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Last feed update: Thursday September 21st, 2017 03:29:52 PM

Take stock of research ethics in human genome editing

Wednesday September 20th, 2017 12:00:00 AM
Progress in the use of CRISPR–Cas9 for human germline editing highlights some pressing ethical considerations for research on embryos.

Statues that perpetuate lies should not stand

Monday September 18th, 2017 12:00:00 AM
Monuments to the ‘father of gynaecology’ cannot be defended as historical documents because they hide grave injustices, says Harriet A. Washington.

Snow leopards, ancient zero and Cassini’s big finish

Wednesday September 20th, 2017 12:00:00 AM
The week in science: 15–21 September 2017.

Scientists' sexual-harassment case sparks protests at University of Rochester

Thursday September 14th, 2017 12:00:00 AM
Researchers who worked with Florian Jaeger have filed a complaint with the US government after the university cleared his name.

Sharks can live a lot longer than researchers realized

Wednesday September 20th, 2017 12:00:00 AM
Errors in past studies could undermine conservation plans.

Cassini crashes into Saturn — but could still deliver big discoveries

Friday September 15th, 2017 12:00:00 AM
Data from spacecraft could help determine the age of Saturn's rings and the persistence of its magnetic field.

Marine scientists allege Japan has blocked researchers from joining South Korean ship

Tuesday September 19th, 2017 12:00:00 AM
Controversy over vessel's name may impede oceanographic collaboration.

Researchers unite in quest for ‘standard model’ of the brain

Tuesday September 19th, 2017 12:00:00 AM
Modelled on big physics projects, the International Brain Lab will bring together some of the world’s pre-eminent neuroscientists to probe a single behaviour.

How the Internet of cells has biologists buzzing

Wednesday September 20th, 2017 12:00:00 AM
Networks of nanotubes may allow cells to share everything from infections and cancer to dementia-linked proteins.

Cancer patients need better care, not just more technology

Tuesday September 19th, 2017 12:00:00 AM
Treating cancer with the latest drugs and techniques is costly and will not improve survival globally, warn Richard Sullivan, C. S. Pramesh and Christopher M. Booth.

Bring on the bodyNET

Wednesday September 20th, 2017 12:00:00 AM
Stretchable sensors, circuits and batteries are about to change our relationships with electronics and each other, explain Bryant Chu and colleagues.

Relativity: Final ascent of physics

Wednesday September 20th, 2017 12:00:00 AM
Robert P. Crease applauds the third volume of a thrilling guide to a special pursuit.

Fiction: The science in Sherlock Holmes

Wednesday September 20th, 2017 12:00:00 AM
Maria Konnikova detects the fictional sleuth's inner researcher, 130 years on from his 'birth'.

Statues: sculpting a tarnished legacy

Monday September 18th, 2017 12:00:00 AM
Nature's editors have often courted controversy by taking provocative stances. In some cases, such as the 1908 editorial supporting the admission of women to scientific societies (Nature78, 226–228, 1908), this has reflected well on the journal's legacy.

Statues: researchers to mind their history

Monday September 18th, 2017 12:00:00 AM
Your Editorial created one more flashpoint in the current US debate about Confederate monuments (see Nature549, 5–6; 10.1038/549005b2017 and Naturehttp://doi.org/ccvm; 2017).The concern is what kind of history we memorialize in the statues of J.

Statues: an editorial response

Monday September 18th, 2017 12:00:00 AM
In the 7 September issue of Nature, we published an Editorial that provoked a widespread response (Nature549, 5–6; 10.1038/549005b2017). We have since published representative criticisms, including those in this issue, as well as a

Sea-level rise: No chaos in the satellite-data record

Wednesday September 20th, 2017 12:00:00 AM
The use of the slang term snafu (indicating a confused or chaotic state) in your headline 'Satellite snafu masked true sea-level rise for decades' undermines the satellite record's crucial contribution to the precise measurement of indicators of Earth's changing climate (Nature547, 265

Historical data: Hidden in the past

Wednesday September 20th, 2017 12:00:00 AM
Old photos, logbooks and papers are a gold mine for fields such as ecology and climatology.

