2017-02-21Scientists in the United States and elsewhere ought to address the needs and employment prospects of taxpayers who have seen little benefit from scientific advances.
2017-02-22The European Union is dragging its feet on gene-editing rules and scientists should push the issue.
2017-02-22A proposal to massively expand the number of bodies called planets raises interesting questions.
2017-02-21Public trust demands greater openness from those whose research is used to set policy, argues Stefan Pfenninger.
2017-02-22The ancestor of all living vertebrates may have had gills, a finding that adds to a long-standing debate about the evolutionary history of gills.In jawless animals such as lampreys, gills form from the embryo's innermost layer of cells, or 'endoderm', whereas in jawed vertebrates,
2017-02-22A computer that mimics the way the brain works, and contains both optical and electronic parts, can recognize simple speech three times faster than earlier devices that used only optical components.Reservoir computers use neural networks made of interconnected units that relay signals in recurrent,
2017-02-22A range of cancers could have new treatment options thanks to the discovery that a metabolite made by many tumours increases their vulnerability to a class of drug.Tumours resort to a number of metabolic tricks to support their continued growth and survival. One metabolite
2017-02-22The immense East Antarctic ice sheet may be more vulnerable to rising temperatures in the Weddell Sea than previously thought.Earlier studies have predicted that most of the ice lost from Antarctica as a result of global warming will be from the West Antarctic Ice
2017-02-22The dwarf planet Ceres hosts organic compounds that are possible ingredients for life.NASA's Dawn spacecraft is orbiting Ceres (pictured), which is also the largest asteroid in the Solar System, and the craft has previously spotted signs of salts, ice and other basic
2017-02-22A 245-million-year-old fossil of a pregnant reptile offers the first evidence for live birth in the animal group that includes modern birds and crocodiles.Live birth has evolved dozens of times in vertebrates, but has never been seen in archosauromorphs, which emerged around 260 million
2017-02-22A tiny camera made of four different lenses 3D-printed on a chip can generate images with high resolution in the centre — similarly to the way the eyes of eagles and humans work.Simon Thiele and his colleagues at the University of Stuttgart, Germany, printed
2017-02-22A mysterious disorder that causes seizures in children in East Africa could be due to an autoimmune reaction.In Tanzania, Uganda and South Sudan, nodding syndrome causes children's heads to drop and results in epileptic seizures, cognitive impairment and sometimes death. Although people with the
2017-02-22Narrow bands of water vapour that typically travel over the ocean and dump huge volumes of rain on land, often causing flooding and landslides, come with another hazard — extreme wind.Duane Waliser of the Jet Propulsion Laboratory in Pasadena, California, and Bin Guan of
2017-02-22The week in science: 17–23 February 2017.
2017-02-22Maximum-security biolab is part of plan to build network of BSL-4 facilities across China.
2017-02-15The US Patent and Trademark Office issues a verdict in legal tussle over rights to genome-editing technology.
2017-02-20Rift through Larsen C ice shelf has grown to 175 kilometres, and collapse of nearby ice shelves could offer a glimpse of its future.
2017-02-20Policy experts want scientists at the table when government decides on environmental protection and membership of international collaborations.
2017-02-16DNA of 500-year-old bacteria is first direct evidence of an epidemic — one of humanity's deadliest — that occurred after Spanish conquest.
2017-02-20A host of detailed cell atlases could revolutionize understanding of cancer and other diseases.
2017-02-22How rediscovered chemical tags on DNA and RNA are shaking up the field.
2017-02-22Jeffrey S. Mogil and Malcolm R. Macleod propose a new kind of paper that combines the flexibility of basic research with the rigour of clinical trials.
2017-02-22Margaret Catley-Carlson plunges into a study of a dwindling resource — groundwater.
2017-02-22Barbara Kiser reviews five of the week's best science picks.
