The Watchers of the Water

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AGE-modified basement membrane cooperates with Endo180 to promote epithelial cell invasiveness and decrease prostate cancer survival

Biomechanical strain imposed by age-related thickening of the basal lamina and augmented tissue stiffness in the prostate gland coincides with increased cancer risk. Here we hypothesized that the structural alterations in the basal lamina associated with age can induce mechanotransduction pathways in prostate epithelial cells (PECs) to promote invasiveness and cancer progression. To demonstrate this, we developed a 3D model of PEC acini in which thickening and stiffening of basal lamina matrix was induced by advanced glycation end-product (AGE)-dependent non-enzymatic crosslinking of its major components, collagen IV and laminin. We used this model to demonstrate that antibody targeted blockade of CTLD2, the second of eight C-type lectin-like domains in Endo180 (CD280, CLEC13E, KIAA0709, MRC2, TEM9, uPARAP) that can recognize glycosylated collagens, reversed actinomyosin-based contractility [myosin-light chain-2 (MLC2) phosphorylation], loss of cell polarity, loss of cell–cell junctions, luminal infiltration and basal invasion induced by AGE-modified basal lamina matrix in PEC acini. Our in vitro results were concordant with luminal occlusion of acini in the prostate glands of adult Endo180ΔEx2–6/ΔEx2–6 mice, with constitutively exposed CTLD2 and decreased survival of men with early (non-invasive) prostate cancer with high epithelial Endo180 expression and levels of AGE. These findings indicate that AGE-dependent modification of the basal lamina induces invasive behaviour in non-transformed PECs via a molecular mechanism linked to cancer progression. This study provides a rationale for targeting CTLD2 in Endo180 in prostate cancer and other pathologies in which increased basal lamina thickness and tissue stiffness are driving factors

Phonon Pulse Shape Discrimination in SuperCDMS Soudan

SuperCDMS is the next phase of the Cryogenic Dark Matter Search experiment, which measures both phonon and charge signals generated by particle recoils within a germanium target mass. Charge signals are employed both in the definition of a fiducial volume and in the rejection of electron recoil background events. Alternatively, phonons generated by the charge carriers can also be used for the same two goals. This paper describes preliminary efforts to observe and quantify these contributions to the phonon signal and then use them to reject background events. A simple analysis using only one pulse shape parameter shows bulk electron recoil vs. bulk nuclear recoil discrimination to the level of 1:10^3 (limited by the statistics of the data), with little degradation in discrimination ability down to at least 7 keV recoil energy. Such phonon-only discrimination can provide a useful cross-check to the standard discrimination methods, and it also points towards the potential of a device optimized for a phonon-only measurement.Comment: Low Temperature Detector 14 conference proceedings, to be published in a special issue of the Journal of Low Temperature Physic

SADI, SHARE, and the in silico scientific method

<p>Abstract</p> <p>Background</p> <p>The emergence and uptake of Semantic Web technologies by the Life Sciences provides exciting opportunities for exploring novel ways to conduct <it>in silico</it> science. Web Service Workflows are already becoming first-class objects in “the new way”, and serve as explicit, shareable, referenceable representations of how an experiment was done. In turn, Semantic Web Service projects aim to facilitate workflow construction by biological domain-experts such that workflows can be edited, re-purposed, and re-published by non-informaticians. However the aspects of the scientific method relating to explicit discourse, disagreement, and hypothesis generation have remained relatively impervious to new technologies.</p> <p>Results</p> <p>Here we present SADI and SHARE - a novel Semantic Web Service framework, and a reference implementation of its client libraries. Together, SADI and SHARE allow the semi- or fully-automatic discovery and pipelining of Semantic Web Services in response to <it>ad hoc</it> user queries.</p> <p>Conclusions</p> <p>The semantic behaviours exhibited by SADI and SHARE extend the functionalities provided by Description Logic Reasoners such that novel assertions can be automatically added to a data-set without logical reasoning, but rather by analytical or annotative services. This behaviour might be applied to achieve the “semantification” of those aspects of the <it>in silico</it> scientific method that are not yet supported by Semantic Web technologies. We support this suggestion using an example in the clinical research space.</p

