Hot off the presses! April 3 New England Journal

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Hot off the presses! May 01

The May 01 issue of the is now up on Pubget (About ): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• In this issue
  - Nature Reviews Microbiology 8(5):309 (2010)
  The phrase 'good fences make good neighbours' suggests that keeping a little distance between ourselves and our immediate neighbours can be important to maintain good community relations. This phrase could equally be applied to the microbial world, in which the communities can comprise a range of different microorganisms that are often competing for limited resources.
• Editorial: China: a life sciences giant
  - Nature Reviews Microbiology 8(5):310 (2010)
  A recent press release from Nature China showed that the number of articles published by Chinese researchers in five top research journals (Cell, Science, Nature, The Lancet and The New England Journal of Medicine) nearly doubled between 2008 and 2009, providing a clear indication of the growth of life science research in China. Since 2007, China has ranked second only to the United States in terms of the number of scientific publications produced, and the indication is that the trends of increasing quantity and, importantly, quality will continue for the foreseeable future.
• Fungal genetics: Expanding horizons through chromosome exchange
  - Nature Reviews Microbiology 8(5):311 (2010)
  Members of the ascomycete fungi genus Fusarium range from plant pathogens to soil dwellers. The publication of a genomic comparison of several Fusarium species sheds light on the differences between these species and shows that horizontal transfer of entire chromosomes between species has important consequences for the lifestyle and host range of these pathogens.
• Bacterial virulence: Modifying virulent behaviour
  - Nature Reviews Microbiology 8(5):312 (2010)
  Post-translational modification of cell surface factors is known to be important for the virulence of many bacterial pathogens, including Campylobacter jejuni, a major worldwide cause of bacterial diarrhoea. Now, Cullen and Trent describe the identification of a phosphoethanolamine transferase that modifies components of the flagella and lipo-oligosaccharide in the C. jejuni
• Techniques and applications: Real-time view of AMP-mediated killing
  - Nature Reviews Microbiology 8(5):312 (2010)
  Atomic force microscopy (AFM) has provided microbiologists with powerful images of bacterial cells and cell surface structures at the nanometre scale. However, image acquisition times of several minutes per frame have limited the use of AFM for studying highly dynamic cellular processes.
• Plant immunity: Helping plants to fight back
  - Nature Reviews Microbiology 8(5):312 (2010)
  A new report in Nature Biotechnology shows that a pattern recognition receptor (PRR) can be transferred between two plant families, conferring broad-spectrum bacterial resistance.Plants, like humans, can detect pathogen-associated molecular patterns (PAMPs) using cell surface PRRs.
• In brief: Fungal physiology, Viral immune evasion, Metagenomics
  - Nature Reviews Microbiology 8(5):313 (2010)
  N-acetylglucosamine induces white to opaque switching, a mating prerequisite in Candida albicans Huang , G.et al. PLoS Pathog. 6, e1000806 (2010) (doi: 10.1371/journal.ppat.1000806)
• HIV: Second hideout for HIV-1
  - Nature Reviews Microbiology 8(5):314 (2010)
  Immature multipotent haematopoietic progenitor cells (HPCs) are a second reservoir of latent HIV-1 infection, according to a new report in Nature Medicine.Although highly active antiretroviral therapy (HAART) has greatly reduced mortality from HIV-1 infection, it cannot completely eradicate the virus owing to viral persistence as a provirus in latently infected cells.
• Bacterial secretion: The two faces of MycP1
  - Nature Reviews Microbiology 8(5):314 (2010)
  Mycobacterium tuberculosis uses ESX1, a type VII secretion system, to deliver virulence factors into host cells. Because some of the proteins secreted by ESX1, such as ESAT6 (also known as EsxA), are important for virulence and also highly immunogenic, the system is transcriptionally regulated to maintain a balance between virulence and immunogenicity.
• A glut from the gut: metagenomics takes a giant step foward
  - Nature Reviews Microbiology 8(5):315 (2010)
  Interest in the bacteria that inhabit the human gut has increased greatly in recent years, as technological advancements have allowed new discoveries. This month's Genome Watch reviews a recent study of the microorganisms in the human gut that sets a new marker for the field of metagenomics.
• In the News
  - Nature Reviews Microbiology 8(5):316 (2010)
  A new class of drug that could be used to treat tuberculosis has been identified.
• Bacteriophage resistance mechanisms
  Labrie SJ Samson JE Moineau S - Nature Reviews Microbiology 8(5):317 (2010)
  Phages are now acknowledged as the most abundant microorganisms on the planet and are also possibly the most diversified. This diversity is mostly driven by their dynamic adaptation when facing selective pressure such as phage resistance mechanisms, which are widespread in bacterial hosts. When infecting bacterial cells, phages face a range of antiviral mechanisms, and they have evolved multiple tactics to avoid, circumvent or subvert these mechanisms in order to thrive in most environments. In this Review, we highlight the most important antiviral mechanisms of bacteria as well as the counter-attacks used by phages to evade these systems.
• Anaplasma phagocytophilum and Ehrlichia chaffeensis: subversive manipulators of host cells
  Rikihisa Y - Nature Reviews Microbiology 8(5):328 (2010)
  Anaplasma spp. and Ehrlichia spp. cause several emerging human infectious diseases. Anaplasma phagocytophilum and Ehrlichia chaffeensis are transmitted between mammals by blood-sucking ticks and replicate inside mammalian white blood cells and tick salivary-gland and midgut cells. Adaptation to a life in eukaryotic cells and transmission between hosts has been assisted by the deletion of many genes that are present in the genomes of free-living bacteria (including genes required for the biosynthesis of lipopolysaccharide and peptidoglycan), by the acquisition of a cholesterol uptake pathway and by the expansion of the repertoire of genes encoding the outer-membrane porins and type IV secretion system. Here, I review the specialized properties and other adaptations of these intracellular bacteria.
• Medically important bacterial–fungal interactions
  Peleg AY Hogan DA Mylonakis E - Nature Reviews Microbiology 8(5):340 (2010)
  Whether it is in the setting of disease or in a healthy state, the human body contains a diverse range of microorganisms, including bacteria and fungi. The interactions between these taxonomically diverse microorganisms are highly dynamic and dependent on a multitude of microorganism and host factors. Human disease can develop from an imbalance between commensal bacteria and fungi or from invasion of particular host niches by opportunistic bacterial and fungal pathogens. This Review describes the clinical and molecular characteristics of bacterial–fungal interactions that are relevant to human disease.
• A look behind closed doors: interaction of persistent viruses with dendritic cells
  Lambotin M Raghuraman S Stoll-Keller F Baumert TF Barth H - Nature Reviews Microbiology 8(5):350 (2010)
  Persistent infections with HIV, hepatitis B virus and hepatitis C virus are major causes of morbidity and mortality worldwide. As sentinels of the immune system, dendritic cells (DCs) are crucial for the generation of protective antiviral immunity. Recent advances in our understanding of the role of DCs during infection with these viruses provide insights into the mechanisms used by these viruses to exploit DC function and evade innate and adaptive immunity. In this Review we highlight the current knowledge about the interaction between DCs and these viruses and the underlying mechanisms that might influence the outcome of viral infections.
• The arrival, establishment and spread of exotic diseases: patterns and predictions
  Randolph SE Rogers DJ - Nature Reviews Microbiology 8(5):361 (2010)
  The impact of human activities on the principles and processes governing the arrival, establishment and spread of exotic pathogens is illustrated by vector-borne diseases such as malaria, dengue, chikungunya, West Nile, bluetongue and Crimean–Congo haemorrhagic fevers. Competent vectors, which are commonly already present in the areas, provide opportunities for infection by exotic pathogens that are introduced by travel and trade. At the same time, the correct combination of environmental conditions (both abiotic and biotic) makes many far-flung parts of the world latently and predictably, but differentially, permissive to persistent transmission cycles. Socioeconomic factors and nutritional status determine human exposure to disease and resistance to infection, respectively, so that disease incidence can vary independently of biological cycles.
• Detecting genomic islands using bioinformatics approaches
  - Nature Reviews Microbiology 8(5):373 (2010)
  Bacterial genomes contain clusters of genes that are acquired by horizontal transfer, called genomic islands (GIs). GIs are frequently associated with microbial adaptations that are of medical and environmental interest, and they have had a substantial impact on bacterial evolution. Therefore, there is growing interest in efficiently identifying GIs in newly sequenced bacterial genomes. Several computational methods for detecting GIs have been developed recently, presenting researchers with a myriad of choices. Here, we discuss the limitations and benefits of the main approaches that are available and present guidelines to aid researchers in effectively identifying these important genomic regions.

Hot off the presses! Dec 01 Nat Rev Cancer

The Dec 01 issue of the Nat Rev Cancer is now up on Pubget (About Nat Rev Cancer): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• 
  - Nat Rev Cancer 10(12):809 (2010)
  