The coded messenger

Wednesday September 20th, 2017 12:00:00 AM
It's in your make-up.

Lysis, lysogeny and virus–microbe ratios

Wednesday September 20th, 2017 12:00:00 AM
ARISING FROM B.Knowleset al. Nature531, 466–470 (2016); doi:10.1038/nature17193In response to the Article by Knowles et al., we present analyses that we believe challenge the Piggyback-the-Winner model and the proposed mechanistic link

Knowles & Rohwer reply

Wednesday September 20th, 2017 12:00:00 AM
REPLYING TO J. S.Weitz, S. J.Beckett, J. R.Brum, B. B.Cael & J.DushoffNature549, 10.1038/nature23295 (2017)Most bacteria are lysogens. However, lysogeny has languished in viral ecology as research has gravitated

Nanotechnology: A molecular assembler

Wednesday September 20th, 2017 12:00:00 AM
The idea of nanometre-scale machines that can assemble molecules has long been thought of as the stuff of science fiction. Such a machine has now been built — and might herald a new model for organic synthesis. See Letter p.374

Cell signalling: Red alert about lipid's role in skin cancer

Wednesday September 6th, 2017 12:00:00 AM
Some versions of the MC1R protein are associated with red hair and an increased risk of developing a skin cancer called melanoma. It emerges that a lipid that binds MC1R might provide a target to reduce this risk. See Letter p.399

Materials science: Long-lived electrodes for plastic batteries

Wednesday September 20th, 2017 12:00:00 AM
Organic materials are potential substitutes for the costly transition-metal oxides used in battery electrodes, but their stability is often poor. A polymer design that uses intermolecular interactions solves this problem.

Neuroscience: From embryo mutation to adult degeneration

Wednesday August 30th, 2017 12:00:00 AM
Mutations in embryonic blood-cell precursors called erythro-myeloid progenitors cause abnormal activation of their descendants — immune cells called microglia — leading to neurodegeneration in mice. See Letter p.389

Metallurgy: No more tears for metal 3D printing

Wednesday September 20th, 2017 12:00:00 AM
3D printing could revolutionize manufacturing processes involving metals, but few industrially useful alloys are compatible with the technique. A method has been developed that might open up the 3D printing of all metals. See Letter p.365

Cell biology: The persistence of memory

Wednesday September 6th, 2017 12:00:00 AM
Live imaging reveals that whether or not a daughter cell proliferates is influenced by two molecular factors inherited from its mother, providing insight into how the behaviour of a newly born cell can be predetermined. See Letter p.404

Rabies screen reveals GPe control of cocaine-triggered plasticity

Wednesday September 13th, 2017 12:00:00 AM
Identification of neural circuit changes that contribute to behavioural plasticity has routinely been conducted on candidate circuits that were preselected on the basis of previous results. Here we present an unbiased method for identifying experience-triggered circuit-level changes in neuronal ensembles in mice. Using rabies virus

The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation

Wednesday September 13th, 2017 12:00:00 AM
Type 2 innate lymphoid cells (ILC2s) both contribute to mucosal homeostasis and initiate pathologic inflammation in allergic asthma. However, the signals that direct ILC2s to promote homeostasis versus inflammation are unclear. To identify such molecular cues, we profiled mouse lung-resident ILCs using single-cell RNA sequencing

