174 research outputs found
Dynamic stroma reorganization drives blood vessel dysmorphia during glioma growth
Glioma growth and progression are characterized by abundant development of blood vessels that are highly aberrant and poorly functional, with detrimental consequences for drug delivery efficacy. The mechanisms driving this vessel dysmorphia during tumor progression are poorly understood. Using longitudinal intravital imaging in a mouse glioma model, we identify that dynamic sprouting and functional morphogenesis of a highly branched vessel network characterize the initial tumor growth, dramatically changing to vessel expansion, leakage, and loss of branching complexity in the later stages. This vascular phenotype transition was accompanied by recruitment of predominantly pro-inflammatory M1-like macrophages in the early stages, followed by in situ repolarization to M2-like macrophages, which produced VEGF-A and relocate to perivascular areas. A similar enrichment and perivascular accumulation of M2 versus M1 macrophages correlated with vessel dilation and malignancy in human glioma samples of different WHO malignancy grade. Targeting macrophages using anti-CSF1 treatment restored normal blood vessel patterning and function. Combination treatment with chemotherapy showed survival benefit, suggesting that targeting macrophages as the key driver of blood vessel dysmorphia in glioma progression presents opportunities to improve efficacy of chemotherapeutic agents. We propose that vessel dysfunction is not simply a general feature of tumor vessel formation, but rather an emergent property resulting from a dynamic and functional reorganization of the tumor stroma and its angiogenic influences
The Śnieżka peatland as a candidate for the Global Boundary Stratotype Section and Point for the Anthropocene series
The subalpine, atmospherically fed Śnieżka peatland, located in the Polish part of the Sudetes, is one of the nominated candidates for the GSSP of the Anthropocene. Data from two profiles, Sn1 (2012) and Sn0 (2020), from this site are critical for distinguishing the proposed epoch, while an additional core Sn2 is presented to support main evidence. The Sn0 archive contains a wide array of critical markers such as plutonium (Pu), radiocarbon (F14C), fly ash particles, Hg and stable C and N isotopes which are consistent with the previously well documented 210Pb/14C dated Sn1 profile, which provides a high-resolution and comprehensive database of trace elements and rare earth elements (REE), Pb isotopes, Pu, Cs, pollen and testate amoebae. The 1952 worldwide appearance of Pu, owing to its global synchronicity and repeatability between the cores, is proposed here as a primary marker of the Anthropocene, supported by the prominent upturn of selected chemostratigraphic and biostratigraphic indicators as well as the appearance of technofossils and artificial radionuclides
Proceedings of the second "international Traveling Workshop on Interactions between Sparse models and Technology" (iTWIST'14)
The implicit objective of the biennial "international - Traveling Workshop on
Interactions between Sparse models and Technology" (iTWIST) is to foster
collaboration between international scientific teams by disseminating ideas
through both specific oral/poster presentations and free discussions. For its
second edition, the iTWIST workshop took place in the medieval and picturesque
town of Namur in Belgium, from Wednesday August 27th till Friday August 29th,
2014. The workshop was conveniently located in "The Arsenal" building within
walking distance of both hotels and town center. iTWIST'14 has gathered about
70 international participants and has featured 9 invited talks, 10 oral
presentations, and 14 posters on the following themes, all related to the
theory, application and generalization of the "sparsity paradigm":
Sparsity-driven data sensing and processing; Union of low dimensional
subspaces; Beyond linear and convex inverse problem; Matrix/manifold/graph
sensing/processing; Blind inverse problems and dictionary learning; Sparsity
and computational neuroscience; Information theory, geometry and randomness;
Complexity/accuracy tradeoffs in numerical methods; Sparsity? What's next?;
Sparse machine learning and inference.Comment: 69 pages, 24 extended abstracts, iTWIST'14 website:
http://sites.google.com/site/itwist1
Indonesian Throughflow drove Australian climate form humid Pliocene to arid Pleistocene
Late Miocene to mid-Pleistocene sedimentary proxy records reveal that northwest Australia underwent an abrupt transition from dry to humid climate conditions at 5.5 million years (Ma), likely receiving year-round rainfall, but after ~3.3 Ma, climate shifted toward an increasingly seasonal precipitation regime. The progressive constriction of the Indonesian Throughflow likely decreased continental humidity and transferred control of northwest Australian climate from the Pacific to the Indian Ocean, leading to drier conditions punctuated by monsoonal precipitation. The northwest dust pathway and fully established seasonal and orbitally controlled precipitation were in place by ~2.4 Ma, well after the intensification of Northern Hemisphere glaciation. The transition from humid to arid conditions was driven by changes in Pacific and Indian Ocean circulation and regional atmospheric moisture transport, influenced by the emerging Maritime Continent. We conclude that the Maritime Continent is the switchboard modulating teleconnections between tropical and high-latitude climate systems.published_or_final_versio
