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Animal models: Dogged pursuit

Nature - Wed, 11/26/2014 - 01:00

Animal models: Dogged pursuit

Nature. doi:10.1038/515S172a

Author: Emily Sohn

In the study of haemophilia, man really does have a best friend.

Categories: Literature

Correction

Nature - Wed, 11/26/2014 - 01:00

Correction

Nature 515, 7528 (2014). http://www.nature.com/doifinder/10.1038/515492g

The Outlook article 'The search for the rice of the future' (Nature514, S60–S61;10.1038/514S60a2014) wrongly stated that a flood-resistant gene was bred into rice by Pamela Ronald. In fact, the breeding was done by David Mackill, Abdelbagi

Categories: Literature

Climate science: El Niño's variable history

Nature - Wed, 11/26/2014 - 01:00

Climate science: El Niño's variable history

Nature 515, 7528 (2014). doi:10.1038/515494a

Authors: Josephine R. Brown

A study of the El Niño phenomenon over the past 21,000 years suggests that El Niño responded in complex ways to a changing climate, with several competing factors playing a part in its varying strength. See Letter p.550

Categories: Literature

Cancer: Antitumour immunity gets a boost

Nature - Wed, 11/26/2014 - 01:00

Cancer: Antitumour immunity gets a boost

Nature 515, 7528 (2014). doi:10.1038/515496a

Authors: Jedd D. Wolchok & Timothy A. Chan

Five papers extend the list of cancers that respond to therapies that restore antitumour immunity by blocking the PD-1 pathway, and characterize those patients who respond best. See Letters p.558, p.563, p.568, p.572 & p.577

Categories: Literature

Astronomy: Cosmic triangles and black-hole masses

Nature - Wed, 11/26/2014 - 01:00

Astronomy: Cosmic triangles and black-hole masses

Nature 515, 7528 (2014). doi:10.1038/515498a

Authors: Martin Elvis

A geometric measurement of the distance to a nearby galaxy implies a larger mass for its central black hole than previously calculated, and a consequent increase for most other masses of such black holes. See Letter p.528

Categories: Literature

Immunology: Tolerance lies in the timing

Nature - Wed, 11/26/2014 - 01:00

Immunology: Tolerance lies in the timing

Nature 515, 7528 (2014). doi:10.1038/515502a

Authors: Nicholas R. J. Gascoigne

During immune-cell development, potentially self-reactive T cells are eliminated. It emerges that recruitment of a co-receptor bound to the T-cell receptor by the enzyme Lck is the rate-limiting step in this negative selection.

Categories: Literature

Belowground biodiversity and ecosystem functioning

Nature - Wed, 11/26/2014 - 01:00

Belowground biodiversity and ecosystem functioning

Nature 515, 7528 (2014). doi:10.1038/nature13855

Authors: Richard D. Bardgett & Wim H. van der Putten

Evidence is mounting that the immense diversity of microorganisms and animals that live belowground contributes significantly to shaping aboveground biodiversity and the functioning of terrestrial ecosystems. Our understanding of how this belowground biodiversity is distributed, and how it regulates the structure and functioning of terrestrial ecosystems, is rapidly growing. Evidence also points to soil biodiversity as having a key role in determining the ecological and evolutionary responses of terrestrial ecosystems to current and future environmental change. Here we review recent progress and propose avenues for further research in this field.