A binary main-belt comet

Wednesday September 20th, 2017 12:00:00 AM
Asteroids are primitive Solar System bodies that evolve both collisionally and through disruptions arising from rapid rotation. These processes can lead to the formation of binary asteroids and to the release of dust, both directly and, in some cases, through uncovering frozen volatiles. In a subset of the asteroids called main-belt comets, the sublimation of excavated volatiles causes transient comet-like activity. Torques exerted by sublimation measurably influence the spin rates of active comets and might lead to the splitting of bilobate comet nuclei. The kilometre-sized main-belt asteroid 288P (300163) showed activity for several months around its perihelion 2011 (ref. 11), suspected to be sustained by the sublimation of water ice and supported by rapid rotation, while at least one component rotates slowly with a period of 16 hours (ref. 14). The object 288P is part of a young family of at least 11 asteroids that formed from a precursor about 10 kilometres in diameter during a shattering collision 7.5 million years ago. Here we report that 288P is a binary main-belt comet. It is different from the known asteroid binaries in its combination of wide separation, near-equal component size, high eccentricity and comet-like activity. The observations also provide strong support for sublimation as the driver of activity in 288P and show that sublimation torques may play an important part in binary orbit evolution.

Tunable interacting composite fermion phases in a half-filled bilayer-graphene Landau level

Wednesday September 20th, 2017 12:00:00 AM
Non-Abelian anyons are a type of quasiparticle with the potential to encode quantum information in topological qubits protected from decoherence. Experimental systems that are predicted to harbour non-Abelian anyons include p-wave superfluids, superconducting systems with strong spin–orbit coupling, and paired states of interacting composite fermions that emerge at even denominators in the fractional quantum Hall (FQH) regime. Although even-denominator FQH states have been observed in several two-dimensional systems, small energy gaps and limited tunability have stymied definitive experimental probes of their non-Abelian nature. Here we report the observation of robust even-denominator FQH phases at half-integer Landau-level filling in van der Waals heterostructures consisting of dual-gated, hexagonal-boron-nitride-encapsulated bilayer graphene. The measured energy gap is three times larger than observed previously. We compare these FQH phases with numerical and theoretical models while simultaneously controlling the carrier density, layer polarization and magnetic field, and find evidence for the paired Pfaffian phase that is predicted to host non-Abelian anyons. Electric-field-controlled level crossings between states with different Landau-level indices reveal a cascade of FQH phase transitions, including a continuous phase transition between the even-denominator FQH state and a compressible composite fermion liquid. Our results establish graphene as a pristine and tunable experimental platform for studying the interplay between topology and quantum criticality, and for detecting non-Abelian qubits.

3D printing of high-strength aluminium alloys

Wednesday September 20th, 2017 12:00:00 AM
Metal-based additive manufacturing, or three-dimensional (3D) printing, is a potentially disruptive technology across multiple industries, including the aerospace, biomedical and automotive industries. Building up metal components layer by layer increases design freedom and manufacturing flexibility, thereby enabling complex geometries, increased product customization and shorter time to market, while eliminating traditional economy-of-scale constraints. However, currently only a few alloys, the most relevant being AlSi10Mg, TiAl6V4, CoCr and Inconel 718, can be reliably printed; the vast majority of the more than 5,500 alloys in use today cannot be additively manufactured because the melting and solidification dynamics during the printing process lead to intolerable microstructures with large columnar grains and periodic cracks. Here we demonstrate that these issues can be resolved by introducing nanoparticles of nucleants that control solidification during additive manufacturing. We selected the nucleants on the basis of crystallographic information and assembled them onto 7075 and 6061 series aluminium alloy powders. After functionalization with the nucleants, we found that these high-strength aluminium alloys, which were previously incompatible with additive manufacturing, could be processed successfully using selective laser melting. Crack-free, equiaxed (that is, with grains roughly equal in length, width and height), fine-grained microstructures were achieved, resulting in material strengths comparable to that of wrought material. Our approach to metal-based additive manufacturing is applicable to a wide range of alloys and can be implemented using a range of additive machines. It thus provides a foundation for broad industrial applicability, including where electron-beam melting or directed-energy-deposition techniques are used instead of selective laser melting, and will enable additive manufacturing of other alloy systems, such as non-weldable nickel superalloys and intermetallics. Furthermore, this technology could be used in conventional processing such as in joining, casting and injection moulding, in which solidification cracking and hot tearing are also common issues.

