Controls on development and diversity of Early Archean stromatolites

The ≈3,450-million-year-old Strelley Pool Formation in Western Australia contains a reef-like assembly of laminated sedimentary accretion structures (stromatolites) that have macroscale characteristics suggestive of biological influence. However, direct microscale evidence of biology—namely, organic microbial remains or biosedimentary fabrics—has to date eluded discovery in the extensively-recrystallized rocks. Recently-identified outcrops with relatively good textural preservation record microscale evidence of primary sedimentary processes, including some that indicate probable microbial mat formation. Furthermore, we find relict fabrics and organic layers that covary with stromatolite morphology, linking morphologic diversity to changes in sedimentation, seafloor mineral precipitation, and inferred microbial mat development. Thus, the most direct and compelling signatures of life in the Strelley Pool Formation are those observed at the microscopic scale. By examining spatiotemporal changes in microscale characteristics it is possible not only to recognize the presence of probable microbial mats during stromatolite development, but also to infer aspects of the biological inputs to stromatolite morphogenesis. The persistence of an inferred biological signal through changing environmental circumstances and stromatolite types indicates that benthic microbial populations adapted to shifting environmental conditions in early oceans

A simple proof of the Markoff conjecture for prime powers

We give a simple and independent proof of the result of Jack Button and Paul Schmutz that the Markoff conjecture on the uniqueness of the Markoff triples (a,b,c), where a, b, and c are in increasing order, holds whenever $c$ is a prime power.Comment: 5 pages, no figure

Targeting SHP-1,2 and SHIP pathways – a novel strategy for cancer treatment?

Well balanced levels of tyrosine phosphorylation, maintained by the reversible and coordinated actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), are critical for a wide range of cellular processes including growth, differentiation, metabolism, migration, and survival. Aberrant tyrosine phosphorylation, as a result of a perturbed balance between the activities of PTKs and PTPs, however, is linked to the pathogenesis of numerous human diseases, including cancer, suggesting that PTPs may be innovative molecular targets for cancer treatment. Two PTPs that have an important inhibitory role in lymphocytes and other haematopoietic cells are SHP-1 and SHP-2 (SH2 domain-containing phosphatases 1 and 2), SHP-1,2 have been shown to promote cell growth and act by both upregulating positive signaling pathways and by downregulating negative signaling pathways. SHIP (SH2 domain-containing inositol phosphatase) is another inhibitory phosphatase that is rather specific for the inositol phospholipid phosphatidylinositol-3,4,5-trisphosphate (PIP3). SHIP acts as a negative regulator of immune response by hydrolysing PIP3, and, as a result, a SHIP defiency results in myeloproliferation and B cell lymphoma in mice. This strong validation of SHP-1,2 and SHIP as oncology targets has generated considerable interest in the development of small molecule inhibitors as potential therapeutic agents for haematologic malignancies and solid tumours, however, SHP-1,2 and SHIP have proven to be an extremely difficult target for drug discovery, due primarily to the highly conserved and positively charged nature of its PTP active site. The majority of reported PTP inhibitors lack either appropriate selectivity or membrane permeability, limiting their utility in modulating the activity of the intracellular PTPs. In order to overcome these caveats novel techniques have been employed to synthesise new inhibitors that specifically attentuate the PTP-dependent signaling inside the cell and amongst them some are already in clinical development (e.g., SHP-1 inhibitor sodium stibogluconate; SHP-2 inhibitor TNO155; SHIP-1 activator AQX-1125). In this review the mechanisms of action and the clinical development of newly available SHP-1,2 and SHIP inhibitors and activators are decribed and the major issues facing this rapidly evolving field are discussed

Targeting developmental pathways: the Achilles Heel of cancer?