2017-02-22Hans Rosling (1948–2017), physician and epidemiologist, famously upturned assumptions widely held by the public and by the development community — assumptions that, thanks to US President Donald Trump, are back in the spotlight. A recurring theme of Rosling's was that family sizes have been shrinking
2017-02-22On behalf of the Scientific Advisory Council of the influenza data-sharing initiative GISAID (www.gisaid.org), I suggest that the principles of this long-standing and successful programme could be extended to help speed on-the-ground responses to other emergent viral threats.GISAID operates under a unique
2017-02-22Public support for China's nuclear-energy programme plummeted after Japan's Fukushima disaster in 2011. So far, however, there have been no reported protests against a proposed nuclear power plant in Zhangzhou in southeast China. Other nations could learn from the strategy used by the authorities to
2017-02-22The proliferation of scientific journals is making it harder for editors to recruit peer reviewers. Various incentives (see, for example, Nature514, 274;10.1038/514274a2014) have not substantially changed an archaic system. I propose a smart solution that would benefit reviewers, authors
2017-02-22Statistician who campaigned for better science in court.
2017-02-22As it embraces competitive international science, Poland is becoming a force to be reckoned with.
2017-02-22Savings plan offers pension mobility for researchers in Europe.
2017-02-22Men outnumber women in most US science sectors.
2017-02-22Dreams of another world.
2017-02-08A systematic analysis of bipolar cells, which act as a central signalling conduit in the retina, reveals that the neurons' diverse responses to light are generated largely by feedback from neighbouring amacrine cells. See Article p.439
2017-02-22Statistical analysis has revealed a simple rule for the occurrence of warm periods during the Quaternary, whereas on much longer timescales geological data have confirmed that the Solar System is chaotic. See Article p.427& Letter p.468
2017-02-22Optimal protein synthesis requires bases in transfer RNAs to be modified. A key modification has been shown to involve an unusual two-step mechanism that entails the sequential activities of two enzymes. See Letter p.494
2017-02-22Seven small planets whose surfaces could harbour liquid water have been spotted around a nearby dwarf star. If such a configuration is common in planetary systems, our Galaxy could be teeming with Earth-like planets. See Letter p.456
2017-02-2250 Years AgoThe view that “Mankind takes his dental problems with him wherever he goes” was the theme of the paper read by B. Lawrence Shalit to the conference on “Planetology and Space Mission Planning” ... Mr Shalit put forward his plan for dental
2017-02-15Chemists have long aspired to synthesize two-dimensional polymers that are fully conjugated — an attribute that imparts potentially useful properties. Just such a material has been prepared using a solid-state polymerization reaction.
2017-02-15It emerges that blood-cancer-targeting drugs that block a tumour-survival pathway also activate a mutation-causing enzyme in mice and in human cells. This might have implications for the clinical use of these drugs. See Letter p.489
2017-02-22The pacing of glacial–interglacial cycles during the Quaternary period (the past 2.6 million years) is attributed to astronomically driven changes in high-latitude insolation. However, it has not been clear how astronomical forcing translates into the observed sequence of interglacials. Here we show that before one
2017-01-25The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287
2017-02-08The retina extracts visual features for transmission to the brain. Different types of bipolar cell split the photoreceptor input into parallel channels and provide the excitatory drive for downstream visual circuits. Mouse bipolar cell types have been described at great anatomical and genetic detail, but
2017-02-15A highly protective malaria vaccine would greatly facilitate the prevention and elimination of malaria and containment of drug-resistant parasites. A high level (more than 90%) of protection against malaria in humans has previously been achieved only by immunization with radiation-attenuated Plasmodium falciparum (Pf) sporozoites (PfSPZ) inoculated by mosquitoes; by intravenous injection of aseptic, purified, radiation-attenuated, cryopreserved PfSPZ (‘PfSPZ Vaccine’); or by infectious PfSPZ inoculated by mosquitoes to volunteers taking chloroquine or mefloquine (chemoprophylaxis with sporozoites). We assessed immunization by direct venous inoculation of aseptic, purified, cryopreserved, non-irradiated PfSPZ (‘PfSPZ Challenge’) to malaria-naive, healthy adult volunteers taking chloroquine for antimalarial chemoprophylaxis (vaccine approach denoted as PfSPZ-CVac). Three doses of 5.12 × 104 PfSPZ of PfSPZ Challenge at 28-day intervals were well tolerated and safe, and prevented infection in 9 out of 9 (100%) volunteers who underwent controlled human malaria infection ten weeks after the last dose (group III). Protective efficacy was dependent on dose and regimen. Immunization with 3.2 × 103 (group I) or 1.28 × 104 (group II) PfSPZ protected 3 out of 9 (33%) or 6 out of 9 (67%) volunteers, respectively. Three doses of 5.12 × 104 PfSPZ at five-day intervals protected 5 out of 8 (63%) volunteers. The frequency of Pf-specific polyfunctional CD4 memory T cells was associated with protection. On a 7,455 peptide Pf proteome array, immune sera from at least 5 out of 9 group III vaccinees recognized each of 22 proteins. PfSPZ-CVac is a highly efficacious vaccine candidate; when we are able to optimize the immunization regimen (dose, interval between doses, and drug partner), this vaccine could be used for combination mass drug administration and a mass vaccination program approach to eliminate malaria from geographically defined areas.