Metallic molybdenum disulfide nanosheet-based electrochemical actuators

Wednesday August 30th, 2017 12:00:00 AM
Actuators that convert electrical energy to mechanical energy are useful in a wide variety of electromechanical systems and in robotics, with applications such as steerable catheters, adaptive wings for aircraft and drag-reducing wind turbines. Actuation systems can be based on various stimuli, such as heat, solvent adsorption/desorption, or electrochemical action (in systems such as carbon nanotube electrodes, graphite electrodes, polymer electrodes and metals). Here we demonstrate that the dynamic expansion and contraction of electrode films formed by restacking chemically exfoliated nanosheets of two-dimensional metallic molybdenum disulfide (MoS2) on thin plastic substrates can generate substantial mechanical forces. These films are capable of lifting masses that are more than 150 times that of the electrode over several millimetres and for hundreds of cycles. Specifically, the MoS2 films are able to generate mechanical stresses of about 17 megapascals—higher than mammalian muscle (about 0.3 megapascals) and comparable to ceramic piezoelectric actuators (about 40 megapascals)—and strains of about 0.6 per cent, operating at frequencies up to 1 hertz. The actuation performance is attributed to the high electrical conductivity of the metallic 1T phase of MoS2 nanosheets, the elastic modulus of restacked MoS2 layers (2 to 4 gigapascals) and fast proton diffusion between the nanosheets. These results could lead to new electrochemical actuators for high-strain and high-frequency applications.

Stereodivergent synthesis with a programmable molecular machine

Wednesday September 20th, 2017 12:00:00 AM
It has been convincingly argued that molecular machines that manipulate individual atoms, or highly reactive clusters of atoms, with Ångström precision are unlikely to be realized. However, biological molecular machines routinely position rather less reactive substrates in order to direct chemical reaction sequences, from sequence-specific synthesis by the ribosome to polyketide synthases, where tethered molecules are passed from active site to active site in multi-enzyme complexes. Artificial molecular machines have been developed for tasks that include sequence-specific oligomer synthesis and the switching of product chirality, a photo-responsive host molecule has been described that is able to mechanically twist a bound molecular guest, and molecular fragments have been selectively transported in either direction between sites on a molecular platform through a ratchet mechanism. Here we detail an artificial molecular machine that moves a substrate between different activating sites to achieve different product outcomes from chemical synthesis. This molecular robot can be programmed to stereoselectively produce, in a sequential one-pot operation, an excess of any one of four possible diastereoisomers from the addition of a thiol and an alkene to an α,β-unsaturated aldehyde in a tandem reaction process. The stereodivergent synthesis includes diastereoisomers that cannot be selectively synthesized through conventional iminium–enamine organocatalysis. We anticipate that future generations of programmable molecular machines may have significant roles in chemical synthesis and molecular manufacturing.

The Apostasia genome and the evolution of orchids

Wednesday September 13th, 2017 12:00:00 AM
Constituting approximately 10% of flowering plant species, orchids (Orchidaceae) display unique flower morphologies, possess an extraordinary diversity in lifestyle, and have successfully colonized almost every habitat on Earth. Here we report the draft genome sequence of Apostasia shenzhenica, a representative of one of two genera that form a sister lineage to the rest of the Orchidaceae, providing a reference for inferring the genome content and structure of the most recent common ancestor of all extant orchids and improving our understanding of their origins and evolution. In addition, we present transcriptome data for representatives of Vanilloideae, Cypripedioideae and Orchidoideae, and novel third-generation genome data for two species of Epidendroideae, covering all five orchid subfamilies. A. shenzhenica shows clear evidence of a whole-genome duplication, which is shared by all orchids and occurred shortly before their divergence. Comparisons between A. shenzhenica and other orchids and angiosperms also permitted the reconstruction of an ancestral orchid gene toolkit. We identify new gene families, gene family expansions and contractions, and changes within MADS-box gene classes, which control a diverse suite of developmental processes, during orchid evolution. This study sheds new light on the genetic mechanisms underpinning key orchid innovations, including the development of the labellum and gynostemium, pollinia, and seeds without endosperm, as well as the evolution of epiphytism; reveals relationships between the Orchidaceae subfamilies; and helps clarify the evolutionary history of orchids within the angiosperms.