Developmental pathways (e.g., Notch, Hippo, Hedgehog, Wnt, and TGF-β/BMP/FGF) are networks of genes that act co-ordinately to establish the body plan, and disruptions of genes in one pathway can have effects in related pathways and may result in serious dysmorphogenesis or cancer. Interestingly, all developmental pathways are highly conserved cell signalling systems present in almost all multicellular organisms. In addition, they have a crucial role in cell proliferation, apoptosis, differentiation, and finally in organ development. Of note, almost all of these pathways promote oncogenesis through synergistic associations with the Hippo signalling pathway, and several lines of evidence have also indicated that these pathways (e.g., Wnt/β-catenin) may be implicated in checkpoint inhibitor resistance (e.g., CTLA-4, PD-1, and PD-L1). Since Notch inhibition in vivo results in partial loss of its stemness features such as self-renewal, chemoresistance, invasive and migratory potential, and tumorigenesis, these highly conserved developmental pathways are regarded as being critical for regulation of self-renewal in both embryonic and adult stem cells and hence are likely to be implicated in the maintenance of cancer stem cells. Many small molecules are currently in preclinical and early clinical development, and only two compounds are approved for treatment of advanced or metastatic basal cell carcinoma (vismodegib and sonidegib). Furthermore, therapeutic targeting of cancer stem cells using drugs that disrupt activated developmental pathways may also represent an attractive strategy that is potentially relevant to many types of malignancy, notably blood cancers, where the evidence for leukaemia stem cells is well established. Future work will hopefully pave the way for the development of new strategies for targeting these pervasive oncogenic pathways

Caco<inf>3</inf> precipitation in multilayered cyanobacterial mats: Clues to explain the alternation of micrite and sparite layers in calcareous stromatolites

© 2015 by the authors; licensee MDPI, Basel, Switzerland. Marine cyanobacterial mats were cultured on coastal sediments (Nivå Bay, Øresund, Denmark) for over three years in a closed system. Carbonate particles formed in two different modes in the mat: (i) through precipitation of submicrometer-sized grains of Mg calcite within the mucilage near the base of living cyanobacterial layers, and (ii) through precipitation of a variety of mixed Mg calcite/aragonite morphs in layers of degraded cyanobacteria dominated by purple sulfur bacteria. The 13C values were about 2‰ heavier in carbonates from the living cyanobacterial zones as compared to those generated in the purple bacterial zones. Saturation indices calculated with respect to calcite, aragonite, and dolomite inside the mats showed extremely high values across the mat profile. Such high values were caused by high pH and high carbonate alkalinity generated within the mats in conjunction with increased concentrations of calcium and magnesium that were presumably stored in sheaths and extracellular polymer substances (EPS) of the living cyanobacteria and liberated during their post-mortem degradation. The generated CaCO3 morphs were highly similar to morphs reported from heterotrophic bacterial cultures, and from bacterially decomposed cyanobacterial biomass emplaced in Ca-rich media. They are also similar to CaCO3 morphs precipitated from purely inorganic solutions. No metabolically (enzymatically) controlled formation of particular CaCO3 morphs by heterotrophic bacteria was observed in the studied mats. The apparent alternation of in vivo and post-mortem generated calcareous layers in the studied cyanobacterial mats may explain the alternation of fine-grained (micritic) and coarse-grained (sparitic) laminae observed in modern and fossil calcareous cyanobacterial microbialites as the result of a probably similar multilayered mat organization

The association between premorbid cognitive ability and social functioning and suicide among young men: A historical-prospective cohort study

Previous studies have found associations between low cognitive ability and later completed suicide. The aim of this study was to examine the association between cognitive ability and social functioning in adolescence, and later completed suicide in a large population-based longitudinal study. Data from the Israeli Draft Board Register for 634,655 Israeli male adolescents aged 16 and 17 was linked to a causes-of-death data registry, with a mean follow-up of 10.6 years for completed suicide. Our results show that in males without a psychiatric diagnosis, both low (adjusted HR=1.51, 95% CI: 1.19–1.92) and high (adjusted HR=1.36, 95% CI: 1.04–1.77) cognitive ability, and very poor (adjusted HR=2.30, 95% CI: 1.34–3.95) and poor (adjusted HR=1.64, 95% CI: 1.34–2.07) social functioning were associated with increased risk for later completed suicide; however positive predictive values were low (PPVs=0.09% and 0.10%, for low cognitive ability and very poor or poor social functioning, respectively). No association between cognitive ability or social functioning and risk for suicide was found in males with a psychiatric diagnosis. These data do not support the clinical utility of screening for such potential predictors