2017-02-15Adipose tissue is a major site of energy storage and has a role in the regulation of metabolism through the release of adipokines. Here we show that mice with an adipose-tissue-specific knockout of the microRNA (miRNA)-processing enzyme Dicer (ADicerKO), as well as humans with lipodystrophy,
2017-02-22One aim of modern astronomy is to detect temperate, Earth-like exoplanets that are well suited for atmospheric characterization. Recently, three Earth-sized planets were detected that transit (that is, pass in front of) a star with a mass just eight per cent that of the Sun, located 12 parsecs away. The transiting configuration of these planets, combined with the Jupiter-like size of their host star—named TRAPPIST-1—makes possible in-depth studies of their atmospheric properties with present-day and future astronomical facilities. Here we report the results of a photometric monitoring campaign of that star from the ground and space. Our observations reveal that at least seven planets with sizes and masses similar to those of Earth revolve around TRAPPIST-1. The six inner planets form a near-resonant chain, such that their orbital periods (1.51, 2.42, 4.04, 6.06, 9.1 and 12.35 days) are near-ratios of small integers. This architecture suggests that the planets formed farther from the star and migrated inwards. Moreover, the seven planets have equilibrium temperatures low enough to make possible the presence of liquid water on their surfaces.
2017-02-13Reciprocity is a general, fundamental principle governing various physical systems, which ensures that the transfer function—the transmission of a physical quantity, say light intensity—between any two points in space is identical, regardless of geometrical or material asymmetries. Breaking this transmission symmetry offers enhanced control over signal transport, isolation and source protection. So far, devices that break reciprocity (and therefore show non-reciprocity) have been mostly considered in dynamic systems involving electromagnetic, acoustic and mechanical wave propagation associated with fields varying in space and time. Here we show that it is possible to break reciprocity in static systems, realizing mechanical metamaterials that exhibit vastly different output displacements under excitation from different sides, as well as one-way displacement amplification. This is achieved by combining large nonlinearities with suitable geometrical asymmetries and/or topological features. In addition to extending non-reciprocity and isolation to statics, our work sheds light on energy propagation in nonlinear materials with asymmetric crystalline structures and topological properties. We anticipate that breaking reciprocity will open avenues for energy absorption, conversion and harvesting, soft robotics, prosthetics and optomechanics.