Hippocampal LTP and contextual learning require surface diffusion of AMPA receptors

Wednesday September 13th, 2017 12:00:00 AM
Long-term potentiation (LTP) of excitatory synaptic transmission has long been considered a cellular correlate for learning and memory. Early LTP (less than 1 h) had initially been explained either by presynaptic increases in glutamate release or by direct modification of postsynaptic AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor function. Compelling models have more recently proposed that synaptic potentiation can occur by the recruitment of additional postsynaptic AMPA receptors (AMPARs), sourced either from an intracellular reserve pool by exocytosis or from nearby extra-synaptic receptors pre-existing on the neuronal surface. However, the exact mechanism through which synapses can rapidly recruit new AMPARs during early LTP remains unknown. In particular, direct evidence for a pivotal role of AMPAR surface diffusion as a trafficking mechanism in synaptic plasticity is still lacking. Here, using AMPAR immobilization approaches, we show that interfering with AMPAR surface diffusion markedly impairs synaptic potentiation of Schaffer collaterals and commissural inputs to the CA1 area of the mouse hippocampus in cultured slices, acute slices and in vivo. Our data also identify distinct contributions of various AMPAR trafficking routes to the temporal profile of synaptic potentiation. In addition, AMPAR immobilization in vivo in the dorsal hippocampus inhibited fear conditioning, indicating that AMPAR diffusion is important for the early phase of contextual learning. Therefore, our results provide a direct demonstration that the recruitment of new receptors to synapses by surface diffusion is a critical mechanism for the expression of LTP and hippocampal learning. Since AMPAR surface diffusion is dictated by weak Brownian forces that are readily perturbed by protein–protein interactions, we anticipate that this fundamental trafficking mechanism will be a key target for modulating synaptic potentiation and learning.

A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease

Wednesday August 30th, 2017 12:00:00 AM
The pathophysiology of neurodegenerative diseases is poorly understood and there are few therapeutic options. Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss, and chronic glial activation. Whether microglial activation, which is generally viewed as a secondary process, is harmful or protective in neurodegeneration remains unclear. Late-onset neurodegenerative disease observed in patients with histiocytoses, which are clonal myeloid diseases associated with somatic mutations in the RAS–MEK–ERK pathway such as BRAF(V600E), suggests a possible role of somatic mutations in myeloid cells in neurodegeneration. Yet the expression of BRAF(V600E) in the haematopoietic stem cell lineage causes leukaemic and tumoural diseases but not neurodegenerative disease. Microglia belong to a lineage of adult tissue-resident myeloid cells that develop during organogenesis from yolk-sac erythro-myeloid progenitors (EMPs) distinct from haematopoietic stem cells. We therefore hypothesized that a somatic BRAF(V600E) mutation in the EMP lineage may cause neurodegeneration. Here we show that mosaic expression of BRAF(V600E) in mouse EMPs results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder. This is associated with accumulation of ERK-activated amoeboid microglia in mice, and is also observed in human patients with histiocytoses. In the mouse model, neurobehavioural signs, astrogliosis, deposition of amyloid precursor protein, synaptic loss and neuronal death were driven by ERK-activated microglia and were preventable by BRAF inhibition. These results identify the fetal precursors of tissue-resident macrophages as a potential cell-of-origin for histiocytoses and demonstrate that a somatic mutation in the EMP lineage in mice can drive late-onset neurodegeneration. Moreover, these data identify activation of the MAP kinase pathway in microglia as a cause of neurodegeneration and this offers opportunities for therapeutic intervention aimed at the prevention of neuronal death in neurodegenerative diseases.

cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein–DNA ladders

Wednesday September 13th, 2017 12:00:00 AM
Cytosolic DNA arising from intracellular pathogens triggers a powerful innate immune response. It is sensed by cyclic GMP–AMP synthase (cGAS), which elicits the production of type I interferons by generating the second messenger 2′3′-cyclic-GMP–AMP (cGAMP). Endogenous nuclear or mitochondrial DNA can also be sensed by cGAS under certain conditions, resulting in sterile inflammation. The cGAS dimer binds two DNA ligands shorter than 20 base pairs side-by-side, but 20-base-pair DNA fails to activate cGAS in vivo and is a poor activator in vitro. Here we show that cGAS is activated in a strongly DNA length-dependent manner both in vitro and in human cells. We also show that cGAS dimers form ladder-like networks with DNA, leading to cooperative sensing of DNA length: assembly of the pioneering cGAS dimer between two DNA molecules is ineffective; but, once formed, it prearranges the flanking DNA to promote binding of subsequent cGAS dimers. Remarkably, bacterial and mitochondrial nucleoid proteins HU and mitochondrial transcription factor A (TFAM), as well as high-mobility group box 1 protein (HMGB1), can strongly stimulate long DNA sensing by cGAS. U-turns and bends in DNA induced by these proteins pre-structure DNA to nucleate cGAS dimers. Our results suggest a nucleation-cooperativity-based mechanism for sensitive detection of mitochondrial DNA and pathogen genomes, and identify HMGB/TFAM proteins as DNA-structuring host factors. They provide an explanation for the peculiar cGAS dimer structure and suggest that cGAS preferentially binds incomplete nucleoid-like structures or bent DNA.

Palmitoylation-dependent activation of MC1R prevents melanomagenesis

Wednesday September 6th, 2017 12:00:00 AM
The melanocortin-1 receptor (MC1R), a G-protein-coupled receptor, has a crucial role in human and mouse pigmentation. Activation of MC1R in melanocytes by α-melanocyte-stimulating hormone (α-MSH) stimulates cAMP signalling and melanin production and enhances DNA repair after ultraviolet irradiation. Individuals carrying MC1R variants, especially those associated with red hair colour, fair skin and poor tanning ability (denoted as RHC variants), are associated with higher risk of melanoma. However, how MC1R activity is modulated by ultraviolet irradiation, why individuals with red hair are more prone to developing melanoma, and whether the activity of RHC variants might be restored for therapeutic benefit are unknown. Here we demonstrate a potential MC1R-targeted intervention strategy in mice to rescue loss-of-function MC1R in MC1R RHC variants for therapeutic benefit by activating MC1R protein palmitoylation. MC1R palmitoylation, primarily mediated by the protein-acyl transferase ZDHHC13, is essential for activating MC1R signalling, which triggers increased pigmentation, ultraviolet-B-induced G1-like cell cycle arrest and control of senescence and melanomagenesis in vitro and in vivo. Using C57BL/6J-Mc1re/eJ mice, in which endogenous MC1R is prematurely terminated, expressing Mc1r RHC variants, we show that pharmacological activation of palmitoylation rescues the defects of Mc1r RHC variants and prevents melanomagenesis. The results highlight a central role for MC1R palmitoylation in pigmentation and protection against melanoma.

