A genetically humanized mouse model for hepatitis C virus infection

Hepatitis C virus (HCV) remains a major medical problem. Antiviral treatment is only partially effective and a vaccine does not exist. Development of more effective therapies has been hampered by the lack of a suitable small animal model. Although xenotransplantation of immunodeficient mice with human hepatocytes has shown promise, these models are subject to important challenges. Building on the previous observation that CD81 and occludin comprise the minimal human factors required to render mouse cells permissive to HCV entry in vitro, we attempted murine humanization via a genetic approach. Here we show that expression of two human genes is sufficient to allow HCV infection of fully immunocompetent inbred mice. We establish a precedent for applying mouse genetics to dissect viral entry and validate the role of scavenger receptor type B class I for HCV uptake. We demonstrate that HCV can be blocked by passive immunization, as well as showing that a recombinant vaccinia virus vector induces humoral immunity and confers partial protection against heterologous challenge. This system recapitulates a portion of the HCV life cycle in an immunocompetent rodent for the first time, opening opportunities for studying viral pathogenesis and immunity and comprising an effective platform for testing HCV entry inhibitors in vivo.     

Distant metastasis occurs late during the genetic evolution of pancreatic cancer

Metastasis, the dissemination and growth of neoplastic cells in an organ distinct from that in which they originated, is the most common cause of death in cancer patients. This is particularly true for pancreatic cancers, where most patients are diagnosed with metastatic disease and few show a sustained response to chemotherapy or radiation therapy. Whether the dismal prognosis of patients with pancreatic cancer compared to patients with other types of cancer is a result of late diagnosis or early dissemination of disease to distant organs is not known. Here we rely on data generated by sequencing the genomes of seven pancreatic cancer metastases to evaluate the clonal relationships among primary and metastatic cancers. We find that clonal populations that give rise to distant metastases are represented within the primary carcinoma, but these clones are genetically evolved from the original parental, non-metastatic clone. Thus, genetic heterogeneity of metastases reflects that within the primary carcinoma. A quantitative analysis of the timing of the genetic evolution of pancreatic cancer was performed, indicating at least a decade between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell. At least five more years are required for the acquisition of metastatic ability and patients die an average of two years thereafter. These data provide novel insights into the genetic features underlying pancreatic cancer progression and define a broad time window of opportunity for early detection to prevent deaths from metastatic disease.     

A 61-million-person experiment in social influence and political mobilization

Human behaviour is thought to spread through face-to-face social networks, but it is difficult to identify social influence effects in observational studies, and it is unknown whether online social networks operate in the same way. Here we report results from a randomized controlled trial of political mobilization messages delivered to 61 million Facebook users during the 2010 US congressional elections. The results show that the messages directly influenced political self-expression, information seeking and real-world voting behaviour of millions of people. Furthermore, the messages not only influenced the users who received them but also the users' friends, and friends of friends. The effect of social transmission on real-world voting was greater than the direct effect of the messages themselves, and nearly all the transmission occurred between 'close friends' who were more likely to have a face-to-face relationship. These results suggest that strong ties are instrumental for spreading both online and real-world behaviour in human social networks.     

A massive, cooling-flow-induced starburst in the core of a luminous cluster of galaxies

In the cores of some clusters of galaxies the hot intracluster plasma is dense enough that it should cool radiatively in the cluster's lifetime, leading to continuous 'cooling flows' of gas sinking towards the cluster centre, yet no such cooling flow has been observed. The low observed star-formation rates and cool gas masses for these 'cool-core' clusters suggest that much of the cooling must be offset by feedback to prevent the formation of a runaway cooling flow. Here we report X-ray, optical and infrared observations of the galaxy cluster SPT-CLJ2344-4243 (ref. 11) at redshift z = 0.596. These observations reveal an exceptionally luminous (8.2?×?10(45)?erg?s(-1)) galaxy cluster that hosts an extremely strong cooling flow (around 3,820 solar masses a year). Further, the central galaxy in this cluster appears to be experiencing a massive starburst (formation of around 740 solar masses a year), which suggests that the feedback source responsible for preventing runaway cooling in nearby cool-core clusters may not yet be fully established in SPT-CLJ2344-4243. This large star-formation rate implies that a significant fraction of the stars in the central galaxy of this cluster may form through accretion of the intracluster medium, rather than (as is currently thought) assembling entirely via mergers.     

Regulation of cancer cell migration and bone metastasis by RANKL

Bone metastases are a frequent complication of many cancers that result in severe disease burden and pain. Since the late nineteenth century, it has been thought that the microenvironment of the local host tissue actively participates in the propensity of certain cancers to metastasize to specific organs, and that bone provides an especially fertile 'soil'. In the case of breast cancers, the local chemokine milieu is now emerging as an explanation for why these tumours preferentially metastasize to certain organs. However, as the inhibition of chemokine receptors in vivo only partially blocks metastatic behaviour, other factors must exist that regulate the preferential metastasis of breast cancer cells. Here we show that the cytokine RANKL (receptor activator of NF-kappaB ligand) triggers migration of human epithelial cancer cells and melanoma cells that express the receptor RANK. RANK is expressed on cancer cell lines and breast cancer cells in patients. In a mouse model of melanoma metastasis, in vivo neutralization of RANKL by osteoprotegerin results in complete protection from paralysis and a marked reduction in tumour burden in bones but not in other organs. Our data show that local differentiation factors such as RANKL have an important role in cell migration and the tissue-specific metastatic behaviour of cancer cells.