2017-02-06The rise of oxygen on the early Earth (about 2.4 billion years ago) caused a reorganization of marine nutrient cycles, including that of nitrogen, which is important for controlling global primary productivity. However, current geochemical records lack the temporal resolution to address the nature and timing of the biogeochemical response to oxygenation directly. Here we couple records of ocean redox chemistry with nitrogen isotope (15N/14N) values from approximately 2.31-billion-year-old shales of the Rooihoogte and Timeball Hill formations in South Africa, deposited during the early stages of the first rise in atmospheric oxygen on the Earth (the Great Oxidation Event). Our data fill a gap of about 400 million years in the temporal 15N/14N record and provide evidence for the emergence of a pervasive aerobic marine nitrogen cycle. The interpretation of our nitrogen isotope data in the context of iron speciation and carbon isotope data suggests biogeochemical cycling across a dynamic redox boundary, with primary productivity fuelled by chemoautotrophic production and a nitrogen cycle dominated by nitrogen loss processes using newly available marine oxidants. This chemostratigraphic trend constrains the onset of widespread nitrate availability associated with ocean oxygenation. The rise of marine nitrate could have allowed for the rapid diversification and proliferation of nitrate-using cyanobacteria and, potentially, eukaryotic phytoplankton.
2017-02-22Variations in the Earth’s orbit and spin vector are a primary control on insolation and climate; their recognition in the geological record has revolutionized our understanding of palaeoclimate dynamics, and has catalysed improvements in the accuracy and precision of the geological timescale. Yet the secular evolution of the planetary orbits beyond 50 million years ago remains highly uncertain, and the chaotic dynamical nature of the Solar System predicted by theoretical models has yet to be rigorously confirmed by well constrained (radioisotopically calibrated and anchored) geological data. Here we present geological evidence for a chaotic resonance transition associated with interactions between the orbits of Mars and the Earth, using an integrated radioisotopic and astronomical timescale from the Cretaceous Western Interior Basin of what is now North America. This analysis confirms the predicted chaotic dynamical behaviour of the Solar System, and provides a constraint for refining numerical solutions for insolation, which will enable a more precise and accurate geological timescale to be produced.
2017-02-06Exceptionally preserved fossils provide crucial insights into extinct body plans and organismal evolution. Molluscs, one of the most disparate animal phyla, radiated rapidly during the early Cambrian period (approximately 535–520 million years ago (Ma)). The problematic fossil taxa Halkieria and Orthrozanclus (grouped in Sachitida) have been assigned variously to stem-group annelids, brachiopods, stem-group molluscs or stem-group aculiferans (Polyplacophora and Aplacophora), but their affinities have remained controversial owing to a lack of preserved diagnostic characters. Here we describe a new early sachitid, Calvapilosa kroegeri gen. et sp. nov. from the Fezouata biota of Morocco (Early Ordovician epoch, around 478 Ma). The new taxon is characterized by the presence of a single large anterior shell plate and polystichous radula bearing a median tooth and several lateral and uncinal teeth in more than 125 rows. Its flattened body is covered by hollow spinose sclerites, and a smooth, ventral girdle flanks an extensive mantle cavity. Phylogenetic analyses resolve C. kroegeri as a stem-group aculiferan together with other single-plated forms such as Maikhanella (Siphogonuchites) and Orthrozanclus; Halkieria is recovered closer to the aculiferan crown. These genera document the stepwise evolution of the aculiferan body plan from forms with a single, almost conchiferan-like shell through two-plated taxa such as Halkieria, to the eight-plated crown-group aculiferans. C. kroegeri therefore provides key evidence concerning the long debate about the crown molluscan affinities of sachitids. This new discovery strongly suggests that the possession of only a single calcareous shell plate and the presence of unmineralised sclerites are plesiomorphic (an ancestral trait) for the molluscan crown.
2017-02-13The maternal-to-zygotic transition (MZT) is one of the most profound and tightly orchestrated processes during the early life of embryos, yet factors that shape the temporal pattern of vertebrate MZT are largely unknown. Here we show that over one-third of zebrafish maternal messenger RNAs (mRNAs) can be N6-methyladenosine (m6A) modified, and the clearance of these maternal mRNAs is facilitated by an m6A-binding protein, Ythdf2. Removal of Ythdf2 in zebrafish embryos decelerates the decay of m6A-modified maternal mRNAs and impedes zygotic genome activation. These embryos fail to initiate timely MZT, undergo cell-cycle pause, and remain developmentally delayed throughout larval life. Our study reveals m6A-dependent RNA decay as a previously unidentified maternally driven mechanism that regulates maternal mRNA clearance during zebrafish MZT, highlighting the critical role of m6A mRNA methylation in transcriptome switching and animal development.
