C5L2 is critical for the biological activities of the anaphylatoxins C5a and C3a

Complement-derived anaphylatoxins regulate immune and inflammatory responses through G-protein-coupled receptor (GPCR)-mediated signalling. C5L2 (also known as GPR77) is a relatively new GPCR thought to be a non-signalling receptor binding to C5a, on the basis of sequence information and experimental evidence. Here we show, using gene targeting, that C5L2 is required to facilitate C5a signalling in neutrophils, macrophages and fibroblasts in vitro. Deficiency of C5L2 results in reduced inflammatory cell infiltration, suggesting that C5L2 is critical for optimal C5a-mediated cell infiltration in certain in vivo settings. C5L2 is also involved in optimizing C3a-induced signals. Furthermore, like mice incapable of C3a/complement 3a receptor (C3aR) signalling, C5L2-deficient mice are hypersensitive to lipopolysaccharide (LPS)-induced septic shock, show reduced ovalbumin (OVA)-induced airway hyper-responsiveness and inflammation, and are mildly delayed in haematopoietic cell regeneration after gamma-irradiation. Our data indicate that C5L2 can function as a positive modulator for both C5a- and C3a-anaphylatoxin-induced responses.     

A spatially organized representation of colour in macaque cortical area V2

Neurons responding selectively to different colours have been found in various cortical areas in macaque monkeys; however, little is known about whether and how the representation of colour is spatially organized in any cortical area. Cortical area V2 contains modules that respond preferentially to chromatic modulation, which are located in thin cytochrome oxidase stripes. Here we show that within and beyond these modules, gratings of different colours produce activations that peak at different locations. Optical recording of intrinsic signals revealed that the peak regions of the responses to different colours were spatially organized in the same order as colour stimuli are arranged in the DIN (German standard colour chart) colour system. Nearby regions represented colours of a similar hue. We found that the set of colour-specific regions formed 0.07-0.32-mm-wide and approximately 1.3-mm long bands that varied in shape from linear to nearly circular. Our finding suggests that thin stripes in V2 contain functional maps where the colour of a stimulus is represented by the location of its response activation peak.     

Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection

Aicardi-Goutières syndrome (AGS) is an autosomal recessive neurological disorder, the clinical and immunological features of which parallel those of congenital viral infection. Here we define the composition of the human ribonuclease H2 enzyme complex and show that AGS can result from mutations in the genes encoding any one of its three subunits. Our findings demonstrate a role for ribonuclease H in human neurological disease and suggest an unanticipated relationship between ribonuclease H2 and the antiviral immune response that warrants further investigation.     

The history of science as the progress of the human spirit: The historiography of astronomy in the eighteenth century

In the eighteenth century, the historiography of astronomy was part of a wider discussion concerning the history of the human spirit. The concept of the human spirit was very popular among Enlightenment authors because it gave the history of human knowledge continuity, unity and meaning. Using this concept, scientists and historians of science such as Montucla, Lalande, Bailly and Laplace could present the history of astronomy in terms of a progress towards contemporary science that was slow and could be interrupted at times, but was still constant, regular, and necessary. In my paper I intend to explain how the originally philosophical concept of the human spirit was transferred to the history of astronomy. I also introduce the basic principles to which the development of the spirit is subject in astronomy, according to historians of astronomy. The third part of the paper describes how historians of astronomy took into account the effect of social and natural factors on the history of astronomy.     

Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk

To identify risk variants for multiple myeloma, we conducted a genome-wide association study of 1,675 individuals with multiple myeloma and 5,903 control subjects. We identified risk loci for multiple myeloma at 3p22.1 (rs1052501 in ULK4; odds ratio (OR) = 1.32; P = 7.47 × 10(-9)) and 7p15.3 (rs4487645, OR = 1.38; P = 3.33 × 10(-15)). In addition, we observed a promising association at 2p23.3 (rs6746082, OR = 1.29; P = 1.22 × 10(-7)). Our study identifies new genomic regions associated with multiple myeloma risk that may lead to new etiological insights.     

Land-atmosphere coupling and climate change in Europe

Increasing greenhouse gas concentrations are expected to enhance the interannual variability of summer climate in Europe and other mid-latitude regions, potentially causing more frequent heatwaves. Climate models consistently predict an increase in the variability of summer temperatures in these areas, but the underlying mechanisms responsible for this increase remain uncertain. Here we explore these mechanisms using regional simulations of recent and future climatic conditions with and without land-atmosphere interactions. Our results indicate that the increase in summer temperature variability predicted in central and eastern Europe is mainly due to feedbacks between the land surface and the atmosphere. Furthermore, they suggest that land-atmosphere interactions increase climate variability in this region because climatic regimes in Europe shift northwards in response to increasing greenhouse gas concentrations, creating a new transitional climate zone with strong land-atmosphere coupling in central and eastern Europe. These findings emphasize the importance of soil-moisture-temperature feedbacks (in addition to soil-moisture-precipitation feedbacks) in influencing summer climate variability and the potential migration of climate zones with strong land-atmosphere coupling as a consequence of global warming. This highlights the crucial role of land-atmosphere interactions in future climate change.     

Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab

HER2 (also known as Neu, ErbB2) is a member of the epidermal growth factor receptor (EGFR; also known as ErbB) family of receptor tyrosine kinases, which in humans includes HER1 (EGFR, ERBB1), HER2, HER3 (ERBB3) and HER4 (ERBB4). ErbB receptors are essential mediators of cell proliferation and differentiation in the developing embryo and in adult tissues, and their inappropriate activation is associated with the development and severity of many cancers. Overexpression of HER2 is found in 20-30% of human breast cancers, and correlates with more aggressive tumours and a poorer prognosis. Anticancer therapies targeting ErbB receptors have shown promise, and a monoclonal antibody against HER2, Herceptin (also known as trastuzumab), is currently in use as a treatment for breast cancer. Here we report crystal structures of the entire extracellular regions of rat HER2 at 2.4 A and human HER2 complexed with the Herceptin antigen-binding fragment (Fab) at 2.5 A. These structures reveal a fixed conformation for HER2 that resembles a ligand-activated state, and show HER2 poised to interact with other ErbB receptors in the absence of direct ligand binding. Herceptin binds to the juxtamembrane region of HER2, identifying this site as a target for anticancer therapies.     

Extreme crustal oxygen isotope signatures preserved in coesite in diamond

The anomalously high and low oxygen isotope values observed in eclogite xenoliths from the upper mantle beneath cratons have been interpreted as indicating that the parent rock of the eclogites experienced alteration on the ancient sea floor. Recognition of this genetic lineage has provided the foundation for a model of the evolution of the continents whereby imbricated slabs of oceanic lithosphere underpin and promote stabilization of early cratons. Early crustal growth is thought to have been enhanced by the addition of slab-derived magmas, leaving an eclogite residuum in the upper mantle beneath the cratons. But the oxygen isotope anomalies observed in eclogite xenoliths are small relative to those in altered ocean-floor basalt and intermediate-stage subduction-zone eclogites, and this has hindered acceptance of the hypothesis that the eclogite xenoliths represent subducted and metamorphosed ocean-floor basalts. We present here the oxygen isotope composition of eclogitic mineral inclusions, analysed in situ in diamonds using an ion microprobe/secondary ion mass spectrometer. The oxygen isotope values of coesite (a polymorph of SiO2) inclusions are substantially higher than previously reported for xenoliths from the subcratonic mantle, but are typical of subduction-zone meta-basalts, and accordingly provide strong support for the link between altered ocean-floor basalts and mantle eclogite xenoliths.     

Structure and dynamics of the M3 muscarinic acetylcholine receptor

Acetylcholine, the first neurotransmitter to be identified, exerts many of its physiological actions via activation of a family of G-protein-coupled receptors (GPCRs) known as muscarinic acetylcholine receptors (mAChRs). Although the five mAChR subtypes (M1-M5) share a high degree of sequence homology, they show pronounced differences in G-protein coupling preference and the physiological responses they mediate. Unfortunately, despite decades of effort, no therapeutic agents endowed with clear mAChR subtype selectivity have been developed to exploit these differences. We describe here the structure of the G(q/11)-coupled M3 mAChR ('M3 receptor', from rat) bound to the bronchodilator drug tiotropium and identify the binding mode for this clinically important drug. This structure, together with that of the G(i/o)-coupled M2 receptor, offers possibilities for the design of mAChR subtype-selective ligands. Importantly, the M3 receptor structure allows a structural comparison between two members of a mammalian GPCR subfamily displaying different G-protein coupling selectivities. Furthermore, molecular dynamics simulations suggest that tiotropium binds transiently to an allosteric site en route to the binding pocket of both receptors. These simulations offer a structural view of an allosteric binding mode for an orthosteric GPCR ligand and provide additional opportunities for the design of ligands with different affinities or binding kinetics for different mAChR subtypes. Our findings not only offer insights into the structure and function of one of the most important GPCR families, but may also facilitate the design of improved therapeutics targeting these critical receptors.     

VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche

The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Here we demonstrate that bone marrow-derived haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1; also known as Flt1) home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1(+) cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3 (inhibitor of differentiation 3)-competent VEGFR1+ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. We also show that VEGFR1+ cells express VLA-4 (also known as integrin alpha4beta1), and that tumour-specific growth factors upregulate fibronectin--a VLA-4 ligand--in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1+ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1+VLA-4+ clusters dictate organ-specific tumour spread.