Validation of Phonon Physics in the CDMS Detector Monte Carlo

The SuperCDMS collaboration is a dark matter search effort aimed at detecting the scattering of WIMP dark matter from nuclei in cryogenic germanium targets. The CDMS Detector Monte Carlo (CDMS-DMC) is a simulation tool aimed at achieving a deeper understanding of the performance of the SuperCDMS detectors and aiding the dark matter search analysis. We present results from validation of the phonon physics described in the CDMS-DMC and outline work towards utilizing it in future WIMP search analyses.Comment: 6 Pages, 5 Figures, Proceedings of Low Temperature Detectors 14 Conferenc

Fire and biodiversity in the Anthropocene

The workshop leading to this paper was funded by the Centre Tecnològic Forestal de Catalunya and the ARC Centre of Excellence for Environmental Decisions. L.T.K. was supported by a Victorian Postdoctoral Research Fellowship (Victorian Government), a Centenary Fellowship (University of Melbourne), and an Australian Research Council Linkage Project Grant (LP150100765). A.R. was supported by the Xunta de Galicia (Postdoctoral Fellowship ED481B2016/084-0) and the Foundation for Science and Technology under the FirESmart project (PCIF/MOG/0083/2017). A.L.S. was supported by a Marie Skłodowska-Curie Individual Fellowship (746191) under the European Union Horizon 2020 Programme for Research and Innovation. L.R. was supported by the Australian Government’s National Environmental Science Program through the Threatened Species Recovery Hub. L.B. was partially supported by the Spanish Government through the INMODES (CGL2014-59742-C2-2-R) and the ERANET-SUMFORESTS project FutureBioEcon (PCIN-2017-052). This research was supported in part by the U.S. Department of Agriculture, Forest Service, Pacific Southwest Research Station.BACKGROUND Fire has shaped the diversity of life on Earth for millions of years. Variation in fire regimes continues to be a source of biodiversity across the globe, and many plants, animals, and ecosystems depend on particular temporal and spatial patterns of fire. Although people have been using fire to modify environments for millennia, the combined effects of human activities are now changing patterns of fire at a global scale—to the detriment of human society, biodiversity, and ecosystems. These changes pose a global challenge for understanding how to sustain biodiversity in a new era of fire. We synthesize how changes in fire activity are threatening species with extinction across the globe, highlight forward-looking methods for predicting the combined effects of human drivers and fire on biodiversity, and foreshadow emerging actions and strategies that could revolutionize how society manages fire for biodiversity in the Anthropocene. ADVANCES Our synthesis shows that interactions with anthropogenic drivers such as global climate change, land use, and biotic invasions are transforming fire activity and its impacts on biodiversity. More than 4400 terrestrial and freshwater species from a wide range of taxa and habitats face threats associated with modified fire regimes. Many species are threatened by an increase in fire frequency or intensity, but exclusion of fire in ecosystems that need it can also be harmful. The prominent role of human activity in shaping global ecosystems is the hallmark of the Anthropocene and sets the context in which models and actions must be developed. Advances in predictive modeling deliver new opportunities to couple fire and biodiversity data and to link them with forecasts of multiple drivers including drought, invasive plants, and urban growth. Making these connections also provides an opportunity for new actions that could revolutionize how society manages fire. Emerging actions include reintroduction of mammals that reduce fuels, green fire breaks comprising low-flammability plants, strategically letting wildfires burn under the right conditions, managed evolution of populations aided by new genomics tools, and deployment of rapid response teams to protect biodiversity assets. Indigenous fire stewardship and reinstatement of cultural burning in a modern context will enhance biodiversity and human well-being in many regions of the world. At the same time, international efforts to reduce greenhouse gas emissions are crucial to reduce the risk of extreme fire events that contribute to declines in biodiversity. OUTLOOK Conservation of Earth’s biological diversity will be achieved only by recognition of and response to the critical role of fire in shaping ecosystems. Global changes in fire regimes will continue to amplify interactions between anthropogenic drivers and create difficult trade-offs between environmental and social objectives. Scientific input will be crucial for navigating major decisions about novel and changing ecosystems. Strategic collection of data on fire, biodiversity, and socioeconomic variables will be essential for developing models to capture the feedbacks, tipping points, and regime shifts characteristic of the Anthropocene. New partnerships are also needed to meet the challenges ahead. At the local and regional scale, getting more of the “right” type of fire in landscapes that need it requires new alliances and networks to build and apply knowledge. At the national and global scale, biodiversity conservation will benefit from greater integration of fire into national biodiversity strategies and action plans and in the implementation of international agreements and initiatives such as the UN Convention on Biological Diversity. Placing the increasingly important role of people at the forefront of efforts to understand and adapt to changes in fire regimes is central to these endeavors.PostprintPeer reviewe