2017-02-13B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development, yet lesions of the genes encoding these transcription factors occur in over 80% of cases of pre-B-cell acute lymphoblastic leukaemia (ALL). The importance of these lesions in ALL has, until now, remained unclear. Here, by combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, we identify a novel B-lymphoid program for transcriptional repression of glucose and energy supply. Our metabolic analyses revealed that PAX5 and IKZF1 enforce a state of chronic energy deprivation, resulting in constitutive activation of the energy-stress sensor AMPK. Dominant-negative mutants of PAX5 and IKZF1, however, relieved this glucose and energy restriction. In a transgenic pre-B ALL mouse model, the heterozygous deletion of Pax5 increased glucose uptake and ATP levels by more than 25-fold. Reconstitution of PAX5 and IKZF1 in samples from patients with pre-B ALL restored a non-permissive state and induced energy crisis and cell death. A CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets identified the products of NR3C1 (encoding the glucocorticoid receptor), TXNIP (encoding a glucose-feedback sensor) and CNR2 (encoding a cannabinoid receptor) as central effectors of B-lymphoid restriction of glucose and energy supply. Notably, transport-independent lipophilic methyl-conjugates of pyruvate and tricarboxylic acid cycle metabolites bypassed the gatekeeper function of PAX5 and IKZF1 and readily enabled leukaemic transformation. Conversely, pharmacological TXNIP and CNR2 agonists and a small-molecule AMPK inhibitor strongly synergized with glucocorticoids, identifying TXNIP, CNR2 and AMPK as potential therapeutic targets. Furthermore, our results provide a mechanistic explanation for the empirical finding that glucocorticoids are effective in the treatment of B-lymphoid but not myeloid malignancies. Thus, B-lymphoid transcription factors function as metabolic gatekeepers by limiting the amount of cellular ATP to levels that are insufficient for malignant transformation.
2017-02-06Synthetic lethality and collateral lethality are two well-validated conceptual strategies for identifying therapeutic targets in cancers with tumour-suppressor gene deletions. Here, we explore an approach to identify potential synthetic-lethal interactions by screening mutually exclusive deletion patterns in cancer genomes. We sought to identify ‘synthetic-essential’ genes: those that are occasionally deleted in some cancers but are almost always retained in the context of a specific tumour-suppressor deficiency. We also posited that such synthetic-essential genes would be therapeutic targets in cancers that harbour specific tumour-suppressor deficiencies. In addition to known synthetic-lethal interactions, this approach uncovered the chromatin helicase DNA-binding factor CHD1 as a putative synthetic-essential gene in PTEN-deficient cancers. In PTEN-deficient prostate and breast cancers, CHD1 depletion profoundly and specifically suppressed cell proliferation, cell survival and tumorigenic potential. Mechanistically, functional PTEN stimulates the GSK3β-mediated phosphorylation of CHD1 degron domains, which promotes CHD1 degradation via the β-TrCP-mediated ubiquitination–proteasome pathway. Conversely, PTEN deficiency results in stabilization of CHD1, which in turn engages the trimethyl lysine-4 histone H3 modification to activate transcription of the pro-tumorigenic TNF–NF-κB gene network. This study identifies a novel PTEN pathway in cancer and provides a framework for the discovery of ‘trackable’ targets in cancers that harbour specific tumour-suppressor deficiencies.