• Tumour Suppression: YAP tips the balance | PDF (154 KB)
  - Nat Rev Cancer 10(12):811 (2010)
  Yes-associated protein (YAP) is a transcriptional co-activator that shuttles between the cytoplasm and the nucleus. The role of YAP-mediated gene expression in tumorigenesis is unclear, as there are reports that YAP has both oncogenic and tumour suppressive roles.
• Signalling: Finding your inner activator | PDF (216 KB)
  - Nat Rev Cancer 10(12):812 (2010)
  A recent paper published in Cell extends the current understanding of how ligand-mediated activation ofepidermal growth factor receptors (EGFRs) is regulated by showing that a cytoplasmic family of proteins known as the cytohesins affect the conformation of EGFRs.Cytohesins are guanine–nucleotide exchange factors (GEFs) for the ADP ribosylation factors (ARFs) that are involved in vesicular trafficking and cytoskeletal changes.
• Transcription factors: MYC matters | PDF (293 KB)
  - Nat Rev Cancer 10(12):812 (2010)
  Mutation or aberrant regulation of the transcription factor MYC is a common feature of many cancers. Two new studies have added more details to the complexity of MYC regulation in cell development and growth pathways, underscoring the importance of MYC in tumorigenesis.
• Mutagenesis | Signalling | Oncogenes | Therapeutics | PDF (158 KB)
  - Nat Rev Cancer 10(12):813 (2010)
  PiggyBac transposon mutatgenesis: a tool for cancer gene discovery in mice Rad, R.et al. Science, 14 Oct 2010 (doi: 10.1126/science.1193004)
• Therapy: Expanding the horizons of PARP inhibitors | PDF (192 KB)
  - Nat Rev Cancer 10(12):814 (2010)
  Aberrant vascularity in tumours results in hypoxic tumour regions that are distant from blood vessels, as oxygen is poorly delivered to these areas. As drugs are also not efficiently delivered in these circumstances, intratumoral hypoxia is associated with treatment resistance.
• Lung cancer: A regulator of senescence | PDF (225 KB)
  - Nat Rev Cancer 10(12):814 (2010)
  KRAS mutations are common in cancers, but oncogenic KRAS has differing effects — in some cases, it induces hyperproliferation, whereas in others it leads to senescence. A recent study has identified the transcription factor Wilms tumour 1 (WT1) as a key regulator of these two alternative outcomes, providing new insights that might have therapeutic implications for KRAS-driven lung cancers.
• Tumour suppression: The burning issue of p63 | PDF (187 KB)
  - Nat Rev Cancer 10(12):814 (2010)
  The involvement of the p53 family member p63 in tumour suppression and in promoting tumorigenesis has been a matter of debate, and a new paper in Nature now clarifies the tumour suppressor function of p63.The full-length isoform of p63 that contains the transactivation (TA) domain, TAp63, is thought to be a tumour suppressor; so Su, Chakravarti and colleagues investigated this further with cohorts of knockout mice.
• Development | Therapy | Small RNAs | Therapy | PDF (174 KB)
  - Nat Rev Cancer 10(12):815 (2010)
  Drosophila SPARC is a self-protective signal expressed by loser cells during cell competition Portela, M.et al. Dev. Cell 19, 562–573 (2010)
• Lymphomagenesis: The ARTS of cell death | PDF (158 KB)
  - Nat Rev Cancer 10(12):816 (2010)
  The importance of apoptosis as a tumour suppressive mechanism is well documented, especially in the haematopoietic system, but which components of the apoptotic pathway, through either their gain or their loss of function, can promote tumour development is still being established. A recent paper in Genes and Development indicates that reduced expression of the pro-apoptotic protein ARTS, which is an inhibitor of X-linked inhibitor of apoptosis (XIAP), can promote the development of leukaemia and lymphoma by enabling the aberrant survival of haematopoietic stem and progenitor cells.
• Signalling: Without the sun | PDF (179 KB)
  - Nat Rev Cancer 10(12):816 (2010)
  The second messenger cyclic AMP (cAMP) has a key role in numerous cellular processes. In response to melanocyte-stimulating hormone (MSH) cAMP enhances skin pigmentation and protects against ultraviolet (UV)-induced damage, features that imply it would be an attractive skin cancer prevention agent.
• ALK and resistance | PDF (165 KB)
  - Nat Rev Cancer 10(12):817 (2010)
  A small proportion of non-small-cell lung cancers (between 2% and 7%) have a chromosomal translocation that results in the fusion of echinoderm microtubule-associated protein-like kinase 4 (EML4) with anaplastic lymphoma kinase (ALK). Results from a two-part, Phase I trial of one ALK inhibitor, crizotinib (Pfizer), have recently been reported in the New England Journal of Medicine.
• SIRT1: recent lessons from mouse models
  - Nat Rev Cancer 10(12):819 (2010)
  The family of protein deacetylases represented by yeast Sir2 has been the focus of intense investigation because of the longevity activity of Sir2 in yeast, worms and flies. Research in mammals has mainly focused on SIRT1, the closest homologue of Sir2. Emerging evidence from mouse models is yielding a sharper picture, in which SIRT1 is a potent protector from ageing-associated pathologies, such as diabetes, liver steatosis, cardiovascular disease, neurodegeneration and, importantly, various types of cancer.
• Shared and separate functions of polo-like kinases and aurora kinases in cancer
  - Nat Rev Cancer 10(12):825 (2010)
  Large numbers of inhibitors for polo-like kinases and aurora kinases are currently being evaluated as anticancer drugs. Interest in these drugs is fuelled by the idea that these kinases have unique functions in mitosis. Within the polo-like kinase family, the emphasis for targeted therapies has been on polo-like kinase 1 (PLK1), and in the aurora kinase family drugs have been developed to specifically target aurora kinase A (AURKA; also known as STK6) and/or aurora kinase B (AURKB; also known as STK12). Information on the selectivity of these compounds in vivo is limited, but it is likely that off-target effects within the same kinase families will affect efficacy and toxicity profiles. In addition, it is becoming clear that interplay between polo-like kinases and aurora kinases is much more extensive than initially anticipated, and that both kinase families are important factors in the response to classical chemotherapeutics that damage the genome or the mitotic spind! le. In this Review we discuss the implications of these novel insights on the clinical applicability of polo-like kinase and aurora kinase inhibitors.
• Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?
  - Nat Rev Cancer 10(12):842 (2010)
  There is now considerable and increasing evidence for a causal role for aberrant activity of the Ras superfamily of small GTPases in human cancers. These GTPases function as GDP–GTP-regulated binary switches that control many fundamental cellular processes. A common mechanism of GTPase deregulation in cancer is the deregulated expression and/or activity of their regulatory proteins, guanine nucleotide exchange factors (GEFs) that promote formation of the active GTP-bound state and GTPase-activating proteins (GAPs) that return the GTPase to its GDP-bound inactive state. In this Review, we assess the association of GEFs and GAPs with cancer and their druggability for cancer therapeutics.
• Integrin signalling adaptors: not only figurants in the cancer story
  - Nat Rev Cancer 10(12):858 (2010)
  Current evidence highlights the ability of adaptor (or scaffold) proteins to create signalling platforms that drive cellular transformation upon integrin-dependent adhesion and growth factor receptor activation. The understanding of the biological effects that are regulated by these adaptors in tumours might be crucial for the identification of new targets and the development of innovative therapeutic strategies for human cancer. In this Review we discuss the relevance of adaptor proteins in signalling that originates from integrin-mediated cell–extracellular matrix (ECM) adhesion and growth factor stimulation in the context of cell transformation and tumour progression. We specifically underline the contribution of p130 Crk-associated substrate (p130CAS; also known as BCAR1), neural precursor cell expressed, developmentally down-regulated 9 (NEDD9; also known as HEF1), CRK and the integrin-linked kinase (ILK)–pinch–parvin (IPP) complex to cancer, along with the ! more recently identified p140 Cas-associated protein (p140CAP; also known as SRCIN1).
• Does tumour dormancy offer a therapeutic target?
  - Nat Rev Cancer 10(12):871 (2010)
  The increasing number of cancer survivors is cause for celebration, but this expanding population has highlighted the problem of tumour dormancy, which can lead to relapse. As we start to understand more about the biology of dormant cancer cells, we can begin to address how best to treat this form of disease. Preclinical models and initial clinical trials, as exemplified in patients with breast cancer, are paving the way to address how best to treat long-term cancer survivors to minimize the risk of cancer recurrence.
• Why do viruses cause cancer? Highlights of the first century of human tumour virology
  - Nat Rev Cancer 10(12):878 (2010)
  The year 2011 marks the centenary of Francis Peyton Rous's landmark experiments on an avian cancer virus. Since then, seven human viruses have been found to cause 10–15% of human cancers worldwide. Viruses have been central to modern cancer research and provide profound insights into both infectious and non-infectious cancer causes. This diverse group of viruses reveals unexpected connections between innate immunity, immune sensors and tumour suppressor signalling that control both viral infection and cancer. This Timeline article describes common features of human tumour viruses and discusses how new technologies can be used to identify infectious causes of cancer.
• Integrins in cancer: biological implications and therapeutic opportunities
  - Nat Rev Cancer 10(12):890 (2010)
  On page 17 of this article, in the section Targeting αvβ3 and αvβ5 the sentence at the start of the second paragraph that reads "Cilengitide is an inhibitor of both αvβ3 and αvβ5 integrins, and it was selected in our laboratory by screening a library of cyclic RGD peptides in a cell-free receptor assay for their capacity to inhibit integrins αvβ3 and αvβ5 but not αΙΙbβ3 REF. 130)." was incorrectly phrased. The corrected sentence with additional references is given below. "Cilengitide is an inhibitor of both αvβ3 and αvβ5 integrins. We had shown that αvβ3 and αvβ5 integrins were important regulators of angiogenesis and tumour growth49,51,191, 192 and developed a cell-free receptor assay to select for antagonists of integrins αvβ3 and αvβ5 that did not effect integrin αΙΙbβ3 REF. 130). This assay was used to screen a library of integrin binding cyclic RGD peptides designed and synthesized by H. Kessler and colleagues for αvβ3 activity and selectivity193, 194, 195 from which cilengitide was developed196".
• IAPs: from caspase inhibitors to modulators of NF-κB, inflammation and cancer
  - Nat Rev Cancer 10(12):890 (2010)
  On page 574 of this article, the following text was missing from the Acknowledgements. M.G.-H. is supported by grants from the Villum Kann Rasmussen Foundation (VKR07-074), Denmark, and Danish Cancer Society (DP08052 and R2-A206-09-S2). The authors acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Centre at the Royal Marsden Hospital, UK.

Hot off the presses! Jul 12 Cancer Cell

The Jul 12 issue of the Cancer Cell is now up on Pubget (About Cancer Cell): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• The Role of TET2 in Hematologic Neoplasms
  - Cancer Cell 20(1):1-2 (2011)
  TET2 encodes an enzyme that hydroxylates methylcytosine and is frequently targeted by loss-of-function mutations in myelodysplasia, myeloproliferative disorders, and acute myeloid leukemia. In this issue of Cancer Cell, two studies show that inactivation of Tet2 enhances hematopoietic stem cell self renewal and promotes the development of myeloproliferative disorders.
• BCL6: A Novel Target for Therapy of Ph+ B Cell Acute Lymphoblastic Leukemia
  - Cancer Cell 20(1):3-5 (2011)
  BCL6 is a zinc-finger transcriptional repressor known for its oncogenic role in B cell lymphoma. In a recent issue of Nature, Duy et al. describe a novel role for BCL6 at the center of a transcriptional network in Ph+ acute lymphoblastic leukemia cells that modulates their leukemogenicity and response to kinase inhibitors.
• Comprehensive Identification of Somatic Mutations in Chronic Lymphocytic Leukemia
  - Cancer Cell 20(1):5-7 (2011)
  Massively parallel sequencing enables the sequencing of whole genomes, exomes, and transcriptomes from many tumor samples. Thus, it now is possible to comprehensively identify somatic mutations, including single base changes, deletions, insertions, and genomic rearrangements. Early results for hematopoietic tumors show great promise, but many questions remain to be answered.
• Beefing up Prostate Cancer Therapy with Performance-Enhancing (Anti-) Steroids
  - Cancer Cell 20(1):7-9 (2011)
  In the May 26th issue of the New England Journal of Medicine, de Bono et al. report that the inhibition of androgen synthesis by abiraterone acetate prolonged the survival of men with prostate cancer previously treated by androgen suppression.
• Tet2 Loss Leads to Increased Hematopoietic Stem Cell Self-Renewal and Myeloid Transformation
  - Cancer Cell 20(1):11-24 (2011)
  Somatic loss-of-function mutations in the ten-eleven translocation 2 (TET2) gene occur in a significant proportion of patients with myeloid malignancies. Although there are extensive genetic data implicating TET2 mutations in myeloid transformation, the consequences of Tet2 loss in hematopoietic development have not been delineated. We report here an animal model of conditional Tet2 loss in the hematopoietic compartment that leads to increased stem cell self-renewal in vivo as assessed by competitive transplant assays. Tet2 loss leads to a progressive enlargement of the hematopoietic stem cell compartment and eventual myeloproliferation in vivo, including splenomegaly, monocytosis, and extramedullary hematopoiesis. In addition, Tet2+/− mice also displayed increased stem cell self-renewal and extramedullary hematopoiesis, suggesting that Tet2 haploinsufficiency contributes to hematopoietic transformation in vivo.
• TET2 Inactivation Results in Pleiotropic Hematopoietic Abnormalities in Mouse and Is a Recurrent Event during Human Lymphomagenesis
  - Cancer Cell 20(1):25-38 (2011)
  Loss-of-function mutations affecting one or both copies of the Ten-Eleven-translocation (TET)2 gene have been described in various human myeloid malignancies. We report that inactivation of Tet2 in mouse perturbs both early and late steps of hematopoiesis including myeloid and lymphoid differentiation in a cell-autonomous manner, endows the cells with competitive advantage, and eventually leads to the development of malignancies. We subsequently observed TET2 mutations in human lymphoid disorders. TET2 mutations could be detected in immature progenitors endowed with myeloid colony-forming potential. Our results show that the mutations present in lymphoid tumor cells may occur at both early and later steps of lymphoid development and indicate that impairment of TET2 function or/and expression predisposes to the development of hematological malignancies.
• Cell of Origin in AML: Susceptibility to MN1-Induced Transformation Is Regulated by the MEIS1/AbdB-like HOX Protein Complex
  - Cancer Cell 20(1):39-52 (2011)
  Pathways defining susceptibility of normal cells to oncogenic transformation may be valuable therapeutic targets. We characterized the cell of origin and its critical pathways in MN1-induced leukemias. Common myeloid (CMP) but not granulocyte-macrophage progenitors (GMP) could be transformed by MN1. Complementation studies of CMP-signature genes in GMPs demonstrated that MN1-leukemogenicity required the MEIS1/AbdB-like HOX-protein complex. ChIP-sequencing identified common target genes of MN1 and MEIS1 and demonstrated identical binding sites for a large proportion of their chromatin targets. Transcriptional repression of MEIS1 targets in established MN1 leukemias demonstrated antileukemic activity. As MN1 relies on but cannot activate expression of MEIS1/AbdB-like HOX proteins, transcriptional activity of these genes determines cellular susceptibility to MN1-induced transformation and may represent a promising therapeutic target.
• Selective Killing of Mixed Lineage Leukemia Cells by a Potent Small-Molecule DOT1L Inhibitor
  - Cancer Cell 20(1):53-65 (2011)
  Mislocated enzymatic activity of DOT1L has been proposed as a driver of leukemogenesis in mixed lineage leukemia (MLL). The characterization of EPZ004777, a potent, selective inhibitor of DOT1L is reported. Treatment of MLL cells with the compound selectively inhibits H3K79 methylation and blocks expression of leukemogenic genes. Exposure of leukemic cells to EPZ004777 results in selective killing of those cells bearing the MLL gene translocation, with little effect on non-MLL-translocated cells. Finally, in vivo administration of EPZ004777 leads to extension of survival in a mouse MLL xenograft model. These results provide compelling support for DOT1L inhibition as a basis for targeted therapeutics against MLL.
• MLL-Rearranged Leukemia Is Dependent on Aberrant H3K79 Methylation by DOT1L
  - Cancer Cell 20(1):66-78 (2011)
  The histone 3 lysine 79 (H3K79) methyltransferase Dot1l has been implicated in the development of leukemias bearing translocations of the Mixed Lineage Leukemia (MLL) gene. We identified the MLL-fusion targets in an MLL-AF9 leukemia model, and conducted epigenetic profiling for H3K79me2, H3K4me3, H3K27me3, and H3K36me3 in hematopoietic progenitor and leukemia stem cells (LSCs). We found abnormal profiles only for H3K79me2 on MLL-AF9 fusion target loci in LSCs. Inactivation of Dot1l led to downregulation of direct MLL-AF9 targets and an MLL translocation-associated gene expression signature, whereas global gene expression remained largely unaffected. Suppression of MLL translocation-associated gene expression corresponded with dependence of MLL-AF9 leukemia on Dot1l in vivo. These data point to DOT1L as a potential therapeutic target in MLL-rearranged leukemia.
• A Pin1/Mutant p53 Axis Promotes Aggressiveness in Breast Cancer
  - Cancer Cell 20(1):79-91 (2011)
  TP53 missense mutations dramatically influence tumor progression, however, their mechanism of action is still poorly understood. Here we demonstrate the fundamental role of the prolyl isomerase Pin1 in mutant p53 oncogenic functions. Pin1 enhances tumorigenesis in a Li-Fraumeni mouse model and cooperates with mutant p53 in Ras-dependent transformation. In breast cancer cells, Pin1 promotes mutant p53 dependent inhibition of the antimetastatic factor p63 and induction of a mutant p53 transcriptional program to increase aggressiveness. Furthermore, we identified a transcriptional signature associated with poor prognosis in breast cancer and, in a cohort of patients, Pin1 overexpression influenced the prognostic value of p53 mutation. These results define a Pin1/mutant p53 axis that conveys oncogenic signals to promote aggressiveness in human cancers.
• Proinvasion Metastasis Drivers in Early-Stage Melanoma Are Oncogenes
  - Cancer Cell 20(1):92-103 (2011)
  Clinical and genomic evidence suggests that the metastatic potential of a primary tumor may be dictated by prometastatic events that have additional oncogenic capability. To test this "deterministic" hypothesis, we adopted a comparative oncogenomics-guided function-based strategy involving: (1) comparison of global transcriptomes of two genetically engineered mouse models with contrasting metastatic potential, (2) genomic and transcriptomic profiles of human melanoma, (3) functional genetic screen for enhancers of cell invasion, and (4) evidence of expression selection in human melanoma tissues. This integrated effort identified six genes that are potently proinvasive and oncogenic. Furthermore, we show that one such gene, ACP5, confers spontaneous metastasis in vivo, engages a key pathway governing metastasis, and is prognostic in human primary melanomas.
• miR-30b/30d Regulation of GalNAc Transferases Enhances Invasion and Immunosuppression during Metastasis
  - Cancer Cell 20(1):104-118 (2011)
  To metastasize, a tumor cell must acquire abilities such as the capacity to colonize new tissue and evade immune surveillance. Recent evidence suggests that microRNAs can promote the evolution of malignant behaviors by regulating multiple targets. We performed a microRNA analysis of human melanoma, a highly invasive cancer, and found that miR-30b/30d upregulation correlates with stage, metastatic potential, shorter time to recurrence, and reduced overall survival. Ectopic expression of miR-30b/30d promoted the metastatic behavior of melanoma cells by directly targeting the GalNAc transferase GALNT7, resulted in increased synthesis of the immunosuppressive cytokine IL-10, and reduced immune cell activation and recruitment. These data support a key role of miR-30b/30d and GalNAc transferases in metastasis, by simultaneously promoting cellular invasion and immunosuppression.
• Targeting Androgen Receptor in Estrogen Receptor-Negative Breast Cancer
  - Cancer Cell 20(1):119-131 (2011)
  Endocrine therapies for breast cancer that target the estrogen receptor (ER) are ineffective in the 25%–30% of cases that are ER negative (ER–). Androgen receptor (AR) is expressed in 60%–70% of breast tumors, independent of ER status. How androgens and AR regulate breast cancer growth remains largely unknown. We find that AR is enriched in ER– breast tumors that overexpress HER2. Through analysis of the AR cistrome and androgen-regulated gene expression in ER–/HER2+ breast cancers we find that AR mediates ligand-dependent activation of Wnt and HER2 signaling pathways through direct transcriptional induction of WNT7B and HER3. Specific targeting of AR, Wnt or HER2 signaling impairs androgen-stimulated tumor cell growth suggesting potential therapeutic approaches for ER–/HER2+ breast cancers.
• Turning Reciprocal Feedback Regulation into Combination Therapy
  - Cancer Cell 20(1):132 (2011)
  

