Computer simulation of syringomyelia in dogs

Syringomyelia is a pathological condition in which fluid-filled cavities (syringes) form and expand in the spinal cord. Syringomyelia is often linked with obstruction of the craniocervical junction and a Chiari malformation, which is similar in both humans and animals. Some brachycephalic toy breed dogs such as Cavalier King Charles Spaniels (CKCS) are particularly predisposed. The exact mechanism of the formation of syringomyelia is undetermined and consequently with the lack of clinical explanation, engineers and mathematicians have resorted to computer models to identify possible physical mechanisms that can lead to syringes. We developed a computer model of the spinal cavity of a CKCS suffering from a large syrinx. The model was excited at the cranial end to simulate the movement of the cerebrospinal fluid (CSF) and the spinal cord due to the shift of blood volume in the cranium related to the cardiac cycle. To simulate the normal condition, the movement was prescribed to the CSF. To simulate the pathological condition, the movement of CSF was blocked

CD95 maintains stem cell-like and non-classical EMT programs in primary human glioblastoma cells

Glioblastoma (GBM) is one of the most aggressive types of cancer with limited therapeutic options and unfavorable prognosis. Stemness and non-classical epithelial-to-mesenchymal transition (ncEMT) features underlie the switch from normal to neoplastic states as well as resistance of tumor clones to current therapies. Therefore, identification of ligand/receptor systems maintaining this privileged state is needed to devise efficient cancer therapies. In this study, we show that the expression of CD95 associates with stemness and EMT features in GBM tumors and cells and serves as a prognostic biomarker. CD95 expression increases in tumors and with tumor relapse as compared with non- tumor tissue. Recruitment of the activating PI3K subunit, p85, to CD95 death domain is required for maintenance of EMT-related transcripts. A combination of the current GBM therapy, temozolomide, with a CD95 inhibitor dramatically abrogates tumor sphere formation. This study molecularly dissects the role of CD95 in GBM cells and contributes the rational for CD95 inhibition as a GBM therapy

Investigation of fullerenol-induced changes in poroelasticity of human hepatocellular carcinoma by AFM-based creep tests

In this study, atomic force microscopy (AFM) is used to investigate the alterations of the poroelastic properties of hepatocellular carcinoma (SMMC-7721) cells treated with fullerenol. The SMMC-7721 cells were subject to AFM-based creep tests, and a corresponding poroelastic indentation model was used to determine the poroelastic parameters by curve fitting. Comparative analyses indicated that the both permeability and diffusion of fullerenol-treated cells increased significantly while their elastic modulus decreased by a small amount. From the change in the trend of the determined parameter, we verified the corresponding alternations of cytoskeleton (mainly filaments actin), which was reported by the previous study using confocal imaging method. Our investigation on SMMC-7721 cell reveals that the poroelastic properties could provide a better understanding how the cancer cells are affected by fullerenol or potentially other drugs which could find possible applications in drug efficacy test, cancer diagnosis and secure therapies.EU Horizon 2020 projec

Cellular Differentiation of Human Monocytes Is Regulated by Time-Dependent Interleukin-4 Signaling and the Transcriptional Regulator NCOR2.

Human in vitro generated monocyte-derived dendritic cells (moDCs) and macrophages are used clinically, e.g., to induce immunity against cancer. However, their physiological counterparts, ontogeny, transcriptional regulation, and heterogeneity remains largely unknown, hampering their clinical use. High-dimensional techniques were used to elucidate transcriptional, phenotypic, and functional differences between human in vivo and in vitro generated mononuclear phagocytes to facilitate their full potential in the clinic. We demonstrate that monocytes differentiated by macrophage colony-stimulating factor (M-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF) resembled in vivo inflammatory macrophages, while moDCs resembled in vivo inflammatory DCs. Moreover, differentiated monocytes presented with profound transcriptomic, phenotypic, and functional differences. Monocytes integrated GM-CSF and IL-4 stimulation combinatorically and temporally, resulting in a mode- and time-dependent differentiation relying on NCOR2. Finally, moDCs are phenotypically heterogeneous and therefore necessitate the use of high-dimensional phenotyping to open new possibilities for better clinical tailoring of these cellular therapies