Categories: Literature

A dust-parallax distance of 19 megaparsecs to the supermassive black hole in NGC 4151

Nature - Wed, 11/26/2014 - 01:00

A dust-parallax distance of 19 megaparsecs to the supermassive black hole in NGC 4151

Nature 515, 7528 (2014). doi:10.1038/nature13914

Authors: Sebastian F. Hönig, Darach Watson, Makoto Kishimoto & Jens Hjorth

The active galaxy NGC 4151 has a crucial role as one of only two active galactic nuclei for which black hole mass measurements based on emission line reverberation mapping can be calibrated against other dynamical techniques. Unfortunately, effective calibration requires accurate knowledge of the distance to NGC 4151, which is not at present available. Recently reported distances range from 4 to 29 megaparsecs. Strong peculiar motions make a redshift-based distance very uncertain, and the geometry of the galaxy and its nucleus prohibit accurate measurements using other techniques. Here we report a dust-parallax distance to NGC 4151 of megaparsecs. The measurement is based on an adaptation of a geometric method that uses the emission line regions of active galaxies. Because these regions are too small to be imaged with present technology, we use instead the ratio of the physical and angular sizes of the more extended hot-dust emission as determined from time delays and infrared interferometry. This distance leads to an approximately 1.4-fold increase in the dynamical black hole mass, implying a corresponding correction to emission line reverberation masses of black holes if they are calibrated against the two objects with additional dynamical masses.

Categories: Literature

An impenetrable barrier to ultrarelativistic electrons in the Van Allen radiation belts

Nature - Wed, 11/26/2014 - 01:00

An impenetrable barrier to ultrarelativistic electrons in the Van Allen radiation belts

Nature 515, 7528 (2014). doi:10.1038/nature13956

Authors: D. N. Baker, A. N. Jaynes, V. C. Hoxie, R. M. Thorne, J. C. Foster, X. Li, J. F. Fennell, J. R. Wygant, S. G. Kanekal, P. J. Erickson, W. Kurth, W. Li, Q. Ma, Q. Schiller, L. Blum, D. M. Malaspina, A. Gerrard & L. J. Lanzerotti

Early observations indicated that the Earth’s Van Allen radiation belts could be separated into an inner zone dominated by high-energy protons and an outer zone dominated by high-energy electrons. Subsequent studies showed that electrons of moderate energy (less than about one megaelectronvolt) often populate both zones, with a deep ‘slot’ region largely devoid of particles between them. There is a region of dense cold plasma around the Earth known as the plasmasphere, the outer boundary of which is called the plasmapause. The two-belt radiation structure was explained as arising from strong electron interactions with plasmaspheric hiss just inside the plasmapause boundary, with the inner edge of the outer radiation zone corresponding to the minimum plasmapause location. Recent observations have revealed unexpected radiation belt morphology, especially at ultrarelativistic kinetic energies (more than five megaelectronvolts). Here we analyse an extended data set that reveals an exceedingly sharp inner boundary for the ultrarelativistic electrons. Additional, concurrently measured data reveal that this barrier to inward electron radial transport does not arise because of a physical boundary within the Earth’s intrinsic magnetic field, and that inward radial diffusion is unlikely to be inhibited by scattering by electromagnetic transmitter wave fields. Rather, we suggest that exceptionally slow natural inward radial diffusion combined with weak, but persistent, wave–particle pitch angle scattering deep inside the Earth’s plasmasphere can combine to create an almost impenetrable barrier through which the most energetic Van Allen belt electrons cannot migrate.

Categories: Literature

Passive radiative cooling below ambient air temperature under direct sunlight

Nature - Wed, 11/26/2014 - 01:00

Passive radiative cooling below ambient air temperature under direct sunlight

Nature 515, 7528 (2014). doi:10.1038/nature13883

Authors: Aaswath P. Raman, Marc Abou Anoma, Linxiao Zhu, Eden Rephaeli & Shanhui Fan