Hot off the presses! Jan 14 Nature

The Jan 14 issue of the Nature is now up on Pubget (About Nature): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Call for a bigger vision
  - Nature 463(7278):135 (2010)
  Science in Canada cannot realize its full potential without clear direction from government.
• Lessons from a pandemic
  - Nature 463(7278):135 (2010)
  It is time to assess what worked, and what didn't, in the global efforts to cope with swine flu.
• Security ethics
  - Nature 463(7278):136 (2010)
  Manufacturers of computer systems should welcome researchers' efforts to find flaws.
• Biology: Snakes face the heat
  - Nature 463(7278):138 (2010)
  
• Neuroscience: Brain cell gain and cocaine
  - Nature 463(7278):138 (2010)
  
• Materials science: Sequencing with carbon
  - Nature 463(7278):138 (2010)
  
• Cancer biology: Kicking out cancer cells
  - Nature 463(7278):138 (2010)
  
• Geoscience: Extraterrestrial dust
  - Nature 463(7278):138 (2010)
  
• Biogeochemistry: DDT in the ocean
  - Nature 463(7278):138 (2010)
  
• Immunology: Double punch for HIV
  - Nature 463(7278):139 (2010)
  
• Neuroscience: Dark migraine relief
  - Nature 463(7278):139 (2010)
  
• Molecular biology: Flowering time unravelled
  - Nature 463(7278):139 (2010)
  
• Drug discovery: Virtual antibiotic screen
  - Nature 463(7278):139 (2010)
  
• Correction
  - Nature 463(7278):139 (2010)
  
• Journal club
  - Nature 463(7278):139 (2010)
  