β-Glucan-Induced Trained Immunity Protects against <i>Leishmania braziliensis</i> Infection:a Crucial Role for IL-32

American tegumentary leishmaniasis is a vector-borne parasitic disease caused by Leishmania protozoans. Innate immune cells undergo long-term functional reprogramming in response to infection or Bacillus Calmette-Guérin (BCG) vaccination via a process called trained immunity, conferring non-specific protection from secondary infections. Here, we demonstrate that monocytes trained with the fungal cell wall component β-glucan confer enhanced protection against infections caused by Leishmania braziliensis through the enhanced production of proinflammatory cytokines. Mechanistically, this augmented immunological response is dependent on increased expression of interleukin 32 (IL-32). Studies performed using a humanized IL-32 transgenic mouse highlight the clinical implications of these findings in vivo. This study represents a definitive characterization of the role of IL-32γ in the trained phenotype induced by β-glucan or BCG, the results of which improve our understanding of the molecular mechanisms governing trained immunity and Leishmania infection control.</p

Human Footprint and Forest Disturbance Reduce Space Use of Brown Bears (Ursus arctos) Across Europe

Three-quarters of the planet's land surface has been altered by humans, with consequences for animal ecology, movements and related ecosystem functioning. Species often occupy wide geographical ranges with contrasting human disturbance and environmental conditions, yet, limited data availability across species' ranges has constrained our understanding of how human pressure and resource availability jointly shape intraspecific variation of animal space use. Leveraging a unique dataset of 758 annual GPS movement trajectories from 375 brown bears (Ursus arctos) across the species' range in Europe, we investigated the effects of human pressure (i.e., human footprint index), resource availability and predictability, forest cover and disturbance, and area-based conservation measures on brown bear space use. We quantified space use at different spatiotemporal scales during the growing season (May–September): home range size; representing general space requirements, 10-day long-distance displacement distances, and routine 1-day displacement distances. We found large intraspecific variation in brown bear space use across all scales, which was profoundly affected by human footprint index, vegetation productivity, and recent forest disturbances creating opportunity for resource pulses. Bears occupied smaller home ranges and moved less in more anthropized landscapes and in areas with higher resource availability and predictability. Forest disturbances reduced space use while contiguous forest cover promoted longer daily movements. The amount of strictly protected and roadless areas within bear home ranges was too small to affect space use. Anthropized landscapes may hinder the expansion of small and isolated populations, such as the Apennine and Pyrenean, and obstruct population connectivity, for example between the Dinaric Pindos population and the Alpine or Carpathian population. Our findings call for actions to maintain bear movements across landscapes with high human footprint, for example by maintaining forest integrity, to support viable bear populations and their ecosystem functions

Trophic Interactions Are Key to Understanding the Effects of Global Change on the Distribution and Functional Role of the Brown Bear

Biotic interactions are expected to influence species' responses to global changes, but they are rarely considered across broad spatial extents. Abiotic factors are thought to operate at larger spatial scales, while biotic factors, such as species interactions, are considered more important at local scales within communities, in part because of the knowledge gap on species interactions at large spatial scales (i.e., the Eltonian shortfall). We assessed, at a continental scale, (i) the importance of biotic interactions, through food webs, on species distributions, and (ii) how biotic interactions under scenarios of climate and land-use change may affect the distribution of the brown bear (Ursus arctos). We built a highly detailed, spatially dynamic, and empirically sampled food web based on the energy contribution of 276 brown bear food species from different taxa (plants, vertebrates, and invertebrates) and their ensemble habitat models at high resolution across Europe. Then, combining energy contribution and predicted habitat of food species, we modelled energy contribution across space and included these layers within Bayesian-based models of the brown bear distribution in Europe. The inclusion of biotic interactions considerably improved our understanding of brown bear distribution at large (continental) scales compared with Bayesian models including only abiotic factors (climate and land use). Predicted future range shifts, which included changes in the distribution of food species, varied greatly when considering various scenarios of change in biotic factors, providing a warning that future indirect climate and land-use change are likely to have strong but highly uncertain impacts on species biogeography. Our study confirmed that advancing our understanding of ecological networks of species interactions will improve future projections of biodiversity change, especially for modelling species distributions and their functional role under climate and land-use change scenarios, which is key for effective conservation of biodiversity and ecosystem services