2017-02-15Activation-induced cytidine deaminase (AID) is a B-cell-specific enzyme that targets immunoglobulin genes to initiate class switch recombination and somatic hypermutation. In addition, through off-target activity, AID has a much broader effect on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in the development and progression of lymphoma. AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation. The phosphatidylinositol 3-kinase δ (PI3Kδ) pathway regulates AID by suppressing its expression in B cells. Drugs for leukaemia or lymphoma therapy such as idelalisib, duvelisib and ibrutinib block PI3Kδ activity directly or indirectly, potentially affecting AID expression and, consequently, genomic stability in B cells. Here we show that treatment of primary mouse B cells with idelalisib or duvelisib, and to a lesser extent ibrutinib, enhanced the expression of AID and increased somatic hypermutation and chromosomal translocation frequency to the Igh locus and to several AID off-target sites. Both of these effects were completely abrogated in AID-deficient B cells. PI3Kδ inhibitors or ibrutinib increased the formation of AID-dependent tumours in pristane-treated mice. Consistently, PI3Kδ inhibitors enhanced AID expression and translocation frequency to IGH and AID off-target sites in human chronic lymphocytic leukaemia and mantle cell lymphoma cell lines, and patients treated with idelalisib, but not ibrutinib, showed increased somatic hypermutation in AID off-targets. In summary, we show that PI3Kδ or Bruton’s tyrosine kinase inhibitors increase genomic instability in normal and neoplastic B cells by an AID-dependent mechanism. This effect should be carefully considered, as such inhibitors can be administered to patients for years.
2017-02-22Nucleic acids undergo naturally occurring chemical modifications. Over 100 different modifications have been described and every position in the purine and pyrimidine bases can be modified; often the sugar is also modified. Despite recent progress, the mechanism for the biosynthesis of most modifications is not fully understood, owing, in part, to the difficulty associated with reconstituting enzyme activity in vitro. Whereas some modifications can be efficiently formed with purified components, others may require more intricate pathways. A model for modification interdependence, in which one modification is a prerequisite for another, potentially explains a major hindrance in reconstituting enzymatic activity in vitro. This model was prompted by the earlier discovery of tRNA cytosine-to-uridine editing in eukaryotes, a reaction that has not been recapitulated in vitro and the mechanism of which remains unknown. Here we show that cytosine 32 in the anticodon loop of Trypanosoma brucei tRNAThr is methylated to 3-methylcytosine (m3C) as a pre-requisite for C-to-U deamination. Formation of m3C in vitro requires the presence of both the T. brucei m3C methyltransferase TRM140 and the deaminase ADAT2/3. Once formed, m3C is deaminated to 3-methyluridine (m3U) by the same set of enzymes. ADAT2/3 is a highly mutagenic enzyme, but we also show that when co-expressed with the methyltransferase its mutagenicity is kept in check. This helps to explain how T. brucei escapes ‘wholesale deamination’ of its genome while harbouring both enzymes in the nucleus. This observation has implications for the control of another mutagenic deaminase, human AID, and provides a rationale for its regulation.
2017-01-19In mitosis, for each daughter cell to inherit an accurate copy of the genome from the mother cell, sister chromatids in the mother cell must attach to microtubules emanating from opposite poles of the mitotic spindle, a process known as bi-orientation. A surveillance mechanism, termed the spindle assembly checkpoint (SAC), monitors the microtubule attachment process and can temporarily halt the separation of sister chromatids and the completion of mitosis until bi-orientation is complete. SAC failure results in abnormal chromosome numbers, termed aneuploidy, in the daughter cells, a hallmark of many tumours. The HORMA-domain-containing protein mitotic arrest deficient 2 (MAD2) is a subunit of the SAC effector mitotic checkpoint complex (MCC). Structural conversion from the open to the closed conformation of MAD2 is required for MAD2 to be incorporated into the MCC. In vitro, MAD2 conversion and MCC assembly take several hours, but in cells the SAC response is established in a few minutes. Here, to address this discrepancy, we reconstituted a near-complete SAC signalling system with purified components and monitored assembly of the MCC in real time. A marked acceleration in MAD2 conversion and MCC assembly was observed when monopolar spindle 1 (MPS1) kinase phosphorylated the MAD1–MAD2 complex, triggering it to act as the template for MAD2 conversion and therefore contributing to the establishment of a physical platform for MCC assembly. Thus, catalytic activation of the SAC depends on regulated protein–protein interactions that accelerate the spontaneous but rate-limiting conversion of MAD2 required for MCC assembly.