Extended morphometric analysis of neuronal cells with Minkowski valuations

Minkowski valuations provide a systematic framework for quantifying different aspects of morphology. In this paper we apply vector- and tensor-valued Minkowski valuations to neuronal cells from the cat's retina in order to describe their morphological structure in a comprehensive way. We introduce the framework of Minkowski valuations, discuss their implementation for neuronal cells and show how they can discriminate between cells of different types.Comment: 14 pages, 18 postscript figure

MRI in multiple myeloma : a pictorial review of diagnostic and post-treatment findings

Magnetic resonance imaging (MRI) is increasingly being used in the diagnostic work-up of patients with multiple myeloma. Since 2014, MRI findings are included in the new diagnostic criteria proposed by the International Myeloma Working Group. Patients with smouldering myeloma presenting with more than one unequivocal focal lesion in the bone marrow on MRI are considered having symptomatic myeloma requiring treatment, regardless of the presence of lytic bone lesions. However, bone marrow evaluation with MRI offers more than only morphological information regarding the detection of focal lesions in patients with MM. The overall performance of MRI is enhanced by applying dynamic contrast-enhanced MRI and diffusion weighted imaging sequences, providing additional functional information on bone marrow vascularization and cellularity. This pictorial review provides an overview of the most important imaging findings in patients with monoclonal gammopathy of undetermined significance, smouldering myeloma and multiple myeloma, by performing a 'total' MRI investigation with implications for the diagnosis, staging and response assessment. Main message aEuro cent Conventional MRI diagnoses multiple myeloma by assessing the infiltration pattern. aEuro cent Dynamic contrast-enhanced MRI diagnoses multiple myeloma by assessing vascularization and perfusion. aEuro cent Diffusion weighted imaging evaluates bone marrow composition and cellularity in multiple myeloma. aEuro cent Combined morphological and functional MRI provides optimal bone marrow assessment for staging. aEuro cent Combined morphological and functional MRI is of considerable value in treatment follow-up

On multiplicities in length spectra of arithmetic hyperbolic three-orbifolds

Asymptotic laws for mean multiplicities of lengths of closed geodesics in arithmetic hyperbolic three-orbifolds are derived. The sharpest results are obtained for non-compact orbifolds associated with the Bianchi groups SL(2,o) and some congruence subgroups. Similar results hold for cocompact arithmetic quaternion groups, if a conjecture on the number of gaps in their length spectra is true. The results related to the groups above give asymptotic lower bounds for the mean multiplicities in length spectra of arbitrary arithmetic hyperbolic three-orbifolds. The investigation of these multiplicities is motivated by their sensitive effect on the eigenvalue spectrum of the Laplace-Beltrami operator on a hyperbolic orbifold, which may be interpreted as the Hamiltonian of a three-dimensional quantum system being strongly chaotic in the classical limit.Comment: 29 pages, uuencoded ps. Revised version, to appear in NONLINEARIT

The compositional and evolutionary logic of metabolism

Metabolism displays striking and robust regularities in the forms of modularity and hierarchy, whose composition may be compactly described. This renders metabolic architecture comprehensible as a system, and suggests the order in which layers of that system emerged. Metabolism also serves as the foundation in other hierarchies, at least up to cellular integration including bioenergetics and molecular replication, and trophic ecology. The recapitulation of patterns first seen in metabolism, in these higher levels, suggests metabolism as a source of causation or constraint on many forms of organization in the biosphere. We identify as modules widely reused subsets of chemicals, reactions, or functions, each with a conserved internal structure. At the small molecule substrate level, module boundaries are generally associated with the most complex reaction mechanisms and the most conserved enzymes. Cofactors form a structurally and functionally distinctive control layer over the small-molecule substrate. Complex cofactors are often used at module boundaries of the substrate level, while simpler ones participate in widely used reactions. Cofactor functions thus act as "keys" that incorporate classes of organic reactions within biochemistry. The same modules that organize the compositional diversity of metabolism are argued to have governed long-term evolution. Early evolution of core metabolism, especially carbon-fixation, appears to have required few innovations among a small number of conserved modules, to produce adaptations to simple biogeochemical changes of environment. We demonstrate these features of metabolism at several levels of hierarchy, beginning with the small-molecule substrate and network architecture, continuing with cofactors and key conserved reactions, and culminating in the aggregation of multiple diverse physical and biochemical processes in cells.Comment: 56 pages, 28 figure