Cooling is a significant end-use of energy globally and a major driver of peak electricity demand. Air conditioning, for example, accounts for nearly fifteen per cent of the primary energy used by buildings in the United States. A passive cooling strategy that cools without any electricity input could therefore have a significant impact on global energy consumption. To achieve cooling one needs to be able to reach and maintain a temperature below that of the ambient air. At night, passive cooling below ambient air temperature has been demonstrated using a technique known as radiative cooling, in which a device exposed to the sky is used to radiate heat to outer space through a transparency window in the atmosphere between 8 and 13 micrometres. Peak cooling demand, however, occurs during the daytime. Daytime radiative cooling to a temperature below ambient of a surface under direct sunlight has not been achieved because sky access during the day results in heating of the radiative cooler by the Sun. Here, we experimentally demonstrate radiative cooling to nearly 5 degrees Celsius below the ambient air temperature under direct sunlight. Using a thermal photonic approach, we introduce an integrated photonic solar reflector and thermal emitter consisting of seven layers of HfO2 and SiO2 that reflects 97 per cent of incident sunlight while emitting strongly and selectively in the atmospheric transparency window. When exposed to direct sunlight exceeding 850 watts per square metre on a rooftop, the photonic radiative cooler cools to 4.9 degrees Celsius below ambient air temperature, and has a cooling power of 40.1 watts per square metre at ambient air temperature. These results demonstrate that a tailored, photonic approach can fundamentally enable new technological possibilities for energy efficiency. Further, the cold darkness of the Universe can be used as a renewable thermodynamic resource, even during the hottest hours of the day.

Categories: Literature

Evolution and forcing mechanisms of El Niño over the past 21,000 years

Nature - Wed, 11/26/2014 - 01:00

Evolution and forcing mechanisms of El Niño over the past 21,000 years

Nature 515, 7528 (2014). doi:10.1038/nature13963

Authors: Zhengyu Liu, Zhengyao Lu, Xinyu Wen, B. L. Otto-Bliesner, A. Timmermann & K. M. Cobb

The El Niño Southern Oscillation (ENSO) is Earth’s dominant source of interannual climate variability, but its response to global warming remains highly uncertain. To improve our understanding of ENSO’s sensitivity to external climate forcing, it is paramount to determine its past behaviour by using palaeoclimate data and model simulations. Palaeoclimate records show that ENSO has varied considerably since the Last Glacial Maximum (21,000 years ago), and some data sets suggest a gradual intensification of ENSO over the past ∼6,000 years. Previous attempts to simulate the transient evolution of ENSO have relied on simplified models or snapshot experiments. Here we analyse a series of transient Coupled General Circulation Model simulations forced by changes in greenhouse gasses, orbital forcing, the meltwater discharge and the ice-sheet history throughout the past 21,000 years. Consistent with most palaeo-ENSO reconstructions, our model simulates an orbitally induced strengthening of ENSO during the Holocene epoch, which is caused by increasing positive ocean–atmosphere feedbacks. During the early deglaciation, ENSO characteristics change drastically in response to meltwater discharges and the resulting changes in the Atlantic Meridional Overturning Circulation and equatorial annual cycle. Increasing deglacial atmospheric CO2 concentrations tend to weaken ENSO, whereas retreating glacial ice sheets intensify ENSO. The complex evolution of forcings and ENSO feedbacks and the uncertainties in the reconstruction further highlight the challenge and opportunity for constraining future ENSO responses.

Categories: Literature

MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer

Nature - Wed, 11/26/2014 - 01:00

MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer

Nature 515, 7528 (2014). doi:10.1038/nature13904

Authors: Thomas Powles, Joseph Paul Eder, Gregg D. Fine, Fadi S. Braiteh, Yohann Loriot, Cristina Cruz, Joaquim Bellmunt, Howard A. Burris, Daniel P. Petrylak, Siew-leng Teng, Xiaodong Shen, Zachary Boyd, Priti S. Hegde, Daniel S. Chen & Nicholas J. Vogelzang