Competing memories of mitogen and p53 signalling control cell-cycle entry

Wednesday September 6th, 2017 12:00:00 AM
Regulation of cell proliferation is necessary for immune responses, tissue repair, and upkeep of organ function to maintain human health. When proliferating cells complete mitosis, a fraction of newly born daughter cells immediately enter the next cell cycle, while the remaining cells in the same population exit to a transient or persistent quiescent state. Whether this choice between two cell-cycle pathways is due to natural variability in mitogen signalling or other underlying causes is unknown. Here we show that human cells make this fundamental cell-cycle entry or exit decision based on competing memories of variable mitogen and stress signals. Rather than erasing their signalling history at cell-cycle checkpoints before mitosis, mother cells transmit DNA damage-induced p53 protein and mitogen-induced cyclin D1 (CCND1) mRNA to newly born daughter cells. After mitosis, the transferred CCND1 mRNA and p53 protein induce variable expression of cyclin D1 and the CDK inhibitor p21 that almost exclusively determines cell-cycle commitment in daughter cells. We find that stoichiometric inhibition of cyclin D1–CDK4 activity by p21 controls the retinoblastoma (Rb) and E2F transcription program in an ultrasensitive manner. Thus, daughter cells control the proliferation–quiescence decision by converting the memories of variable mitogen and stress signals into a competition between cyclin D1 and p21 expression. We propose a cell-cycle control principle based on natural variation, memory and competition that maximizes the health of growing cell populations.

Alternative evolutionary histories in the sequence space of an ancient protein

Wednesday September 13th, 2017 12:00:00 AM
To understand why molecular evolution turned out as it did, we must characterize not only the path that evolution followed across the space of possible molecular sequences but also the many alternative trajectories that could have been taken but were not. A large-scale comparison of real and possible histories would establish whether the outcome of evolution represents an optimal state driven by natural selection or the contingent product of historical chance events; it would also reveal how the underlying distribution of functions across sequence space shaped historical evolution. Here we combine ancestral protein reconstruction with deep mutational scanning to characterize alternative histories in the sequence space around an ancient transcription factor, which evolved a novel biological function through well-characterized mechanisms. We find hundreds of alternative protein sequences that use diverse biochemical mechanisms to perform the derived function at least as well as the historical outcome. These alternatives all require prior permissive substitutions that do not enhance the derived function, but not all require the same permissive changes that occurred during history. We find that if evolution had begun from a different starting point within the network of sequences encoding the ancestral function, outcomes with different genetic and biochemical forms would probably have resulted; this contingency arises from the distribution of functional variants in sequence space and epistasis between residues. Our results illuminate the topology of the vast space of possibilities from which history sampled one path, highlighting how the outcome of evolution depends on a serial chain of compounding chance events.

The cryo-electron microscopy structure of human transcription factor IIH

Wednesday September 13th, 2017 12:00:00 AM
Human transcription factor IIH (TFIIH) is part of the general transcriptional machinery required by RNA polymerase II for the initiation of eukaryotic gene transcription. Composed of ten subunits that add up to a molecular mass of about 500 kDa, TFIIH is also essential for nucleotide excision repair. The seven-subunit TFIIH core complex formed by XPB, XPD, p62, p52, p44, p34, and p8 is competent for DNA repair, while the CDK-activating kinase subcomplex, which includes the kinase activity of CDK7 as well as the cyclin H and MAT1 subunits, is additionally required for transcription initiation. Mutations in the TFIIH subunits XPB, XPD, and p8 lead to severe premature ageing and cancer propensity in the genetic diseases xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy, highlighting the importance of TFIIH for cellular physiology. Here we present the cryo-electron microscopy structure of human TFIIH at 4.4 Å resolution. The structure reveals the molecular architecture of the TFIIH core complex, the detailed structures of its constituent XPB and XPD ATPases, and how the core and kinase subcomplexes of TFIIH are connected. Additionally, our structure provides insight into the conformational dynamics of TFIIH and the regulation of its activity.

Erratum: Genome-scale activation screen identifies a lncRNA locus regulating a gene neighbourhood

Wednesday September 20th, 2017 12:00:00 AM
Nature548, 343–346 (2017); doi:10.1038/nature23451Owing to an error during the production process, this Letter was not published online on 9 August 2017, as originally stated, and was instead first published online on 11 August 2017. The Letter






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