthropogenic activities will remain the dominant global marine Pb source, even in the absence of leaded petrol combustion

Vitalism in Early Modern Medical and Philosophical Thought

Vitalism is a notoriously deceptive term. It is very often defined as the view, in biology, in early modern medicine and differently, in early modern philosophy, that living beings differ from the rest of the physical universe due to their possessing an additional ‘life-force’, ‘vital principle’, ‘entelechy’, enormon or élan vital. Such definitions most often have an explicit pejorative dimension: vitalism is a primitive or archaic view, that has somehow survived the emergence of modern science (the latter being defined in many different ways, from demystified Cartesian reductionism to experimental medicine, biochemistry or genetics: Cimino and Duchesneau eds. 1997, Normandin and Wolfe eds. 2013). Such dismissive definitions of vitalism are meant to dispense with argument or analysis. Curiously, the term has gained some popularity in English-language scholarship on early modern philosophy in the past few decades, where it is used without any pejorative dimension, to refer to a kind of ‘active matter’ view, in which matter is not reducible to the (mechanistic) properties of size, shape and motion, possessing instead some internal dynamism or activity (see e.g. James 1999, Boyle 2018, Borcherding forthcoming). The latter meaning is close to what the Cambridge Platonist Ralph Cudworth termed ‘hylozoism’, namely the attribution of life, agency or mind to matter, and he implicitly targeted several figures I shall mention here, notably Margaret Cavendish and Francis Glisson, for holding this view. However, one point I shall make in this entry is that when vitalism first appears by name, and as a self-designation, in the Montpellier School (associated with the Faculty of Medicine at the University of Montpellier, in the second half of the eighteenth century; thus vitalisme appears first, followed shortly thereafter by Vitalismus in German, with ‘vitalism’ appearing in English publications only in the early nineteenth century: Toepfer 2011), it is quite different from both the more ‘supernatural’ view described above – chiefly espoused by its rather obsessive opponents – and from the more neutral, but also de-biologized philosophical view (that of e.g. Cavendish or Conway who are, broadly speaking naturalists). Rather than appealing to a metaphysics of vital force, or of self-organizing matter, this version of vitalism, which I shall refer to as ‘medical vitalism’, seems to be more of a ‘systemic’ theory: an attempt to grasp and describe top-level (‘organizational’, ‘organismic’, ‘holistic’) features of living systems (Wolfe 2017, 2019). In this entry I seek to introduce some periodization in our thinking about early modern (and Enlightenment) vitalism, emphasizing the difference between the seventeenth-century context and that of the following generations – culminating in the ideas of the Montpellier School. This periodization should also function as a kind of taxonomy or at least distinction between some basic types of vitalism. As I discuss in closing, these distinctions can cut across the texts and figures we are dealing with, differently: metaphysical vs. non-metaphysical vitalism, philosophical vs. medical vitalism, medical vs. ‘embryological’ vitalism, and so on. A difference I can only mention but not explore in detail is that the more medically grounded, ‘organismic’ vitalism is significantly post-Cartesian while the more biological/embryological vitalism is, inasmuch as it is a dynamic, self-organizing matter theory, an extension of Renaissance ideas (chymiatry, Galenism and in general theories of medical spirits). I examine successively vitalism’s Renaissance prehistory, its proliferation as ‘vital matter theory’ in seventeenth-century England (in authors such as Cavendish, Conway and Glisson, with brief considerations on Harvey and van Helmont), and its mature expression in eighteenth-century Montpellier (notably with Bordeu and Ménuret de Chambaud)