There have been no major advances for the treatment of metastatic urothelial bladder cancer (UBC) in the last 30 years. Chemotherapy is still the standard of care. Patient outcomes, especially for those in whom chemotherapy is not effective or is poorly tolerated, remain poor. One hallmark of UBC is the presence of high rates of somatic mutations. These alterations may enhance the ability of the host immune system to recognize tumour cells as foreign owing to an increased number of antigens. However, these cancers may also elude immune surveillance and eradication through the expression of programmed death-ligand 1 (PD-L1; also called CD274 or B7-H1) in the tumour microenvironment. Therefore, we examined the anti-PD-L1 antibody MPDL3280A, a systemic cancer immunotherapy, for the treatment of metastatic UBC. MPDL3280A is a high-affinity engineered human anti-PD-L1 monoclonal immunoglobulin-G1 antibody that inhibits the interaction of PD-L1 with PD-1 (PDCD1) and B7.1 (CD80). Because PD-L1 is expressed on activated T cells, MPDL3280A was engineered with a modification in the Fc domain that eliminates antibody-dependent cellular cytotoxicity at clinically relevant doses to prevent the depletion of T cells expressing PD-L1. Here we show that MPDL3280A has noteworthy activity in metastatic UBC. Responses were often rapid, with many occurring at the time of the first response assessment (6 weeks) and nearly all were ongoing at the data cutoff. This phase I expansion study, with an adaptive design that allowed for biomarker-positive enriched cohorts, demonstrated that tumours expressing PD-L1-positive tumour-infiltrating immune cells had particularly high response rates. Moreover, owing to the favourable toxicity profile, including a lack of renal toxicity, patients with UBC, who are often older and have a higher incidence of renal impairment, may be better able to tolerate MPDL3280A versus chemotherapy. These results suggest that MPDL3280A may have an important role in treating UBC—the drug received breakthrough designation status by the US Food and Drug Administration (FDA) in June 2014.

Categories: Literature

Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients

Nature - Wed, 11/26/2014 - 01:00

Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients

Nature 515, 7528 (2014). doi:10.1038/nature14011

Authors: Roy S. Herbst, Jean-Charles Soria, Marcin Kowanetz, Gregg D. Fine, Omid Hamid, Michael S. Gordon, Jeffery A. Sosman, David F. McDermott, John D. Powderly, Scott N. Gettinger, Holbrook E. K. Kohrt, Leora Horn, Donald P. Lawrence, Sandra Rost, Maya Leabman, Yuanyuan Xiao, Ahmad Mokatrin, Hartmut Koeppen, Priti S. Hegde, Ira Mellman, Daniel S. Chen & F. Stephen Hodi

The development of human cancer is a multistep process characterized by the accumulation of genetic and epigenetic alterations that drive or reflect tumour progression. These changes distinguish cancer cells from their normal counterparts, allowing tumours to be recognized as foreign by the immune system. However, tumours are rarely rejected spontaneously, reflecting their ability to maintain an immunosuppressive microenvironment. Programmed death-ligand 1 (PD-L1; also called B7-H1 or CD274), which is expressed on many cancer and immune cells, plays an important part in blocking the ‘cancer immunity cycle’ by binding programmed death-1 (PD-1) and B7.1 (CD80), both of which are negative regulators of T-lymphocyte activation. Binding of PD-L1 to its receptors suppresses T-cell migration, proliferation and secretion of cytotoxic mediators, and restricts tumour cell killing. The PD-L1–PD-1 axis protects the host from overactive T-effector cells not only in cancer but also during microbial infections. Blocking PD-L1 should therefore enhance anticancer immunity, but little is known about predictive factors of efficacy. This study was designed to evaluate the safety, activity and biomarkers of PD-L1 inhibition using the engineered humanized antibody MPDL3280A. Here we show that across multiple cancer types, responses (as evaluated by Response Evaluation Criteria in Solid Tumours, version 1.1) were observed in patients with tumours expressing high levels of PD-L1, especially when PD-L1 was expressed by tumour-infiltrating immune cells. Furthermore, responses were associated with T-helper type 1 (TH1) gene expression, CTLA4 expression and the absence of fractalkine (CX3CL1) in baseline tumour specimens. Together, these data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is re-invigorated on antibody treatment.