• News briefing: 14 January 2010
  - Nature 463(7278):140 (2010)
  The week in science This article is best viewed as a PDF Policy|Research|Events|Business|People|Market Watch|The week ahead|Number crunch|Sound Bites In a long-awaited report, a top-level US government working group last week called for tightened security measures for scientists working with the most dangerous pathogens. The toughened measures include assessing individual scientists for their security risk every three years instead of every five as currently required. The working group also recommended that 82 biological select agents and toxins currently listed for tough security regulations should be graded according to the level of risk they pose, with biosecurity measures targeted accordingly. The food industry should be more open about its research on nanotechnology for food and food packaging, the United Kingdom's House of Lords Science and Technology Committee recommended in an 8 January report. It said that companies were reluctant to talk about their work in the area, an attitude that might engender public suspicion. The report also repeated calls for more research into the health and safety risks of nanomaterials. On 7 January, the US Environmental Protection Agency proposed to override a controversial decision made in 2008 by the administration of President George W. Bush that ignored the agency's science advisers in setting air-quality standards. The administration of President Barack Obama is now proposing to ratchet down the limit for smog, also known as ground-level ozone, from 0.075 parts per million (p.p.m.) to between 0.06 and 0.07 p.p.m.; before 2008, the standard was 0.084 p.p.m.. The United Nations Educational, Scientific and Cultural Organization (UNESCO) is setting up a task force by the end of January to review how it creates its prizes. The move by the Paris-based organization follows complaints from some of its member states about a US$3-million life-sciences award sponsored by President Teodoro Obiang Nguema Mbasogo of Equatorial Guinea. Delegations had expressed concern over association with the country's record of human-rights abuses. The prize, due to be awarded in February, has been postponed pending the review's outcome in April, says UNESCO spokeswoman Sue Williams. British universities have protested that impending budget cuts could devastate the country's higher-education system. Wendy Piatt, director-general of the Russell Group of 20 leading UK universities, together with Michael Arthur, who chairs the group's board, wrote in the newspaper The Guardian that the sector faced 'meltdown' and argued for special protection. Cuts to UK science and university spending are likely to fall between hundreds of millions and billions of pounds. The University of Wisconsin-Madison has been ordered to report more frequently on its animal care to the National Institutes of Health (NIH), after an unannounced inspection by agency officials last month found numerous deficiencies. In an 18 December letter publicized last week by WISC-TV, the NIH ordered the university to enhance its oversight of the number of animals it uses in experiments, ensure appropriate temperature controls in animal transport vehicles and improve sanitation in chicken houses. Eric Sandgren, director of the university's Research Animal Resources Center, emphasized that, overall, federal officials "were pleased with the programme". Separately, it emerged last week that a primate had died of malnutrition in spring 2009 at the University of Washington's National Primate Research Center. A newly publicized US Department of Agriculture inspection report noted that the oversight deficiencies that allowed this to happen have now been corrected. In the United States, inflation-adjusted spending on biomedical research grew by 3.4% a year between 2003 and 2007 — less than half the annual growth rate of 7.8% between 1994 and 2003, according to a recent study (E. R. Dorsey et al. J. Am. Med. Assoc. 303, 137–143; 2010). The analysis includes funding from all levels of government together with contributions from industry and private sources. For 2008, figures were available only from industry and the National Institutes of Health. Their combined 2008 spending of US$88.8 billion, adjusted for inflation, represents a 1.6% decline from 2007. J. MCARTHUR/SEA SHEPHERD CONSERV. SOC./AFP A boat owned by anti-whaling group the Sea Shepherd Conservation Society, based in Friday Harbor, Washington, has sunk after tangling with a ship from a Japanese whaling fleet. The society, which regularly spars with the fleet to disrupt whale hunting, claims that the harpoon vessel Shonan Maru 2 deliberately rammed its fast carbon-fibre trimaran, the Ady Gil, in the Southern Ocean on 6 January (pictured); it sank two days later. The Shonan Maru 2 is one of a fleet of ships owned by Japan's Institute for Cetacean Research, which organizes an annual whale hunt for 'scientific research' in Antarctic waters. The institute says that the protest boat collided with the ship after attacking it. The European Commission has awarded key contracts for Europe's ambitious and long-delayed satellite-navigation system, Galileo. OHB System in Bremen, Germany, secured €566 million (US$810 million) to build the first 14 satellites for the network, which is intended to rival the US Global Positioning System. Arianespace, based near Paris, France, got a €397-million contract to launch the first ten spacecraft on Soyuz rockets. The network is scheduled to begin operation in early 2014. Contracts remain to be awarded for up to 16 more satellites and for ground-control operations. Drug-company revenues from the supply of H1N1 pandemic-flu vaccines may be lower than expected because of slowing demand. Last week, France and Germany said they would cancel millions of doses ordered from major suppliers. Britain, Spain, the Netherlands and Switzerland are among other countries hoping to halt supplies, return unused vaccines or donate surplus stock to other nations. The US government has not yet decided whether to cancel orders or sell surplus vaccines, although it has already scaled back its order from Australian firm CSL (as contractually allowed). Total investment in wind, solar, and biofuels systems surged by 25% to US$37.3 billion in the Asia-Pacific region in 2009. This put the region's clean-energy spending ahead of that in the Americas ($32 billion) for the first time. However, it was still behind the Europe, Middle East and Africa region ($42.2 billion), according to data released on 7 January by analysts New Energy Finance. S. CLARKE/REX FEATURES In the face of a major financial crisis, the Royal Institution of Great Britain has made redundant its director, Susan Greenfield (pictured). Greenfield, a neuroscientist at the University of Oxford, UK, has led the institution since 1998 and had recently overseen a £22-million (US$35.5-million) refurbishment of its headquarters in central London. Last month it emerged that restricted endowments had been spent on the renovations and that the institution was short of funds (see Nature 462, 833; 2009). In a statement, Greenfield said she was "saddened and dismayed" by the decision, and would appeal to an employment tribunal over her dismissal. SOURCE: POINT CARBON Trade in the carbon market skyrocketed in 2009, but the price of emissions permits — allowances to emit a tonne of carbon dioxide or greenhouse gases with equivalent impact — fell heavily. Oslo-based consultancy Point Carbon estimates that 8.2 billion tonnes of CO2 equivalent exchanged hands across the world market last year, up 68% from 2008. Yet its weighted-average world carbon price ended the year at €11.40 (US$16.55), down from €18.87 in 2008. The European Union's emissions trading system (ETS) accounted for 77% of the world's carbon market last year. Its carbon prices, already dropping by the end of 2008, fell further as traders realized that power plants and other carbon-intensive industries had a large surplus of carbon permits. This was because the economic recession was lowering energy demand, as reflected by falling gas prices (see graph). In the end, says Point Carbon's analyst Stig Schjølset, carbon prices avoided the violent fluctuations seen in previous years. The main event for 2010 carbon markets will be the United States' cap-and-trade scheme. If established in line with the proposal being debated in Congress, it would allot three times as many permits as the ETS's current cap, says Schjølset — vastly expanding carbon trade. Sigma Xi, the research society based in North Carolina, hosts ScienceOnline2010, the fourth annual conference exploring science on the Internet. → www.scienceonline2010.com An annular solar eclipse sweeps across Africa and eastern Asia: at its peak above the Indian Ocean, it will last for more than 11 minutes. → go.nature.com/6Wk6O8 The Science and Engineering Indicators 2010 — biennial statistics detailing the state of US science and engineering — are presented to the president and to Congress. → go.nature.com/1AxGAo The United Nations' Educational, Scientific and Cultural Organization (UNESCO) launches its exhibition on biodiversity in Paris. → go.nature.com/kBCHMR The world-record number of digits to which Fabrice Bellard, a French software engineer, claims to have computed π, using only a desktop computer. "The future of human spaceflight will not be paid out of the hide of the science budget." NASA Administrator Charles Bolden, speaking at the American Astronomical Society's 2010 winter meeting, tells astronomers that NASA's science funding will not be plundered to support human spaceflight. Source: go.nature.com/aty14t There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Publish or perish in China
  - Nature 463(7278):142 (2010)
  The pressure to rack up publications in high-impact journals could encourage misconduct, some say. Under pressure: one-third of researchers surveyed in China admit to plagiarism, falsification or fabrication of data.K. Brofsky/Getty The latest in a string of high-profile academic fraud cases in China underscores the problems of an academic-evaluation system that places disproportionate emphasis on publications, critics say. Editors at the UK-based journal Acta Crystallographica Section E last month retracted 70 published crystal structures that they allege are fabrications by researchers at Jinggangshan University in Jiangxi province. Further retractions, the editors say, are likely. Chinese universities often award cash prizes, housing benefits or other perks on the basis of high-profile publications, and the pressure to publish seems to be growing. A new study from Wuhan University, for instance, estimates that the market for dubious science-publishing activities, such as ghostwriting papers on nonexistent research, was of the order of 1 billion renminbi (US$150 million) in 2009 — five times the amount in 2007. In other studies, one in three researchers surveyed at major universities and research institutions admitted to committing plagiarism, falsification or fabrication of data. "The extent of the misconduct is disturbing," says Nicholas Steneck, director of the Research Ethics and Integrity Program at the University of Michigan in Ann Arbor. "It highlights the challenges China faces as it struggles to rapidly improve the research capacity of a very large system — with significant variations in quality — to be a world-class player in science." Two weeks ago, reacting to the retractions of the crystallography papers, Jinggangshang University fired the correspondent authors, Zhong Hua and Liu Tao. It is unclear whether their co-authors, who include researchers from other institutions in China, will also be investigated. "Counting the number of publications becomes the norm." The journal's editors say that the discrepancies came to light during tests of software designed to flag possible errors and unusual chemical features, such as abnormal distances between atoms. The software identified a large number of crystal structures that didn't make sense chemically; further checking, the editors say, suggests that the authors simply changed one or more atoms of an existing compound of known structure, then presented that structure as new. Zhong and Liu could not be reached for comment. Editors at the journal are now checking the authenticity of other published crystal structures, including all submissions from Jinggangshan University. Half of the 200,000-odd crystal structures published by the journal during the past five years have come from China. William Harrison, a chemist at the University of Aberdeen, UK, who is one of three section editors for the journal, would not discuss the ongoing investigation but says that the generation of large numbers of structures by one group would not necessarily raise questions, because diffractometers can easily collect a couple of data sets a day. "In terms of papers submitted to Acta E, the vast majority coming from China are correctly determined structures, and they make a valuable contribution to science," he says. Nevertheless, the Wuhan University study suggests that misconduct could be widespread in many fields. The team, led by computer scientist Shen Yang, used website analyses and onsite investigations to identify a wide range of dubious publishing activities. These include ghostwriting theses and academic papers on fictional research, bypassing peer-review for payment, and forging copies of legitimate Chinese or international journals. The researchers analysed the most popular 800 websites involved in such activities — which together rack up 210,000 hits a day — and found that the cost of each transaction is typically 600–12,000 renminbi. Three-quarters of the demand comes from universities and institutions, says Shen. "There is a massive production chain for the entire publishing process," he says. Concerned by such trends, China's science ministry commissioned a survey of researchers, the results of which remain under wraps. However, several sources revealed to Nature that roughly one-third of more than 6,000 surveyed across six top institutions admitted to plagiarism, falsification or fabrication. Many blamed the culture of jigong jinli — seeking quick success and short-term gain — as the top reason for such practices, says Zeng Guopin, director of the Institute of Science Technology and Society at Tsinghua University in Beijing who was involved in running the survey. The second most-cited cause is bureaucratic interference in academic activities in China. Most academic evaluation — from staff employment and job promotion to funding allocation — is carried out by bureaucrats who are not experts in the field in question, says Fang Shimin, a US-trained biochemist who runs a website called 'New Threads' that exposes research misconduct in China. "When that happens, counting the number of publications, rather than assessing the quality of research, becomes the norm of evaluation," he says. Cao Nanyan, a colleague of Zeng's at Tsinghua, conducted a similar survey commissioned by the Beijing municipality, which surveyed 2,000 researchers from 10 universities and research institutions. It, too, found that roughly one-third of respondents admitted to illegitimate practices. ADVERTISEMENT To critics such as Rao Yi, dean of the life-science school at Peking University in Beijing, the lack of severe sanctions for fraudsters, even in high-profile cases, also contributes to rampant academic fraud. Many researchers criticize the fact that Chen Jin, a former researcher at Shanghai Jiao Tong University who is accused of falsely claiming to have developed a series of digital signal-processing chips, was fired with no other repercussions. Meanwhile, others involved in the scandal have gone unpunished. "You send out a very wrong signal when such high-profile cases are not dealt with properly," says Rao. There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Streamlined chemical tests rebuffed
  - Nature 463(7278):142 (2010)
  Europe impedes introduction of REACH safety assessments. Watership downer: testing the toxicity of chemicals over two generations rather than just one will mean the deaths of millions more animals.K. GULDBRANDSEN/SPL Europe's chemical regulator is threatening to stall safety studies that toxicologists say could prevent millions of animals being used in tests over the next eight years. European Union (EU) legislation requires that chemicals be tested in two generations of animals to assess the effects on their reproductive systems. But proposed new tests would allow just one generation of animals to be used, with additional tests on a second generation required only if the first round raised concerns. But the European Chemicals Agency (ECHA) in Helsinki, which implements the EU's REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) legislation and is responsible for issuing guidance on tests, says that there is not yet enough evidence to rely on one-generation testing. Toxicologists who advocate the switch, however, say that their scientific case is "overwhelming". They argue that REACH will fail unless the new test is adopted, because the two-generation tests are too expensive, demand too many animals, and require laboratory space and manpower that the EU simply doesn't have. "Everyone is longing for this change to happen. It's the only way to make the legislation feasible," says toxicologist Thomas Hartung, former head of the European Centre for the Validation of Alternative Methods in Ispra, Italy, and now at Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. He estimates that using the extended one-generation study would reduce animal use in REACH by 40–60%. "Costs would be reduced in a similar range," he says. "We can't perform all the two-generation studies that we are required to perform under REACH," adds Susanne Böhn, a toxicologist for BASF, a chemical company headquartered in Ludwigshafen, Germany. REACH came into force in 2007, and is the world's most extensive attempt at improving the safe use of chemicals. All chemicals sold in the EU in quantities of more than one tonne per year must be registered, along with toxicity data, by 2018. The ECHA estimates that about 30,000 substances will be logged, requiring 9 million animals to be used in tests costing €1.3 billion (US$1.9 billion). But a study by Hartung suggests that this is a gross underestimate, and that at least 68,000 chemicals will have to be registered, requiring the use of 54 million animals (T. Hartung and C. Rovida Nature 460, 1080–1081; 2009). The Organisation for Economic Co-operation and Development (OECD) is drawing up guidelines for its member states for a one-generation study. These would include a more extensive battery of tests that are not routinely performed in the existing two-generation studies, including histopathology and neurobehavioural tests. OECD member states, except for Sweden, agreed on a draft of the guidelines at a meeting on 21–23 October 2009 in Paris. At the meeting, Elizabeth Méndez, a toxicologist at the US Environmental Protection Agency (EPA), presented an analysis of 350 substances — mostly pesticides — showing that only one would not have been picked up as dangerous had a second-generation study not been performed. "There is a great deal of redundancy in the second-generation tests," she says. The EPA has already begun trialling the extended one-generation tests on a case-by-case basis. Another study (G. Janer et al. Reprod. Toxicol. 24, 97–102; 2007) found that in 176 multi-generation studies on 148 substances, there were only three instances in which reproductive toxicity was not identified until the second-generation test. ADVERTISEMENT But it is up to the ECHA to recommend that the new tests be used in REACH, and the agency, which attended the October meeting, is not convinced by such studies. At the meeting, agency representatives expressed concern that some fertility effects could be missed in a one-generation study, and criticized the EPA analysis for not considering whether reproductive effects seen in the second-generation tests were more severe than in the first. In a statement to Nature, the ECHA said: "The two-generation study is the only study that covers effects on reproduction after exposure during all life stages." The agency added that the scientific evaluation of the OECD's guidelines is "on-going", and that it "considers it premature to evaluate the impacts on the number of test animals and costs of the test designs under development". Hartung points out that the OECD, which is expected to approve a final version of the guidelines for one-generation tests in March, could use its political cl! out to lobby for European regulators to approve the tests. There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Disease epidemic killing only US bats