Development and refinement of proxy-climate indicators from peats
Peat, especially from acidic mires (bogs), is a natural archive of past environmental change. Reconstructions of past climate from bogs commenced in the 19th Century through examination of visible peat stratigraphy, and later formed the basis for a postglacial climatic scheme widely used in Northwest Europe. Nevertheless, misconceptions as to how bogs grow led to a 50-year lacuna in peat-climate study, before the concept of "cyclic regeneration" in bogs was refuted. In recent decades, research using proxyclimate indicators from bogs has burgeoned. A range of proxies for past hydrological change has been developed, as well as use of pollen, bog oaks and pines and other data to reconstruct past temperatures. Most of this proxy-climate research has been carried out in Northern Europe, but peat-based research in parts of Asia and North America has increased, particularly during the last decade, while research has also been conducted in Australia, New Zealand and South America. This paper reviews developments in proxy-climate reconstructions from peatlands; chronicles use of a range of palaeo-proxies such as visible peat stratigraphy, plant macrofossils, peat humification, testate amoebae and non-pollen palynomorphs; and explains the use of wiggle-match radiocarbon dating and relationship to climate shifts. It details other techniques being used increasingly, such as biomarkers, stable-isotopes, inorganic geochemistry and estimation of dust flux; and points to new proxies under development. Although explicit protocols have been developed recently for research on ombrotrophic mires, it must be recognised that not all proxies and techniques have universal applicability, owing to differences in species assemblages, mire formation, topographic controls, and geochemical characteristics
Single-cell profiling and zebrafish avatars reveal LGALS1 as immunomodulating target in glioblastoma
Glioblastoma (GBM) remains the most malignant primary brain tumor, with a median survival rarely exceeding 2 years. Tumor heterogeneity and an immunosuppressive microenvironment are key factors contributing to the poor response rates of current therapeutic approaches. GBM-associated macrophages (GAMs) often exhibit immunosuppressive features that promote tumor progression. However, their dynamic interactions with GBM tumor cells remain poorly understood. Here, we used patient-derived GBM stem cell cultures and combined single-cell RNA sequencing of GAM-GBM co-cultures and real-time in vivo monitoring of GAM-GBM interactions in orthotopic zebrafish xenograft models to provide insight into the cellular, molecular, and spatial heterogeneity. Our analyses revealed substantial heterogeneity across GBM patients in GBM-induced GAM polarization and the ability to attract and activate GAMs—features that correlated with patient survival. Differential gene expression analysis, immunohistochemistry on original tumor samples, and knock-out experiments in zebrafish subsequently identified LGALS1 as a primary regulator of immunosuppression. Overall, our work highlights that GAM-GBM interactions can be studied in a clinically relevant way using co-cultures and avatar models, while offering new opportunities to identify promising immune-modulating targets
Lead content and isotopic composition in submound and recent soils of the Volga upland
Literature data on the historical reconstructions of the atmospheric lead deposition in Europe and the isotopic composition of the ores that are potential sources of the anthropogenic lead in the atmospheric deposition in the lower Volga steppes during different time periods have been compiled. The effect of the increasing anthropogenic lead deposition recorded since the Bronze Age on the level of soil contamination has been investigated. For the first time paleosol buried under a burial mound of the Bronze Age has been used as a reference point to assess of the current contamination level. The contents and isotopic compositions of the mobile and total lead have been determined in submound paleosols of different ages and their recent remote and roadside analogues. An increase in the content and fraction of the mobile lead and a shift of its isotopic composition toward less radiogenic values (typical for lead from the recent anthropogenic sources) has been revealed when going from a Bronze-Age paleosol to a recent soil. In the Bronze-Age soil, the isotopic composition of the mobile lead is inherited from the parent rock to a greater extent than in the modern soils, where the lead is enriched with the less radiogenic component. The effect of the anthropogenic component is traced in the analysis of the mobile lead, but it is barely visible for the total lead. An exception is provided by the recent roadside soils characterized by increased contents and the significantly less radiogenic isotopic composition of the mobile and total lead
Posture Does Not Matter! Paw Usage and Grasping Paw Preference in a Small-Bodied Rooting Quadrupedal Mammal