Categories: Literature

PD-1 blockade induces responses by inhibiting adaptive immune resistance

Nature - Wed, 11/26/2014 - 01:00

PD-1 blockade induces responses by inhibiting adaptive immune resistance

Nature 515, 7528 (2014). doi:10.1038/nature13954

Authors: Paul C. Tumeh, Christina L. Harview, Jennifer H. Yearley, I. Peter Shintaku, Emma J. M. Taylor, Lidia Robert, Bartosz Chmielowski, Marko Spasic, Gina Henry, Voicu Ciobanu, Alisha N. West, Manuel Carmona, Christine Kivork, Elizabeth Seja, Grace Cherry, Antonio J. Gutierrez, Tristan R. Grogan, Christine Mateus, Gorana Tomasic, John A. Glaspy, Ryan O. Emerson, Harlan Robins, Robert H. Pierce, David A. Elashoff, Caroline Robert & Antoni Ribas

Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types. One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8+ T cells (termed adaptive immune resistance). Here we show that pre-existing CD8+ T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analysed samples from 46 patients with metastatic melanoma obtained before and during anti-PD-1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next-generation sequencing for T-cell antigen receptors (TCRs). In serially sampled tumours, patients responding to treatment showed proliferation of intratumoral CD8+ T cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8-, PD-1- and PD-L1-expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression after therapeutic PD-1 blockade requires pre-existing CD8+ T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance.

Categories: Literature

Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing

Nature - Wed, 11/26/2014 - 01:00

Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing

Nature 515, 7528 (2014). doi:10.1038/nature14001

Authors: Mahesh Yadav, Suchit Jhunjhunwala, Qui T. Phung, Patrick Lupardus, Joshua Tanguay, Stephanie Bumbaca, Christian Franci, Tommy K. Cheung, Jens Fritsche, Toni Weinschenk, Zora Modrusan, Ira Mellman, Jennie R. Lill & Lélia Delamarre

Human tumours typically harbour a remarkable number of somatic mutations. If presented on major histocompatibility complex class I molecules (MHCI), peptides containing these mutations could potentially be immunogenic as they should be recognized as ‘non-self’ neo-antigens by the adaptive immune system. Recent work has confirmed that mutant peptides can serve as T-cell epitopes. However, few mutant epitopes have been described because their discovery required the laborious screening of patient tumour-infiltrating lymphocytes for their ability to recognize antigen libraries constructed following tumour exome sequencing. We sought to simplify the discovery of immunogenic mutant peptides by characterizing their general properties. We developed an approach that combines whole-exome and transcriptome sequencing analysis with mass spectrometry to identify neo-epitopes in two widely used murine tumour models. Of the >1,300 amino acid changes identified, ∼13% were predicted to bind MHCI, a small fraction of which were confirmed by mass spectrometry. The peptides were then structurally modelled bound to MHCI. Mutations that were solvent-exposed and therefore accessible to T-cell antigen receptors were predicted to be immunogenic. Vaccination of mice confirmed the approach, with each predicted immunogenic peptide yielding therapeutically active T-cell responses. The predictions also enabled the generation of peptide–MHCI dextramers that could be used to monitor the kinetics and distribution of the anti-tumour T-cell response before and after vaccination. These findings indicate that a suitable prediction algorithm may provide an approach for the pharmacodynamic monitoring of T-cell responses as well as for the development of personalized vaccines in cancer patients.

Categories: Literature

Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens

Nature - Wed, 11/26/2014 - 01:00

Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens

Nature 515, 7528 (2014). doi:10.1038/nature13988

Authors: Matthew M. Gubin, Xiuli Zhang, Heiko Schuster, Etienne Caron, Jeffrey P. Ward, Takuro Noguchi, Yulia Ivanova, Jasreet Hundal, Cora D. Arthur, Willem-Jan Krebber, Gwenn E. Mulder, Mireille Toebes, Matthew D. Vesely, Samuel S. K. Lam, Alan J. Korman, James P. Allison, Gordon J. Freeman, Arlene H. Sharpe, Erika L. Pearce, Ton N. Schumacher, Ruedi Aebersold, Hans-Georg Rammensee, Cornelis J. M. Melief, Elaine R. Mardis, William E. Gillanders, Maxim N. Artyomov & Robert D. Schreiber

