How to share underground reservoirs

Many resources, such as oil, gas, or water, are extracted from porous soils and their exploration is often shared among different companies or nations. We show that the effective shares can be obtained by invading the porous medium simultaneously with various fluids. Partitioning a volume in two parts requires one division surface while the simultaneous boundary between three parts consists of lines. We identify and characterize these lines, showing that they form a fractal set consisting of a single thread spanning the medium and a surrounding cloud of loops. While the spanning thread has fractal dimension ${1.55\pm0.03}$, the set of all lines has dimension ${1.69\pm0.02}$. The size distribution of the loops follows a power law and the evolution of the set of lines exhibits a tricritical point described by a crossover with a negative dimension at criticality

Tumour-derived CSF2/granulocyte macrophage colony stimulating factor controls myeloid cell accumulation and progression of gliomas

BACKGROUND: Malignant tumours release factors, which attract myeloid cells and induce their polarisation to pro-invasive, immunosuppressive phenotypes. Brain-resident microglia and peripheral macrophages accumulate in the tumour microenvironment of glioblastoma (GBM) and induce immunosuppression fostering tumour progression. Macrophage colony stimulating factors (CSFs) control the recruitment of myeloid cells during peripheral cancer progression, but it is disputable, which CSFs drive their accumulation in gliomas. METHODS: The expression of CSF2 (encoding granulocyte-macrophage colony stimulating factor) was determined in TCGA datasets and five human glioma cell lines. Effects of stable CSF2 knockdown in glioma cells or neutralising CSF2 or receptor CSF2Rα antibodies on glioma invasion were tested in vitro and in vivo. RESULTS: CSF2 knockdown or blockade of its signalling reduced microglia-dependent glioma invasion in microglia-glioma co-cultures. CSF2-deficient human glioma cells encapsulated in cell-impermeable hollow fibres and transplanted to mouse brains, failed to attract microglia, but stimulated astrocyte recruitment. CSF2-depleted gliomas were smaller, attracted less microglia and macrophages, and provided survival benefit in tumour-bearing mice. Apoptotic microglia/macrophages were detected in CSF2-depleted tumours. CONCLUSIONS: CSF2 is overexpressed in a subset of mesenchymal GBMs in association with high immune gene expression. Tumour-derived CSF2 attracts, supports survival and induces pro-tumorigenic polarisation of microglia and macrophages

Comparative Analysis of mRNA Targets for Human PUF-Family Proteins Suggests Extensive Interaction with the miRNA Regulatory System

Genome-wide identification of mRNAs regulated by RNA-binding proteins is crucial to uncover post-transcriptional gene regulatory systems. The conserved PUF family RNA-binding proteins repress gene expression post-transcriptionally by binding to sequence elements in 3′-UTRs of mRNAs. Despite their well-studied implications for development and neurogenesis in metazoa, the mammalian PUF family members are only poorly characterized and mRNA targets are largely unknown. We have systematically identified the mRNAs associated with the two human PUF proteins, PUM1 and PUM2, by the recovery of endogenously formed ribonucleoprotein complexes and the analysis of associated RNAs with DNA microarrays. A largely overlapping set comprised of hundreds of mRNAs were reproducibly associated with the paralogous PUM proteins, many of them encoding functionally related proteins. A characteristic PUF-binding motif was highly enriched among PUM bound messages and validated with RNA pull-down experiments. Moreover, PUF motifs as well as surrounding sequences exhibit higher conservation in PUM bound messages as opposed to transcripts that were not found to be associated, suggesting that PUM function may be modulated by other factors that bind conserved elements. Strikingly, we found that PUF motifs are enriched around predicted miRNA binding sites and that high-confidence miRNA binding sites are significantly enriched in the 3′-UTRs of experimentally determined PUM1 and PUM2 targets, strongly suggesting an interaction of human PUM proteins with the miRNA regulatory system. Our work suggests extensive connections between the RBP and miRNA post-transcriptional regulatory systems and provides a framework for deciphering the molecular mechanism by which PUF proteins regulate their target mRNAs

Pathogenesis, diagnosis and management of pneumorrhachis

Pneumorrhachis (PR), the presence of intraspinal air, is an exceptional but eminent radiographic finding, accompanied by different aetiologies and possible pathways of air entry into the spinal canal. By reviewing the literature and analysing a personal case of traumatic cervical PR after head injury, we present current data regarding the pathoanatomy, clinical and radiological presentation, diagnosis and differential diagnosis and treatment modalities of patients with PR and associated pathologies to highlight this uncommon phenomenon and outline aetiology-based guidelines for the practical management of PR. Air within the spinal canal can be divided into primary and secondary PR, descriptively classified into extra- or intradural PR and aetiologically subsumed into iatrogenic, traumatic and nontraumatic PR. Intraspinal air is usually found isolated not only in the cervical, thoracic and, less frequently, the lumbosacral regions but can also be located in the entire spinal canal. PR is almost exceptional associated with further air distributions in the body. The pathogenesis and aetiologies of PR are multifold and can be a diagnostic challenge. The diagnostic procedure should include spinal CT, the imaging tool of choice. PR has to be differentiated from free intraspinal gas collections and the coexistence of air and gas within the spinal canal has to be considered differential diagnostically. PR usually represents an asymptomatic epiphenomenon but can also be symptomatic by itself as well as by its underlying pathology. The latter, although often severe, might be concealed and has to be examined carefully to enable adequate patient treatment. The management of PR has to be individualized and frequently requires a multidisciplinary regime

PAK proteins and YAP-1 signalling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis

Fibrosis due to extracellular matrix (ECM) secretion from myofibroblasts complicates many chronic liver diseases causing scarring and organ failure. Integrin-dependent interaction with scar ECM promotes pro-fibrotic features. However, the pathological intracellular mechanism in liver myofibroblasts is not completely understood, and further insight could enable therapeutic efforts to reverse fibrosis. Here, we show that integrin beta-1, capable of binding integrin alpha-11, regulates the pro-fibrotic phenotype of myofibroblasts. Integrin beta-1 expression is upregulated in pro-fibrotic myofibroblasts in vivo and is required in vitro for production of fibrotic ECM components, myofibroblast proliferation, migration and contraction. Serine/threonine-protein kinase proteins, also known as P21-activated kinase (PAK), and the mechanosensitive factor, Yes-associated protein 1 (YAP-1) are core mediators of pro-fibrotic integrin beta-1 signalling, with YAP-1 capable of perpetuating integrin beta-1 expression. Pharmacological inhibition of either pathway in vivo attenuates liver fibrosis. PAK protein inhibition, in particular, markedly inactivates the pro-fibrotic myofibroblast phenotype, limits scarring from different hepatic insults and represents a new tractable therapeutic target for treating liver fibrosis