BACKGROUND: Recent results in birds, marsupials, rodents and nonhuman primates suggest that phylogeny and ecological factors such as body size, diet and postural habit of a species influence limb usage and the direction and strength of limb laterality. To examine to which extent these findings can be generalised to small-bodied rooting quadrupedal mammals, we studied trees shrews (Tupaia belangeri). METHODOLOGY/PRINCIPAL FINDINGS: We established a behavioural test battery for examining paw usage comparable to small-bodied primates and tested 36 Tupaia belangeri. We studied paw usage in a natural foraging situation (simple food grasping task) and measured the influence of varying postural demands (triped, biped, cling, sit) on paw preferences by applying a forced-food grasping task similar to other small-bodied primates. Our findings suggest that rooting tree shrews prefer mouth over paw usage to catch food in a natural foraging situation. Moreover, we demonstrated that despite differences in postural demand, tree shrews show a strong and consistent individual paw preference for grasping across different tasks, but no paw preference at a population level. CONCLUSIONS/SIGNIFICANCE: Tree shrews showed less paw usage than small-bodied quadrupedal and arboreal primates, but the same paw preference. Our results confirm that individual paw preferences remain constant irrespective of postural demand in some small-bodied quadrupedal non primate and primate mammals which do not require fine motoric control for manipulating food items. Our findings suggest that the lack of paw/hand preference for grasping food at a population level is a universal pattern among those species and that the influence of postural demand on manual lateralisation in quadrupeds may have evolved in large-bodied species specialised in fine manipulations of food items
Predicting Outcomes of Prostate Cancer Immunotherapy by Personalized Mathematical Models
Therapeutic vaccination against disseminated prostate cancer (PCa) is partially effective in some PCa patients. We hypothesized that the efficacy of treatment will be enhanced by individualized vaccination regimens tailored by simple mathematical models.We developed a general mathematical model encompassing the basic interactions of a vaccine, immune system and PCa cells, and validated it by the results of a clinical trial testing an allogeneic PCa whole-cell vaccine. For model validation in the absence of any other pertinent marker, we used the clinically measured changes in prostate-specific antigen (PSA) levels as a correlate of tumor burden. Up to 26 PSA levels measured per patient were divided into each patient's training set and his validation set. The training set, used for model personalization, contained the patient's initial sequence of PSA levels; the validation set contained his subsequent PSA data points. Personalized models were simulated to predict changes in tumor burden and PSA levels and predictions were compared to the validation set. The model accurately predicted PSA levels over the entire measured period in 12 of the 15 vaccination-responsive patients (the coefficient of determination between the predicted and observed PSA values was R(2) = 0.972). The model could not account for the inconsistent changes in PSA levels in 3 of the 15 responsive patients at the end of treatment. Each validated personalized model was simulated under many hypothetical immunotherapy protocols to suggest alternative vaccination regimens. Personalized regimens predicted to enhance the effects of therapy differed among the patients.Using a few initial measurements, we constructed robust patient-specific models of PCa immunotherapy, which were retrospectively validated by clinical trial results. Our results emphasize the potential value and feasibility of individualized model-suggested immunotherapy protocols
Immunotherapy of pediatric brain tumor patients should include an immunoprevention strategy: a medical hypothesis paper
Adults diagnosed with Glioblastoma multiforme (GBM) are frequently faced with a 7% chance of surviving 2 years compared with pediatric patients with GBM who have a 26% survival rate. Our recent screen of possible glioma-associated antigen precursor protein (TAPP) profiles displayed from different types of pediatric brain tumors showed that pediatric patients contained a subset of the tumor antigens displayed by adult GBM patients. Adult GBM possess at least 27 tumor antigens that can potentially stimulate T cell immune responses, suggesting that these tumors are quite antigenic. In contrast, pediatric brain tumors only expressed nine tumor antigens with mRNA levels that were equivalent to those displayed by adult GBM. These tumor-associated antigens could be used as possible targets of therapeutic immunization for pediatric brain cancer patients. Children have developing immune systems that peak at puberty. An immune response mounted by these pediatric patients might account for their extended life spans, even though the pediatric brain tumors express far fewer total tumor-associated antigens. Here we present a hypothesis that pediatric brain tumor patients might be the best patients to show that immunotherapy can be used to successfully treat established cancers. We speculate that immunotherapy should include a panel of tumor antigens that might prevent the out-growth of more malignant tumor cells and thereby prevent the brain tumor relapse. Thus, pediatric brain tumor patients might provide an opportunity to prove the concept of immunoprevention
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