  - Nature 463(7278):144 (2010)
  European bats seemingly unaffected by fungal infection. A. Hicks, New York State Department of Environmental Conservation/AP Photo This week, wildlife biologist Scott Darling and his small team will snowshoe up to the mouth of Vermont's remote Mount Aeolus cave, once the largest bat hibernation spot in New England. As recently as three years ago, the cave held in excess of 200,000 bats. But this year, the team will change into white protective suits and enter the cave to see if any remain. Aeolus is one of more than 80 sites in the northeastern United States known to have been hit by white-nose syndrome (WNS), a poorly understood disease that has been devastating bat populations since it first appeared in 2006. The syndrome was named after the snowy-white fungus (Geomyces destructans) that grows on the muzzle and sometimes on the wings of afflicted bats while they hibernate (pictured above). For reasons that are still unclear, the bats rouse and fly around when they should be conserving energy; having burned their fat, they eventually starve to death. Over the past three years, bat biologists estimate that one million bats have died from WNS in the United States, with some hibernation sites losing 90–100% of their animals. Many experts are concerned because of the bats' important role in pollination. At Aeolus, "last year we estimate that we found between 10,000 and 20,000 dead bats on the cave floor," says Darling, who works for Vermont's Fish and Wildlife Department in Rutland. And that was just in Guano Hall, the outermost chamber of the cave. Darling and his crew don't go deeper because they want to avoid rousing the remaining bats — "and to be honest, the mortality is so disturbing", he says. "We just can't crawl through so many piles of dead bodies." Even as biologists make their first grim ventures into US caves this year, researchers are scrambling to develop ways to counteract the syndrome and to understand its many mysteries — including why, even though the fungus has been found in European bats as well, the animals there remain healthy. In one line of research, some groups are working to develop chemicals that could slow down or kill the fungus, but these have yet to make it out of the lab and might turn out to harm other fungi in the caves. Other teams are looking at biological controls — bacteria that could spread among the bats, live on their skin, and protect them from the fungus. No quick fix A vaccine could also help, although because of the challenge of vaccinating individual animals, this would probably only be practical for preserving a limited number of an endangered species — such as the Indiana bat, which has lost 30–40% of its population in the past three years. "Unfortunately, these will take years of research, and we're operating under the assumption that we don't have that kind of time," says Jeremy Coleman, the WNS coordinator for the US Fish and Wildlife Service, who is based in Cortland, New York. One problem is that scientists still don't know how the disease kills the bats, although many think that the fungus, which invades the hair follicles and oil glands of the bats' wings, irritates the animals and rouses them from hibernation. It is also known to damage the bats' wings, which may hamper their ability to catch their insect prey should they make it to spring. But it is possible that the fungus is an opportunistic infection, striking bats that are already ill from something else — although no other pathogen has been found. Click for larger image Some clues may come from reports in the past year of white fungus on the muzzles and wings of a small number of bats in at least eight European countries. Four countries — Hungary, Germany, Switzerland and France1 — have confirmed that the fungus is Geomyces destructans, but their bats remain healthy. Adding to the intrigue is a 1983 report that shows a picture of a German bat with powdery white substance around its muzzle2. The report mentions occasional sightings of such bats during routine winter bat surveys, suggesting that the fungus may have been infecting European bats for at least 23 years, apparently without killing them, before showing up in North America. According to David Blehert, a microbiologist at the US Geological Survey's National Wildlife Health Center in Madison, Wisconsin, whose team first described the fungus3, the European bats may have coevolved with the fungus and developed immune resistance. They may also have behavioural adaptations that allow them to escape lethal infection; for example, European bats hibernate in small groups, ranging from 1 to rarely more than 100, whereas bats in the United States usually hibernate in groups of thousands or hundreds of thousands, ripe for rapid spread of disease. "It will be interesting to see what the situation is in two to three years from now," says Blehert. "If the fungus they're seeing now is the same fungus that was anecdotally documented three decades ago, it does suggest that while Geomyces destructans occurs in Europe, white-nose syndrome may not." ADVERTISEMENT But time is not on the side of North American bats. "Any day now I'm expecting the phone to ring with reports of new locations," says Coleman, who is particularly anxious about the disease spreading south and west (see graphic). "Tennessee, Kentucky — those are places with huge numbers of bats," he says. Little brown bats, the predominant species in the Mount Aeolus cave, have been hardest hit, says Thomas Kunz, a biologist at Boston University in Massachusetts. And with the bats normally only producing one pup per year, the populations will struggle to come back. "We're making predictions of extinction," he says. * References * Puechmaille, S. J.et al. Emerg. Infect. Dis. advance online publication doi:10.3201/eid1602.091391 (2010). * Feldmann, R. in Die Säugetiere Westfalens (eds Schröpfer, R. , Feldmann, R. & Vierhaus, H. ) 107-111 (Westfälisches Museum für Naturkunde, 1984). * Blehert, D. S.et al. Science323, 227 (2009). There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Trace that metal
  - Nature 463(7278):145 (2010)
  Collaboration launches effort to track marine nutrients. A project sampler takes the plunge.G. Cutter Ocean life, like human life, needs trace metals to stay healthy, and in some cases even to survive. But although the cycles and concentrations of the ocean's superstar nutrients — phosphorus and nitrates — are relatively well understood, a clear global view of trace metals has remained elusive. Next month, however, an international team will formally launch a major research programme to obtain measurements of trace metals throughout the world's oceans. Potential pay-offs range from improved understanding of the role of ocean plankton in regulating climate change, to better studies of the geological history of the oceans. "We're completely missing information about iron and other metals which are really important to life, and that renders our current understanding of the nutrient system incomplete," says the project's steering committee co-chair Gideon Henderson, a geochemist at the University of Oxford, UK. The programme, called GEOTRACES, involves more than 30 countries and will span the next decade. More than a dozen cruises are planned — the first returned to port on 9 January after sampling in the Indian Ocean — and at least ten more are being discussed. All told, the programme will cost US$100 million to $200 million. GEOTRACES' primary mission is to analyse water samples from various depths, recording levels of trace elements such as iron and cobalt that are hard to measure because the sampling apparatus must be carefully cleaned to avoid contamination. The data should allow investigators to model the sources and cycles of these elements in comparable detail to the current understanding of phosphorus and nitrates. That, in turn, should help to improve the Earth-systems models being developed for the next assessment of the Intergovernmental Panel on Climate Change in 2014. Iron, for instance, is a well-studied trace element because it is involved in regulating phytoplankton production, which anchors the oceanic carbon cycle. But even so, researchers aren't sure of the iron's main sources or the key areas where it upwells from the deep sea. And less-studied elements such as zinc and cobalt could be equally important in some cases in regulating plankton growth (M. A. Saito et al. Limnol. Oceanogr. 53, 276–290; 2008). Another project focus is the isotopes of trace metals, which can aid studies of past climates and ocean currents. For instance, changes in neodymium-isotope levels and in the ratio between the isotopes of protactinium and thorium over time offer independent measures of the historical strength of deep-ocean currents, which are thought to selectively deplete or enhance particular isotopes in sediments. So far, the records of these 'proxies' seem to agree in what they say about flows during some periods, such as over the past 12,000 years, but they disagree about certain events before then, during the last ice age. "The fact is, we could argue for years, but we need more data to resolve the argument," says steering committee co-chair Robert Anderson of Columbia University in New York City. Geochemist Wallace Broecker of Columbia University, who isn't involved in GEOTRACES, calls it "a very healthy programme". Broecker, who led a landmark sampling programme in the 1960s and '70s focusing on the major nutrients, adds: "If they don't know what's really going on today, then of course you're going to make big mistakes in how you read the palaeo records." ADVERTISEMENT Although trace metals can be essential for marine life, at high levels metals such as cadmium and copper can be lethal, and others including lead and mercury can become concentrated in ocean food chains. And the GEOTRACES data could be used to address various environmental questions, including how ongoing changes such as the acidification of the oceans might affect trace-element cycling. "We need to understand the baseline biogeochemical cycles," says Anderson, "before we can say anything meaningful about how global change is going to affect them." There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Pulsar watchers race for gravity waves
  - Nature 463(7278):147 (2010)
  Radio telescopes vie with laser detectors to hunt for signs of massive cosmic collisions. Click for larger image Aided by the Universe's best celestial clocks, radio astronomers are embarking on a search for the almost-imperceptible stretching of the fabric of space by gravitational waves — predicted by Einstein's theory of general relativity but not yet detected directly. The approach is competing with more elaborate and expensive approaches to gravitational wave detection. Since the late 1970s, astronomers have known that gravitational waves affect the arrival time of radio-wave bursts that emanate with clockwork regularity from pulsars, the spinning neutron stars left over from exploded supernovae. Now, the idea has moved from theory to application with the recent discoveries of many millisecond pulsars, which emit radio-wave bursts every thousandth of a second or so, more rapidly and more reliably than 'normal' pulsars. NASA's Fermi Gamma-ray Space Telescope is identifying the locations of dozens of these galactic clocks, allowing radio astronomers to follow up and monitor them. Researchers can deduce whether a passing gravitational wave has jostled Earth by watching for slight variations in the arrival time of pulsar radio-wave bursts — just fractions of a second over the course of years. If these efforts succeed, researchers will have a new tool for exploring the cosmic cataclysms — colliding black holes, for example — that are thought to generate gravitational waves (see graphic). The shoestring effort, involving groups in Australia, Europe and North America, could beat larger and better-funded groups that use laser interferometry to try to detect gravitational waves by their tiny effects on the movements of test masses. "People are finally taking notice," says Scott Ransom, an astronomer at the National Radio Astronomy Observatory in Charlottesville, Virginia, who last week announced the discovery of 17 millisecond pulsars at a meeting of the American Astronomical Society in Washington DC. Ransom says that about 100 millisecond pulsars are known in the Milky Way, but only a handful are bright enough and regular enough to be measured to the precision necessary to hunt gravitational waves. Some 20–40 of these pulsars, enough for a full 'pulsar timing array', would have to be monitored for 5–10 years before a gravitational wave signal would stand out. But with new millisecond pulsars now turning up, researchers are confident that they will soon have enough to compete with the ground-based laser efforts in Italy, Germany and the United States, where physicists have been sifting through petabytes of data for years without bagging so much as a gravitational burp. "Physicists have been sifting through data for years without bagging so much as a gravitational burp." These ground-based groups could still get lucky and detect the gravitational wave signature of a rare event, such as the final moments of a nearby neutron star merger. But capturing such an event is not assured until the main US detector — the Laser Interferometer Gravitational-Wave Observatory (LIGO) in Washington state and Louisiana — is upgraded in 2015 to make it sensitive enough to pick up waves from a much larger volume of the Universe. Pulsar astronomers thus have a shot at first detection. "I think they have a really solid chance of beating the ground-based detectors," says Bruce Allen, director of the Max Planck Institute for Gravitational Physics in Hanover, Germany, who manages shared data analysis among the ground-based detectors. "It's a real race." The end of the race to detect gravitational waves will mark the beginning of gravitational wave astronomy — yet the different approaches are sensitive to vastly different phenomena. Whereas the interferometers would detect the rapid pulses of merging neutron stars, the pulsar timing arrays seek the lower-frequency but stronger background signal that comes from violent mergers of supermassive black holes at the centres of distant galaxies. The Laser Interferometer Space Antenna (LISA), a multibillion-dollar space mission being considered by NASA and the European Space Agency, would be sensitive to the gravitational wave frequencies in between, where events such as merging white dwarfs would stand out. ADVERTISEMENT Thomas Prince, an astrophysicist at the California Institute of Technology in Pasadena and LISA mission scientist for NASA, says that the space- and ground-based interferometers will be better at pinpointing gravitational events in the sky. But Ransom says that by comparison, pulsar timing arrays are "dirt cheap" because they use existing radio telescopes instead of requiring a detector such as LIGO, which cost US$300 million to build and is getting another $200 million for its upgrade. Either way, detecting the Universe's most violent events requires extraordinary sensitivity — temporal in the case of the pulsar timing arrays and spatial in the case of the interferometers. Interferometers already monitor the position of their test masses to better than one part in a million million billion (10–21) — which Prince likens to measuring the distance to a nearby star to within the width of a human hair. There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Two new journals copy the old
  - Nature 463(7278):148 (2010)