The immune system influences the fate of developing cancers by not only functioning as a tumour promoter that facilitates cellular transformation, promotes tumour growth and sculpts tumour cell immunogenicity, but also as an extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion. Yet, clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer-induced immunosuppression. In many individuals, immunosuppression is mediated by cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), two immunomodulatory receptors expressed on T cells. Monoclonal-antibody-based therapies targeting CTLA-4 and/or PD-1 (checkpoint blockade) have yielded significant clinical benefits—including durable responses—to patients with different malignancies. However, little is known about the identity of the tumour antigens that function as the targets of T cells activated by checkpoint blockade immunotherapy and whether these antigens can be used to generate vaccines that are highly tumour-specific. Here we use genomics and bioinformatics approaches to identify tumour-specific mutant proteins as a major class of T-cell rejection antigens following anti-PD-1 and/or anti-CTLA-4 therapy of mice bearing progressively growing sarcomas, and we show that therapeutic synthetic long-peptide vaccines incorporating these mutant epitopes induce tumour rejection comparably to checkpoint blockade immunotherapy. Although mutant tumour-antigen-specific T cells are present in progressively growing tumours, they are reactivated following treatment with anti-PD-1 and/or anti-CTLA-4 and display some overlapping but mostly treatment-specific transcriptional profiles, rendering them capable of mediating tumour rejection. These results reveal that tumour-specific mutant antigens are not only important targets of checkpoint blockade therapy, but they can also be used to develop personalized cancer-specific vaccines and to probe the mechanistic underpinnings of different checkpoint blockade treatments.

Categories: Literature

China’s Lake Ebinur Is Shrinking Dramatically, NASA Image Shows

Yale Environment 360 - Tue, 11/25/2014 - 11:50

As this NASA satellite image shows, Lake Ebinur, located in northwestern China near the border of

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China's Lake Ebinur Kazakhstan, has shrunk by 50 percent since 1955 as a result of development, agriculture, and natural fluctuations in precipitation. The lake’s saline water is light blue, and the dried lake bed appears white due to salts and other minerals that have been left behind as the water evaporates. The lake’s size fluctuates from year to year due to natural variations in snowmelt and rainfall, and human activity also plays a key role, Chinese researchers say. The nearby city of Bole, with a population of 425,000, consumes significant amounts of water, and farmers irrigate their crops — especially cotton — with water that would otherwise flow into the lake, researchers say. Frequent saline dust storms contribute to desertification, damage soils, harm wetlands, and may be hastening the melting of snow and glaciers downwind, researchers say.

Categories: Environmental News

Open access is tiring out peer reviewers

Nature - Tue, 11/25/2014 - 01:00

Open access is tiring out peer reviewers

Nature 515, 7528 (2014). http://www.nature.com/doifinder/10.1038/515467a

Author: Martijn Arns

As numbers of published articles rise, the scholarly review system must adapt to avoid unmanageable burdens and slipping standards, says Martijn Arns.

Categories: Literature

Clinical-trial rules to improve access to results

Nature - Tue, 11/25/2014 - 01:00

Clinical-trial rules to improve access to results

Nature 515, 7528 (2014). http://www.nature.com/doifinder/10.1038/515477a

Author: Sara Reardon

US agencies propose expanded reporting of drug-test data.

Categories: Literature

Key Galapagos research station in trouble

Nature - Tue, 11/25/2014 - 01:00

Key Galapagos research station in trouble

Nature 515, 7528 (2014). http://www.nature.com/doifinder/10.1038/515479a

Author: Aleszu Bajak

Local government’s closure of gift shop could doom Charles Darwin Foundation.

Categories: Literature

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