Saving the world’s terrestrial megafauna

From the late Pleistocene to the Holocene, and now the so called Anthropocene, humans have been driving an ongoing series of species declines and extinctions (Dirzo et al. 2014). Large-bodied mammals are typically at a higher risk of extinction than smaller ones (Cardillo et al. 2005). However, in some circumstances terrestrial megafauna populations have been able to recover some of their lost numbers due to strong conservation and political commitment, and human cultural changes (Chapron et al. 2014). Indeed many would be in considerably worse predicaments in the absence of conservation action (Hoffmann et al. 2015). Nevertheless, most mammalian megafauna face dramatic range contractions and population declines. In fact, 59% of the world’s largest carnivores (≥ 15 kg, n = 27) and 60% of the world’s largest herbivores (≥ 100 kg, n = 74) are classified as threatened with extinction on the International Union for the Conservation of Nature (IUCN) Red List (supplemental table S1 and S2). This situation is particularly dire in sub-Saharan Africa and Southeast Asia, home to the greatest diversity of extant megafauna (figure 1). Species at risk of extinction include some of the world’s most iconic animals—such as gorillas, rhinos, and big cats (figure 2 top row)—and, unfortunately, they are vanishing just as science is discovering their essential ecological roles (Estes et al. 2011). Here, our objectives are to raise awareness of how these megafauna are imperiled (species in supplemental table S1 and S2) and to stimulate broad interest in developing specific recommendations and concerted action to conserve them

Long Term Protection after Immunization with P. berghei Sporozoites Correlates with Sustained IFNγ Responses of Hepatic CD8+ Memory T Cells

Protection against P. berghei malaria can successfully be induced in mice by immunization with both radiation attenuated sporozoites (RAS) arresting early during liver stage development, or sporozoites combined with chloroquine chemoprophylaxis (CPS), resulting in complete intra-hepatic parasite development before killing of blood-stages by chloroquine takes place. We assessed the longevity of protective cellular immune responses by RAS and CPS P. berghei immunization of C57BL/6j mice. Strong effector and memory (TEM) CD8+ T cell responses were induced predominantly in the liver of both RAS and CPS immunized mice while CD4+ T cells with memory phenotype remained at base line levels. Compared to unprotected naïve mice, we found high sporozoite-specific IFNγ ex vivo responses that associated with induced levels of in vivo CD8+ TEM cells in the liver but not spleen. Long term evaluation over a period of 9 months showed a decline of malaria-specific IFNγ responses in RAS and CPS mice that significantly correlated with loss of protection (r2 = 0.60, p<0.0001). The reducing IFNγ response by hepatic memory CD8+ T cells could be boosted by re-exposure to wild-type sporozoites. Our data show that sustainable protection against malaria associates with distinct intra-hepatic immune responses characterized by strong IFNγ producing CD8+ memory T cells

Disruption of plasmepsin-4 and merozoites surface protein-7 genes in Plasmodium berghei induces combined virulence-attenuated phenotype

Blood stage malaria parasites causing a mild and self limited infection in mice have been obtained with either radiation or chemical mutagenesis showing the possibility of developing an attenuated malaria vaccine. Targeted disruption of plasmepsin-4 (pm4) or the merozoite surface protein-7 (msp7) genes also induces a virulence-attenuated phenotype in terms of absence of experimental cerebral malaria (ECM), delayed increase of parasitemia and reduced mortality rate. The decrease in virulence in parasites lacking either pm4 or msp7 is however incomplete and dependent on the parasite and mouse strain combination. The sequential disruption of both genes induced remarkable virulence-attenuated blood-stage parasites characterized by a self-resolving infection with low levels of parasitemia and no ECM. Furthermore, convalescent mice were protected against the challenge with P. berghei or P. yoelii parasites for several months. These observations provide a proof-of-concept step for the development of human malaria vaccines based on genetically attenuated blood-stage parasites