  Volunteer with publisher says duplication was a technical 'mistake'. Some experts have withdrawn from new journals' editorial boards.IMAGEBROKER/ALAMY At least two journals recently launched by the same publisher have duplicated papers online that had been published elsewhere. Late last year, an organization called Scientific Research Publishing reproduced the papers in what its website (www.scirp.org) billed as the first issues of the new journals Journal of Modern Physics and Psychology. Huai-Bei Zhou, a physicist from Wuhan University in China who says he helps to run Scientific Research's journals in a volunteer capacity, says that the reproductions were a mistake caused by posting sample content for the new journals; links to the content have since been removed. And since Nature began its enquiries, the web pages of other journals published by Scientific Research have removed from lists of editorial boards the names of researchers who say they did not agree to such positions. Many of these people thought they had agreed to serve on the board for a different journal with a similar name. Scientific Research recently e-mailed many academics to solicit articles for some of its 34 journals, including some that publish original research. However, what Scientific Research's website labelled as the first issue of the Journal of Modern Physics completely reproduced papers published in 2000 by Britain's Institute of Physics in the open-access New Journal of Physics1–3. The Scientific Research journal Psychology also contains papers that seem to have been published previously, including one in its first issue that was awarded an Ig Nobel Prize in 2000 after being published elsewhere4. Marc Abrahams, organizer of the Ig Nobel awards, contacted Scientific Research in late December asking for more information about the new journal; the issue has since been removed from the website. Neither Psychology nor the Journal of Modern Physics had an editor-in-chief listed on the site. But Zhou says that the duplications are information-technology "mistakes" that would be corrected. "They just set up the website to make it look nice," he says. Scientific Research's website is registered in China, although Zhou says that the organization is based in the United States and is run from there and China. He says it was set up "three or four years ago" by a group of friends and colleagues from these countries to promote exchange between scholars. He declined to tell Nature who these people were or whether he was one of them, although in an e-mail to Abrahams he describes himself as president of Scientific Research. Legal consideration Those involved in the original publications of the physics papers say that they were not notified of Scientific Research's work. Tim Smith, senior publisher for the New Journal of Physics, says that even if the papers were being used to mock up a sample issue of a new journal, they should not have been repurposed without permission. In a PDF of the Journal of Modern Physics issue, all the Institute of Physics branding has been removed and replaced by Journal of Modern Physics branding and reference details; otherwise the papers are identical down to the typeface, font and formatting. Smith says that the institute is exploring potential legal action. "We are discussing it as a matter of urgency," he says. Some academics have also questioned how they came to be added to online lists of advisory board members for various Scientific Research journals. For instance, Thomas Schiano of Mount Sinai Medical Center in New York received an e-mail from Scientific Research saying he was on the editorial board of Psychology. "I am a transplant hepatologist and not a psychiatrist or psychologist," he says, "so found it a bit strange." Schiano's name has since been removed. So have other researchers once listed as editorial board members for Scientific Research's Journal of Biophysical Chemistry, such as Ruth Nussinov, a computational structural biologist at the National Cancer Institute in Frederick, Maryland, and Kwang-Soo Kim, a neurobiologist at Harvard Medical School based in Belmont, Massachusetts. Zhou says that Scientific Research has e-mails from each scientist listed on the website agreeing to the position. Some of them say they thought they had agreed to be on the board of more established journals. "Because of my crazily busy schedule at that time, I did not carefully read their information and mistakenly thought that it was the Journal of Biological Chemistry," says Kim. The home page for the Journal of Biophysical Chemistry contains only the titles and page numbers of four papers in the first issue. Identical paper titles appear in the Journal of Bioscience5–8, published by Springer India, from 2000. Scientific Research's journal Natural Science seems to contain original research papers. A member of its editorial advisory board, James Chou from Harvard Medical School in Boston, Massachusetts, says that he was not aware that any Scientific Research journals had reproduced any published articles, but says that the journals should "definitely retract the duplicate papers". Zhou says that he stands by the organization. Copying articles "is not allowed", he says, and holds that he has "zero tolerance" for such practices. * References * Drescher, H. J. , Hladik, M. , Ostapchenko, S. , Pierog, T. & Werner, K.New J. Phys.2, 31 (2000). * Kurizki, G. , Kofman, A. G. , Kozhekin, A. & Harel, G.New J. Phys.2, 28 (2000). * Behringer, K. & Fantz, U.New J. Phys.2, 23 (2000). * Kruger, J. & Dunning, D.J. Pers. Soc. Psychol.77, 1121-1134 (1999). * Mariappan, P. , Balasundaram, C. & Schmitz, B.J. Biosci.25, 301-313 (2000). * Rehorek, S. J. , Firth, B. T. & Hutchinson, M. N.J. Biosci.25, 181-190 (2000). * Mitra, D. & Johri, M. M.J. Biosci.25, 331-338 (2000). * Mariconda, S. , Namgoong, S.-Y. , Yoon, K.-H. , Jiang, H. & Harshey, R. M.J. Biosci.25, 347-360 (2000). There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• The fickle Y chromosome
  - Nature 463(7278):149 (2010)
  Chimp genome reveals rapid rate of change. His sex chromosome is an evolutionary hotspot.B. Walton/naturepl.com The male sex chromosome, long dismissed as the underachieving runt of the genome, has now been fully sequenced in a common chimpanzee. And comparison with its human counterpart — the only other Y chromosome to have been sequenced in such detail — reveals a rate of change that puts the rest of the genome to shame. The common chimp (Pan troglodytes) and human Y chromosomes are "horrendously different from each other", says David Page of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, who led the work. "It looks like there's been a dramatic renovation or reinvention of the Y chromosome in the chimpanzee and human lineages." Sex chromosomes evolved some 200 million–300 million years ago, but the chimpanzee and human lineages diverged only 6 million–7 million years ago. Comparisons of the chimp and human genomes suggested that not much has changed between the species since1. But those analyses excluded the Y chromosome, much of the genetic sequence of which is made up of palindromes and elaborate mirrored sets of bases that elude standard whole-genome sequencing techniques. Portions of the chimp Y chromosome were sequenced a few years ago2,3, but the full landscape is only now available, after Page and his team precisely sequenced large segments of the chromosome, then stitched them together. They report their findings in a paper published online in Nature on 13 January4. As the earlier studies had suggested, many of the stark changes between the chimp and human Y chromosomes are due to gene loss in the chimp and gene gain in the human. Page's team found that the chimp Y chromosome has only two-thirds as many distinct genes or gene families as the human Y chromosome and only 47% as many protein-coding elements as humans. The remainder of the chimp and human genomes are thought to differ in gene number by less than 1%. Even more striking than the gene loss is the rearrangement of large portions of the chromosome. More than 30% of the chimp Y chromosome lacks an alignable counterpart on the human Y chromosome, and vice versa, whereas this is true for less than 2% of the remainder of the genome. Even the portions that do line up have undergone erratic relocation. In the only other chromosome to have been sequenced to the same degree of completeness in both species, chromosome 21, the authors found much less rearrangement. "If you're marching along the human chromosome 21, you might as well be marching along the chimp chromosome 21. It's like an unbroken piece of glass," says Page. "But the relationship between the human and chimp Y chromosomes has been blown to pieces." ADVERTISEMENT The rapid evolution of the Y chromosome is not a total surprise, because the Y chromosome has no partner during cell division and so largely avoids the exchange of DNA that occurs between partnered chromosomes and keeps modifications in check. "It's expected that they are going to be more different than the rest of the genome, but the extent of it is pretty amazing," says geneticist Christine Disteche at the University of Washington in Seattle. The Y chromosome is also prone to change because most of its characterized genes are involved in producing sperm, which are at the frontline of reproductive fitness, particularly in chimps; receptive females will often mate with many males in one session, so the male with the most virile sperm has the highest likelihood of success. "The Y is full of surprises," Page says. "When we sequenced the chimp genome people thought we'd understand why we have language and write poetry. But one of the most dramatic differences turns out to be sperm production." * References * The Chimpanzee Sequencing and Analysis Consortium . Nature437, 69-87 (2005). * Hughes, J. F.et al. Nature437, 100-103 (2005). * Kuroki, Y.et al. Nature Genet.38, 158-167 (2006). * Hughes, J. F.et al. Naturedoi:10.1038/nature08700 (2010). There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Swine flu: Crisis communicator
  - Nature 463(7278):150 (2010)
  Richard Besser led the United States' top public-health agency as swine flu broke out on its doorstep. And his communication shaped the early days of a pandemic, finds Brendan Maher. Download a PDF of this story Swine flu officially became a national emergency in the United States on a Friday in late October, when US President Barack Obama signed an order giving health facilities extra power to implement crisis operations. The next morning, the daily news programme Good Morning America turned for analysis to its newest health editor, Richard Besser, whose two-metre frame was folded uncomfortably into a swivel chair in the studio's New York newsroom. "This is an extremely challenging communication issue for the government," Besser was saying, explaining why the White House was calling an emergency, but trying not to sound too alarmist. "How do you convey the fact that this is serious … but it's not a 1918 pandemic?" Few people are as qualified to comment on this challenge as Besser. Nine months earlier he had been appointed acting director of the US Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, widely considered the world's pre-eminent public-health agency but one beleaguered with morale issues and a strained budget. It and the broader international health community had been gearing up for a potentially apocalyptic flu pandemic, one that would require a rapid global health response and candid communication to engender trust, not panic. In April, when reports started rolling in that a new influenza virus was infecting people in Mexico and the United States, that pandemic seemed to be emerging on the CDC's doorstep and on Besser's watch, even though he had been put in charge largely as a stop-gap in case of emergency. Many public-health experts now say that they are glad Besser was there when the emergency struck. He has received little attention for his role, which lasted just a few weeks into the pandemic. Yet experts credit him — and particularly his decision-making and calm and upfront communication — with helping the agency through the first perilous days of the outbreak and setting the tone for a rapid and transparent response from the international public-health community. "I was pretty impressed with his style and the way he communicated uncertainty," says Jon Andrus, deputy director for the Pan American Health Organization, a regional office of the World Health Organization. He left you with a sense "that this guy's honest", Andrus says. The CDC has not been faultless: it stumbled on delivering guidance for school closures, and since Besser's departure in June, it has been criticized for over-promising and under-delivering on a vaccine. But Besser did so well with the media t! hat the media invited him to join its ranks. He started at ABC News, which produces the Good Morning America programme, in September, and says he hopes to use his roles as expert and reporter to promote public-health issues. It is hard to measure the effect that the early response and communication in the pandemic had on people's health. Besser can't take responsibility for the mildness of the pandemic thus far, which is due to the nature of the H1N1 virus. But experts, who are already looking to the next wave of this pandemic and any signs of the next pandemic, say that the episode has tested their preparedness plans and identified the spots to patch up. And at least some evidence suggests that communication is a vital part of those plans. Besser points to a poll commissioned by the CDC in late April showing that most of the US public had a fairly clear understanding of what swine flu was and how to avoid catching it. "That struck me," he says. "that communication can be a very powerful tool." "I like working on a setting of crisis." Richard Besser The CDC first acknowledged the existence of swine flu in its Morbidity and Mortality Weekly Report on Tuesday 21 April. The dispatch described how, earlier that month, the CDC had received samples from two children in California who had come down with illness from a flu subtype the local doctors could not identify. CDC researchers determined that it was a virus of swine origin. Its substantial difference from seasonal H1N1 and the fact that neither child had had recent contact with pigs led the authors to suggest that this might be a new virus with the ability to spread from person to person (M. Ginsberg et al. MMWR Morb. Mortal. Wkly Rep. 58, 1–3; 2009). By the next day, the CDC had learned of similar cases in California and Texas — and, more alarmingly, farther afield. "For about two weeks at that time we'd been hearing about unexplained respiratory outbreaks in Mexico," says Lyn Finelli who, as the CDC's chief of influenza surveillance, presented some of the results at the agency's weekly pandemic briefing, which Besser attended. The virus in Mexico seemed to be killing a large number of people who had been hospitalized, and it was clear that the CDC had to find out quickly whether the two countries' cases were related. The agency already had a plan for dealing with a potential pandemic, and Besser decided immediately to activate its Emergency Operations Center at its lowest level — level three — to help facilitate communication between the two countries. Powers of persuasion On Thursday, he asked Anne Schuchat, director of the National Center for Immunization and Respiratory Diseases at the CDC, and Nancy Cox, the head of the influenza division, to deliver a press briefing on what were now seven confirmed cases in the United States, but no deaths. "So far this is not looking like very, very severe influenza," Schuchat said at the briefing. But by now, most signs were pointing to a connection between the cases in the United States and Mexico. Besser pushed the Emergency Operations Center up to level one, its highest. He also e-mailed Dora Hughes, his contact at the Department of Health and Human Services, which oversees the CDC. He needed to get the message, through her, to the top layers of government. "We have a situation that I'm very concerned about," he wrote. Richard Besser briefed the White House on the emerging swine-flu pandemic in April 2009, with Secretary of Homeland Security Janet Napolitano (left) and press secretary Robert Gibbs.M. THEILER/REUTERS It took some convincing, Besser says, but that evening he was on a call with Hughes and Laura Petrou, the department's chief of staff. From the CDC, Schuchat and Phil Navin, director of the emergency-operations division, were on the line. As a thunderstorm raged in Atlanta, they broke down the information available. Besser says he knew he had to be clear that this was scary. When Petrou asked him to tell her how concerned he was, Besser remembers saying, "eight". "She asked, 'Eight?' I said, 'Yeah. Eight.'" After the call was over, Navin commented: "I would have said six!" Navin now concedes that Besser was probably right. Even as they were on the call, Cox was leaving a message on Schuchat's phone. The lab results were in, confirming that the cases in Mexico were caused by the same swine flu virus as the US ones. The next morning, Friday 24 April, the World Health Organization activated its emergency response room and Besser prepared to deliver a briefing from the CDC. Besser has had experience in briefing people in emergencies. After receiving his medical degree from the University of Pennsylvania in 1986, he trained as a paediatrician, and honed his skill at reassuring fraught parents. An interest in public health brought him into the CDC's Epidemic Intelligence Service in 1991 and, except for a brief period doing paediatrics at the University of California, San Diego, he has been at the CDC in various roles ever since. In 2005, he took over as head of the Coordinating Office for Terrorism Preparedness & Emergency Response. It was a time bookended by excitement. He arrived in the office the day after Hurricane Katrina started pounding the southeast coast of the United States. "He had a truly unique leadership style," says Navin, who worked closely with him during the response operation. "People had confidence in him and he had confidence in them." And in January 2009, Besser was in the midst of a ground war in Gaza doing crisis leadership training when the Obama transition team called asking if he would consider running the CDC. He was told that he would not be considered for the permanent job; the administration wanted someone from outside the agency. Even so, Besser agreed. "I love a leadership challenge," he says. Part of the test was to boost morale in the agency after the unpopular restructuring instituted by Besser's predecessor, Julie Gerberding. "It was hard to describe — almost a! sea change — when Rich became acting director," says David Sencer, who headed the CDC from 1966 to 1977. "People were much more open and willing to question decisions, which had not been the case before." The circumstances change In his office at ABC News in New York, Besser talks about the principles he looked to when talking about the H1N1 pandemic. He refers to a CDC pamphlet on crisis and emergency risk communication with the subtitle: 'Be First, Be Right, Be Credible'. Credibility was provided in large measure by Besser's relaxed and telegenic persona. But, he says, "there's an inherent challenge between being first and being right". The agency was working with incomplete information: in particular, data on the severity of the virus were changing rapidly. When the virus spread, would it kill tens — or millions? In his first press briefing that Friday morning in April, Besser tackled the problem head on, admitting that much was unknown. "At the early stages of an outbreak, there's much uncertainty, and probably more than everyone would like." He explained that the agency's guidelines would probably change, and said: "It's very likely that this will be more of a marathon than a sprint." "That statement stands out as stunningly good," says Peter Sandman, a risk-communications consultant and formerly a social scientist at Rutgers University in New Jersey. Although authorities are often tempted to over-reassure the public, Sandman says, Besser gave a clear statement of concern and an indication that the agency would be searching for answers. It was a message he repeated at almost all his briefings for the next two weeks. "The goal was to tell everything we knew and everything we didn't know." Richard Besser Some public-health experts contrast the CDC's recent response with that during the last swine-flu outbreak, which started in early 1976 at Fort Dix, a military base in New Jersey. Under Sencer's direction, the CDC launched a vaccination campaign that inoculated more than 40 million Americans, yet the virus never took hold, the vaccine was blamed for hundreds of cases of the neurological condition Guillain–Barre syndrome and the public-health establishment was demoralized. Harvey Fineberg, president of the Institute of Medicine and co-author of a book about the episode, says that it was a lesson in how to deal with uncertainty. "A fundamental strategic lesson was not to pre-decide what you will be able to decide with more information later," he says. "The second big problem was a failure to ask, 'What information could we learn that would lead us to change course?'" The third lesson, he says, was to work with the media, to maintain a consistent, honest message. Besser and the CDC weren't the only ones practising good communication. The day after Besser's briefing, the World Health Organization declared a public-health emergency, and gave the first of what were to become daily briefings on the virus. Most health officials also heap credit on Mexico for reporting its first cases early, despite the economic hit it took from closed businesses and lost tourism. "It was a level of transparency and communication that was exemplary," says Cox. Julio Frenk, dean of the Harvard School of Public Health in Boston, Massachusetts, and former health minister for Mexico, credits decades of investment in pandemic surveillance and communication internationally. "You don't start building communication lines and trust once the outbreak occurs," he says. By 27 April more than 60 flu cases had been confirmed in the United States and Mexico. By that point Besser had been to Washington DC to brief the White House and appeared on numerous television news programmes. "I was doing all the morning shows, a press conference at noon and then a fair number of the evening shows." The goal, he says, was to "tell everything we knew, everything we didn't know and what we were doing to get the answers", Besser says. One step at a time Not every step was sure-footed. On 28 April Besser approved CDC recommendations that schools — hubs of flu transmission — should close if one student or staff member came down with confirmed flu, and stay closed for 14 days. "Well, that's science. You can shed virus for a week. If you really want to be certain, two weeks," he says. Although the costs and benefits of school closures had been actively debated, Besser wanted to take an aggressive approach. But he didn't fully appreciate the political ramifications. People at the education department, for example, weren't happy that they hadn't been consulted. On 1 May the issue was discussed when Besser was called into White House Chief of Staff Rahm Emanuel's office with others including Kathleen Sebelius, just confirmed as the head of the Department of Health and Human Services. Emanuel wanted to redraft the guidelines; Besser was uncomfortable with changing what should be science-based recommendations. In the end, Besser was handed guidelines with a modest revision — closure for one week followed by reassessment — and asked if the science supported them. From what they knew, it did. "It was extremely gratifying to see that they wanted to ensure that science was supporting the policy," Besser says. Over the next week, as it became apparent the flu was milder than expected, the recommendations were revised, and local health officials struggled to keep up with what they sh! ould do. (Epidemiologists have yet to determine whether the guidelines affected the virus's spread.) Observers also cite communication missteps around the vaccine. Health officials promised some 160 million doses in the summer, but only a fraction of those had materialized by October. The reason was that the H1N1 virus grew slowly in the chicken eggs required to produce the vaccine — exactly the type of uncertainties that Besser and others had warned about. Nevertheless, Mark Nichter, a medical anthropologist at the University of Arizona in Tucson who looks at responses to pandemics, says that the problem dented public trust in the agency and made further advice hard to swallow. "What are these elderly people thinking, or mothers with kids in daycare, with the CDC telling us how important vaccines are, then saying that they're not available?" As fears about the virus abated, the frantic sprint of the first few days stretched out into the marathon that Besser had predicted. Case counts climbed; contracts for vaccine production were signed; and attention turned to the Southern Hemisphere's winter flu season. Everything seemed to be going as well as could be expected, at least according to pandemic plans. Many people were shocked when it was announced on 15 May that Tom Frieden, then New York City health commissioner, would replace Besser the following month. "It was something like a punch in the stomach," says Navin, who had worked with Besser for more than four years. Besser, who had known it was coming, started casting about for other jobs. The long shots, he says, were the two television networks who had contacted him during the outbreak, impressed by his performance on screen. He started at ABC just as the number of autumn swine-flu cases was increasing in the Northern Hemisphere. Besser's audience is now smaller: Good Morning America reaches five million — during CDC press conferences he was playing on every news broadcast in the country. But the atmosphere suits him. "I like working on a setting of crisis," he says. "The news business is a constant crisis." ADVERTISEMENT As for flu, Besser still projects uncertainty. At that Saturday morning broadcast in October, he warned that the worst may be yet to come. "With a pandemic they come in waves," he said, adding that "there likely will be further waves, maybe this spring, maybe into next year". But by that point in his two-minute-long slot, Besser had already delivered his message. Get the vaccine when it arrives, he said. "Do those things to protect your health that you can. But this is not a flu like 1918. This is — the flu." There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Neuroscience: The most vulnerable brains
  - Nature 463(7278):154 (2010)
  Julia lies with her eyes closed in an incubator, twitching her tiny limbs in a quiet, sedated sleep. Like the other babies in this intensive-care unit, she is surrounded by a phalanx of machinery. There are currently no comments.
• Journal Editorials give indication of driving science issues
  - Nature 463(7278):157 (2010)
  By comparing the topics of Editorials published in Nature and Science, we unearthed some fascinating features of the changing policy landscape over the past decade.To analyse the text of the more than 1,500 Editorials published in Nature and Science between January 2000 and July 2009, we used 'VOSviewer' — a mapping technique that categorizes non-specialist documents according to the co-occurrence of words (N. J. van Eck and L. Waltman Scientometrics doi:10.1007/s11192-009-0146-3; 2009
• Let interdisciplinary research begin in undergraduate years
  - Nature 463(7278):157 (2010)
  The UK Higher Education Academy's 2009 report 'Developing undergraduate research and inquiry' (see http://go.nature.com/WtYWpk
• Spanish cuts could do lasting damage to biomedical research
  - Nature 463(7278):157 (2010)
  You were right to criticize the situation faced by basic research in your Editorial on Spain's investment in science (Nature 462, 137–138; 2009).
• To make progress we must remember and learn from the past
  - Nature 463(7278):157 (2010)
  Indira Samarasekera calls for more effective collaboration among universities, governments and the private sector in her Opinion article (Nature 462, 160–161; 2009). Her arguments are not new — they have been central to research policy and sociology of science debates for more than 60 years (see, for example, V.
• Canada needs a polar policy
  - Nature 463(7278):159 (2010)
  A lack of coordination in Arctic research funding leaves scientists without the support they need for fieldwork. John England outlines how Canada can set things right, and show leadership in the north.
• No crystal ball for natural disasters
  - Nature 463(7278):160 (2010)
  Floods and fires aside, the tricky science of prediction is explained in a book that treads a careful line between analysis and anecdotes of awful events, says Andrew Robinson.
• The art of animal colouring
  - Nature 463(7278):161 (2010)
  In Dazzled and Deceived, science writer Peter Forbes examines the role of animal coloration in aiding our understanding of evolution. In particular he looks at protective colouring, which links many aspects of evolution, from genes to selection.
• Distorting the climate message
  - Nature 463(7278):161 (2010)
  Now that the Copenhagen climate negotiations have passed, it may seem as if those who deny the existence of climate change have faded into the background. Yet, in Climate Cover-Up, James Hoggan and Richard Littlemore argue that we should never stop paying attention to the pervasive influence of climate-change scepticism.
• Georgia's fossils on view
  - Nature 463(7278):162 (2010)
  Visitors are now welcome at the Dmanisi archaeological site in Georgia — famed as the location of the oldest hominin fossils to be found outside Africa. The first phase of an on-site museum, a modern wooden-and-steel shelter, opened in September 2009 to protect the central dig and allow the public to explore the site.
• Climate: A moist model monsoon
  - Nature 463(7278):163 (2010)
  Received wisdom about the main driver of the South Asian monsoon comes into question with a report that tests the idea that the Himalayas, not the Tibetan plateau, are the essential topographic ingredient.
• Biochemistry: Tackling unintelligent design
  - Nature 463(7278):164 (2010)
  The key enzyme in photosynthesis, Rubisco, is a relic of a bygone age. The ability to assemble Rubisco in the test tube offers the prospect of genetically manipulating the enzyme to make it fit for the modern world.
• Behavioural ecology: Learn to beat an identity cheat
  - Nature 463(7278):165 (2010)
  Parent birds commonly face the problem of distinguishing their own brood from foreign chicks. Learnt chick-recognition evolves only when parents do not mistakenly learn to reject their own young.
• 50 & 100 years ago
  - Nature 463(7278):166 (2010)
  Under New Zealand conditions of sheep-farming, incisors of grazing sheep wear much more rapidly on improved pasture, chiefly ryegrass (Lolium perenne) and white clover (Trifolium repens), than on the finer native pastures of low carrying capacity. The cause is not nutritional in the generally accepted sense, however.
• Galaxy formation: Gone with the wind?
  - Nature 463(7278):167 (2010)
  Windy weather is forecast where stars are forming. Numerical simulations show that these winds can reshape dwarf galaxies, reconciling their properties with the prevailing theory of galaxy formation.
• Bioinorganic chemistry: Model offers intermediate insight
  - Nature 463(7278):168 (2010)
  Chemical models of enzymes' active sites aid our understanding of biological reactions. Such a model of a reaction intermediate promises to advance our knowledge of the biochemistry of iron-containing haem enzymes.
• Neuroscience: Astrocytes as aide-mémoires
  - Nature 463(7278):169 (2010)
  Memory formation is known to occur at the level of synaptic contacts between neurons. It therefore comes as a surprise that another type of brain cell, the astrocyte, is also involved in establishing memory.
• Main-group elements as transition metals
  - Nature 463(7278):171 (2010)
  The last quarter of the twentieth century and the beginning decade of the twenty-first witnessed spectacular discoveries in the chemistry of the heavier main-group elements. The new compounds that were synthesized highlighted the fundamental differences between their electronic properties and those of the lighter elements to a degree that was not previously apparent. This has led to new structural and bonding insights as well as a gradually increasing realization that the chemistry of the heavier main-group elements more resembles that of transition-metal complexes than that of their lighter main-group congeners. The similarity is underlined by recent work, which has shown that many of the new compounds react with small molecules such as H2, NH3, C2H4 or CO under mild conditions and display potential for applications in catalysis.
• Genome sequence of the palaeopolyploid soybean
  - Nature 463(7278):178 (2010)
  Soybean (Glycine max) is one of the most important crop plants for seed protein and oil content, and for its capacity to fix atmospheric nitrogen through symbioses with soil-borne microorganisms. We sequenced the 1.1-gigabase genome by a whole-genome shotgun approach and integrated it with physical and high-density genetic maps to create a chromosome-scale draft sequence assembly. We predict 46,430 protein-coding genes, 70% more than Arabidopsis and similar to the poplar genome which, like soybean, is an ancient polyploid (palaeopolyploid). About 78% of the predicted genes occur in chromosome ends, which comprise less than one-half of the genome but account for nearly all of the genetic recombination. Genome duplications occurred at approximately 59 and 13 million years ago, resulting in a highly duplicated genome with nearly 75% of the genes present in multiple copies. The two duplication events were followed by gene diversification and loss, and numerous chromosome r! earrangements. An accurate soybean genome sequence will facilitate the identification of the genetic basis of many soybean traits, and accelerate the creation of improved soybean varieties.
• A small-cell lung cancer genome with complex signatures of tobacco exposure
  Pleasance ED Stephens PJ O'Meara S McBride DJ Meynert A Jones D Lin ML Beare D Lau KW Greenman C Varela I Nik-Zainal S Davies HR Ordoñez GR Mudie LJ Latimer C Edkins S Stebbings L Chen L Jia M Leroy C Marshall J Menzies A Butler A Teague JW Mangion J Sun YA McLaughlin SF Peckham HE Tsung EF Costa GL Lee CC Minna JD Gazdar A Birney E Rhodes MD McKernan KJ Stratton MR Futreal PA Campbell PJ - Nature 463(7278):184 (2010)
  Cancer is driven by mutation. Worldwide, tobacco smoking is the principal lifestyle exposure that causes cancer, exerting carcinogenicity through >60 chemicals that bind and mutate DNA. Using massively parallel sequencing technology, we sequenced a small-cell lung cancer cell line, NCI-H209, to explore the mutational burden associated with tobacco smoking. A total of 22,910 somatic substitutions were identified, including 134 in coding exons. Multiple mutation signatures testify to the cocktail of carcinogens in tobacco smoke and their proclivities for particular bases and surrounding sequence context. Effects of transcription-coupled repair and a second, more general, expression-linked repair pathway were evident. We identified a tandem duplication that duplicates exons 3–8 of CHD7 in frame, and another two lines carrying PVT1–CHD7 fusion genes, indicating that CHD7 may be recurrently rearranged in this disease. These findings illustrate the potential for next-gen! eration sequencing to provide unprecedented insights into mutational processes, cellular repair pathways and gene networks associated with cancer.
• A comprehensive catalogue of somatic mutations from a human cancer genome
  Pleasance ED Cheetham RK Stephens PJ McBride DJ Humphray SJ Greenman CD Varela I Lin ML Ordóñez GR Bignell GR Ye K Alipaz J Bauer MJ Beare D Butler A Carter RJ Chen L Cox AJ Edkins S Kokko-Gonzales PI Gormley NA Grocock RJ Haudenschild CD Hims MM James T Jia M Kingsbury Z Leroy C Marshall J Menzies A Mudie LJ Ning Z Royce T Schulz-Trieglaff OB Spiridou A Stebbings LA Szajkowski L Teague J Williamson D Chin L Ross MT Campbell PJ Bentley DR Futreal PA Stratton MR - Nature 463(7278):191 (2010)
  All cancers carry somatic mutations. A subset of these somatic alterations, termed driver mutations, confer selective growth advantage and are implicated in cancer development, whereas the remainder are passengers. Here we have sequenced the genomes of a malignant melanoma and a lymphoblastoid cell line from the same person, providing the first comprehensive catalogue of somatic mutations from an individual cancer. The catalogue provides remarkable insights into the forces that have shaped this cancer genome. The dominant mutational signature reflects DNA damage due to ultraviolet light exposure, a known risk factor for malignant melanoma, whereas the uneven distribution of mutations across the genome, with a lower prevalence in gene footprints, indicates that DNA repair has been preferentially deployed towards transcribed regions. The results illustrate the power of a cancer genome sequence to reveal traces of the DNA damage, repair, mutation and selection processes t! hat were operative years before the cancer became symptomatic.
• Coupled chaperone action in folding and assembly of hexadecameric Rubisco
  - Nature 463(7278):197 (2010)
  Form I Rubisco (ribulose 1,5-bisphosphate carboxylase/oxygenase), a complex of eight large (RbcL) and eight small (RbcS) subunits, catalyses the fixation of atmospheric CO2 in photosynthesis. The limited catalytic efficiency of Rubisco has sparked extensive efforts to re-engineer the enzyme with the goal of enhancing agricultural productivity. To facilitate such efforts we analysed the formation of cyanobacterial form I Rubisco by in vitro reconstitution and cryo-electron microscopy. We show that RbcL subunit folding by the GroEL/GroES chaperonin is tightly coupled with assembly mediated by the chaperone RbcX2. RbcL monomers remain partially unstable and retain high affinity for GroEL until captured by RbcX2. As revealed by the structure of a RbcL8–(RbcX2)8 assembly intermediate, RbcX2 acts as a molecular staple in stabilizing the RbcL subunits as dimers and facilitates RbcL8 core assembly. Finally, addition of RbcS results in RbcX2 release and holoenzyme formation. ! Specific assembly chaperones may be required more generally in the formation of complex oligomeric structures when folding is closely coupled to assembly.
• Bulgeless dwarf galaxies and dark matter cores from supernova-driven outflows
  - Nature 463(7278):203 (2010)
  For almost two decades the properties of 'dwarf' galaxies have challenged the cold dark matter (CDM) model of galaxy formation1. Most observed dwarf galaxies consist of a rotating stellar disk2 embedded in a massive dark-matter halo with a near-constant-density core3. Models based on the dominance of CDM, however, invariably form galaxies with dense spheroidal stellar bulges and steep central dark-matter profiles4, 5, 6, because low-angular-momentum baryons and dark matter sink to the centres of galaxies through accretion and repeated mergers7. Processes that decrease the central density of CDM halos8 have been identified, but have not yet reconciled theory with observations of present-day dwarfs. This failure is potentially catastrophic for the CDM model, possibly requiring a different dark-matter particle candidate9. Here we report hydrodynamical simulations (in a framework10 assuming the presence of CDM and a cosmological constant) in which the inhomogeneous int! erstellar medium is resolved. Strong outflows from supernovae remove low-angular-momentum gas, which inhibits the formation of bulges and decreases the dark-matter density to less than half of what it would otherwise be within the central kiloparsec. The analogues of dwarf galaxies—bulgeless and with shallow central dark-matter profiles—arise naturally in these simulations.
• A large coronal loop in the Algol system
  - Nature 463(7278):207 (2010)
  The close binary Algol system contains a radio-bright KIV subgiant star in a very close (0.062 astronomical units) and rapid (2.86 day) orbit with a main sequence B8 star. Because the rotation periods of the two stars are tidally locked to the orbital period, the rapid rotation drives a magnetic dynamo. A large body of evidence points to the existence of an extended, complex coronal magnetosphere originating at the cooler K subgiant1, 2, 3, 4. The detailed morphology of the subgiant's corona and its possible interaction with its companion are unknown, though theory predicts that the coronal plasma should be confined in a magnetic loop structure5, as seen on the Sun. Here we report multi-epoch radio imaging of the Algol system, in which we see a large, persistent coronal loop approximately one subgiant diameter in height, whose base is straddling the subgiant and whose apex is oriented towards the B8 star. This suggests that a persistent asymmetric magnetic field struct! ure is aligned between the two stars. The loop is larger than anticipated theoretically6, 7, but the size may be the result of a magnetic interaction between the two stars.
• Time-reversal symmetry breaking and spontaneous Hall effect without magnetic dipole order
  Machida Y Nakatsuji S Onoda S Tayama T Sakakibara T - Nature 463(7278):210 (2010)
  Spin liquids are magnetically frustrated systems, in which spins are prevented from ordering or freezing, owing to quantum or thermal fluctuations among degenerate states induced by the frustration. Chiral spin liquids are a hypothetical class of spin liquids in which the time-reversal symmetry is macroscopically broken in the absence of an applied magnetic field or any magnetic dipole long-range order. Even though such chiral spin-liquid states were proposed more than two decades ago1, 2, 3, an experimental realization and observation of such states has remained a challenge. One of the characteristic order parameters in such systems is a macroscopic average of the scalar spin chirality, a solid angle subtended by three nearby spins. In previous experimental reports, however, the spin chirality was only parasitic to the non-coplanar spin structure associated with a magnetic dipole long-range order or induced by the applied magnetic field4, 5, 6, 7, 8, 9, 10, and thus t! he chiral spin-liquid state has never been found. Here, we report empirical evidence that the time-reversal symmetry can be broken spontaneously on a macroscopic scale in the absence of magnetic dipole long-range order. In particular, we employ the anomalous Hall effect4, 11 to directly probe the broken time-reversal symmetry for the metallic frustrated magnet Pr2Ir2O7. An onset of the Hall effect is observed at zero field in the absence of uniform magnetization, within the experimental accuracy, suggesting an emergence of a chiral spin liquid. The origin of this spontaneous Hall effect is ascribed to chiral spin textures4, 5, 12, 13, which are inferred from the magnetic measurements indicating the spin ice-rule formation14, 15.
• Three-dimensional structure determination from a single view
  Raines KS Salha S Sandberg RL Jiang H Rodríguez JA Fahimian BP Kapteyn HC Du J Miao J - Nature 463(7278):214 (2010)
  The ability to determine the structure of matter in three dimensions has profoundly advanced our understanding of nature. Traditionally, the most widely used schemes for three-dimensional (3D) structure determination of an object are implemented by acquiring multiple measurements over various sample orientations, as in the case of crystallography and tomography1, 2, or by scanning a series of thin sections through the sample, as in confocal microscopy3. Here we present a 3D imaging modality, termed ankylography (derived from the Greek words ankylos meaning 'curved' and graphein meaning 'writing'), which under certain circumstances enables complete 3D structure determination from a single exposure using a monochromatic incident beam. We demonstrate that when the diffraction pattern of a finite object is sampled at a sufficiently fine scale on the Ewald sphere, the 3D structure of the object is in principle determined by the 2D spherical pattern. We confirm the t! heoretical analysis by performing 3D numerical reconstructions of a sodium silicate glass structure at 2 Å resolution, and a single poliovirus at 2–3 nm resolution, from 2D spherical diffraction patterns alone. Using diffraction data from a soft X-ray laser, we also provide a preliminary demonstration that ankylography is experimentally feasible by obtaining a 3D image of a test object from a single 2D diffraction pattern. With further development, this approach of obtaining complete 3D structure information from a single view could find broad applications in the physical and life sciences.
• Dominant control of the South Asian monsoon by orographic insulation versus plateau heating
  - Nature 463(7278):218 (2010)
  The Tibetan plateau, like any landmass, emits energy into the atmosphere in the form of dry heat and water vapour, but its mean surface elevation is more than 5 km above sea level. This elevation is widely held to cause the plateau to serve as a heat source that drives the South Asian summer monsoon, potentially coupling uplift of the plateau to climate changes on geologic timescales1, 2, 3, 4, 5. Observations of the present climate, however, do not clearly establish the Tibetan plateau as the dominant thermal forcing in the region: peak upper-tropospheric temperatures during boreal summer are located over continental India, south of the plateau. Here we show that, although Tibetan plateau heating locally enhances rainfall along its southern edge in an atmospheric model, the large-scale South Asian summer monsoon circulation is otherwise unaffected by removal of the plateau, provided that the narrow orography of the Himalayas and adjacent mountain ranges is preserved! . Additional observational and model results suggest that these mountains produce a strong monsoon by insulating warm, moist air over continental India from the cold and dry extratropics. These results call for both a reinterpretation of how South Asian climate may have responded to orographic uplift, and a re-evaluation of how this climate may respond to modified land surface and radiative forcings in coming decades.
• Coots use hatch order to learn to recognize and reject conspecific brood parasitic chicks
  Shizuka D Lyon BE - Nature 463(7278):223 (2010)
  Avian brood parasites and their hosts provide model systems for investigating links between recognition, learning, and their fitness consequences1, 2, 3, 4. One major evolutionary puzzle has continued to capture the attention of naturalists for centuries: why do hosts of brood parasites generally fail to recognize parasitic offspring after they have hatched from the egg5, 6, 7, 8, 9, even when the host and parasitic chicks differ to almost comic degrees7? One prominent theory to explain this pattern proposes that the costs of mistakenly learning to recognize the wrong offspring make recognition maladaptive10. Here we show that American coots, Fulica americana, can recognize and reject parasitic chicks in their brood by using learned cues, despite the fact that the hosts and the brood parasites are of the same species. A series of chick cross-fostering experiments confirm that coots use first-hatched chicks in a brood as referents to learn to recognize their own chicks ! and then discriminate against later-hatched parasitic chicks in the same brood. When experimentally provided with the wrong reference chicks, coots can be induced to discriminate against their own offspring, confirming that the learning errors proposed by theory can exist10. However, learning based on hatching order is reliable in naturally parasitized coot nests because host eggs hatch predictably ahead of parasite eggs. Conversely, a lack of reliable information may help to explain why the evolution of chick recognition is not more common in hosts of most interspecific brood parasites.
• Identification of an aggression-promoting pheromone and its receptor neurons in Drosophila
  Wang L Anderson DJ - Nature 463(7278):227 (2010)
  Aggression is regulated by pheromones in many animal species1, 2, 3. However, in no system have aggression pheromones, their cognate receptors and corresponding sensory neurons been identified. Here we show that 11-cis-vaccenyl acetate (cVA), a male-specific volatile pheromone, robustly promotes male–male aggression in the vinegar fly Drosophila melanogaster. The aggression-promoting effect of synthetic cVA requires olfactory sensory neurons (OSNs) expressing the receptor Or67d4, 5, 6, as well as the receptor itself. Activation of Or67d-expressing OSNs, either by genetic manipulation of their excitability or by exposure to male pheromones in the absence of other classes of OSNs, is sufficient to promote aggression. High densities of male flies can promote aggression by the release of volatile cVA. In turn, cVA-promoted aggression can promote male fly dispersal from a food resource, in a manner dependent on Or67d-expressing OSNs. These data indicate that cVA may media! te negative-feedback control of male population density, through its effect on aggression. Identification of a pheromone–OSN pair controlling aggression in a genetic organism opens the way to unravelling the neurobiology of this evolutionarily conserved behaviour.
• Long-term potentiation depends on release of d-serine from astrocytes
  - Nature 463(7278):232 (2010)
  Long-term potentiation (LTP) of synaptic transmission provides an experimental model for studying mechanisms of memory1. The classical form of LTP relies on N-methyl-d-aspartate receptors (NMDARs), and it has been shown that astroglia can regulate their activation through Ca2+-dependent release of the NMDAR co-agonist d-serine2, 3, 4. Release of d-serine from glia enables LTP in cultures5 and explains a correlation between glial coverage of synapses and LTP in the supraoptic nucleus4. However, increases in Ca2+ concentration in astroglia can also release other signalling molecules, most prominently glutamate6, 7, 8, ATP9 and tumour necrosis factor-α10, 11, whereas neurons themselves can synthesize and supply d-serine12, 13. Furthermore, loading an astrocyte with exogenous Ca2+ buffers does not suppress LTP in hippocampal area CA1 (refs 14–16), and the physiological relevance of experiments in cultures or strong exogenous stimuli applied to astrocytes has been questi! oned17, 18. The involvement of glia in LTP induction therefore remains controversial. Here we show that clamping internal Ca2+ in individual CA1 astrocytes blocks LTP induction at nearby excitatory synapses by decreasing the occupancy of the NMDAR co-agonist sites. This LTP blockade can be reversed by exogenous d-serine or glycine, whereas depletion of d-serine or disruption of exocytosis in an individual astrocyte blocks local LTP. We therefore demonstrate that Ca2+-dependent release of d-serine from an astrocyte controls NMDAR-dependent plasticity in many thousands of excitatory synapses nearby.
• KAP1 controls endogenous retroviruses in embryonic stem cells
  - Nature 463(7278):237 (2010)
  More than forty per cent of the mammalian genome is derived from retroelements, of which about one-quarter are endogenous retroviruses (ERVs)1. Some are still active, notably in mice the highly polymorphic early transposon (ETn)/MusD and intracisternal A-type particles (IAP)2, 3. ERVs are transcriptionally silenced during early embryogenesis by histone and DNA methylation4, 5, 6 (and reviewed in ref. 7), although the initiators of this process, which is essential to protect genome integrity8, remain largely unknown. KAP1 (KRAB-associated protein 1, also known as tripartite motif-containing protein 28, TRIM28) represses genes by recruiting the histone methyltransferase SETDB1, heterochromatin protein 1 (HP1) and the NuRD histone deacetylase complex9, but few of its physiological targets are known. Two lines of evidence suggest that KAP1-mediated repression could contribute to the control of ERVs: first, KAP1 can trigger permanent gene silencing during early embryogenesi! s10, and second, a KAP1 complex silences the retrovirus murine leukaemia virus in embryonic cells11, 12, 13. Consistent with this hypothesis, here we show that KAP1 deletion leads to a marked upregulation of a range of ERVs, in particular IAP elements, in mouse embryonic stem (ES) cells and in early embryos. We further demonstrate that KAP1 acts synergistically with DNA methylation to silence IAP elements, and that it is enriched at the 5′ untranslated region (5′UTR) of IAP genomes, where KAP1 deletion leads to the loss of histone 3 lysine 9 trimethylation (H3K9me3), a hallmark of KAP1-mediated repression. Correspondingly, IAP 5′UTR sequences can impose in cis KAP1-dependent repression on a heterologous promoter in ES cells. Our results establish that KAP1 controls endogenous retroelements during early embryonic development.
• Stomagen positively regulates stomatal density in Arabidopsis
  Sugano SS Shimada T Imai Y Okawa K Tamai A Mori M Hara-Nishimura I - Nature 463(7278):241 (2010)
  Stomata in the epidermal tissues of leaves are valves through which passes CO2, and as such they influence the global carbon cycle1. The two-dimensional pattern and density of stomata in the leaf epidermis are genetically and environmentally regulated to optimize gas exchange2. Two putative intercellular signalling factors, EPF1 and EPF2, function as negative regulators of stomatal development in Arabidopsis, possibly by interacting with the receptor-like protein TMM3, 4, 5, 6. One or more positive intercellular signalling factors are assumed to be involved in stomatal development, but their identities are unknown7. Here we show that a novel secretory peptide, which we designate as stomagen, is a positive intercellular signalling factor that is conserved among vascular plants. Stomagen is a 45-amino--rich peptide that is generated from a 102-amino-acid precursor protein designated as STOMAGEN. Both an in planta analysis and a semi-in-vitro analysis with recombinant and! chemically synthesized stomagen peptides showed that stomagen has stomata-inducing activity in a dose-dependent manner. A genetic analysis showed that TMM is epistatic to STOMAGEN (At4g12970), suggesting that stomatal development is finely regulated by competitive binding of positive and negative regulators to the same receptor. Notably, STOMAGEN is expressed in inner tissues (the mesophyll) of immature leaves but not in the epidermal tissues where stomata develop. This study provides evidence of a mesophyll-derived positive regulator of stomatal density. Our findings provide a conceptual advancement in understanding stomatal development: inner photosynthetic tissues optimize their function by regulating stomatal density in the epidermis for efficient uptake of CO2.
• An allosteric mechanism of Rho-dependent transcription termination
  - Nature 463(7278):245 (2010)
  Rho is the essential RNA helicase that sets the borders between transcription units and adjusts transcriptional yield to translational needs in bacteria1, 2, 3. Although Rho was the first termination factor to be discovered4, the actual mechanism by which it reaches and disrupts the elongation complex (EC) is unknown. Here we show that the termination-committed Rho molecule associates with RNA polymerase (RNAP) throughout the transcription cycle; that is, it does not require the nascent transcript for initial binding. Moreover, the formation of the RNAP–Rho complex is crucial for termination. We show further that Rho-dependent termination is a two-step process that involves rapid EC inactivation (trap) and a relatively slow dissociation. Inactivation is the critical rate-limiting step that establishes the position of the termination site. The trap mechanism depends on the allosterically induced rearrangement of the RNAP catalytic centre by means of the evolutionarily! conserved mobile trigger-loop domain, which is also required for EC dissociation. The key structural and functional similarities, which we found between Rho-dependent and intrinsic (Rho-independent) termination pathways, argue that the allosteric mechanism of termination is general and likely to be preserved for all cellular RNAPs throughout evolution.
• Structural basis for the photoconversion of a phytochrome to the activated Pfr form
  - Nature 463(7278):250 (2010)
  Phytochromes are a collection of bilin-containing photoreceptors that regulate numerous photoresponses in plants and microorganisms through their ability to photointerconvert between a red-light-absorbing, ground state (Pr) and a far-red-light-absorbing, photoactivated state (Pfr)1, 2. Although the structures of several phytochromes as Pr have been determined3, 4, 5, 6, 7, little is known about the structure of Pfr and how it initiates signalling. Here we describe the three-dimensional solution structure of the bilin-binding domain as Pfr, using the cyanobacterial phytochrome from Synechococcus OSB′. Contrary to predictions, light-induced rotation of the A pyrrole ring but not the D ring is the primary motion of the chromophore during photoconversion. Subsequent rearrangements within the protein then affect intradomain and interdomain contact sites within the phytochrome dimer. On the basis of our models, we propose that phytochromes act by propagating reversible l! ight-driven conformational changes in the bilin to altered contacts between the adjacent output domains, which in most phytochromes direct differential phosphotransfer.
• Tough crowd
  - Nature 463(7278):262 (2010)
  It's no joke.