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An engineered protein that binds to the envelope of HIV viruses protects monkeys against infection with a simian–human virus that causes AIDS. This gene-therapy approach might provide an alternative to elusive HIV vaccines. See Letter p.87
Computer simulations have revealed a mechanism by which nanostructures of the material graphene can be driven in one direction by controlling the stiffness of the underlying substrate.
How does marijuana cause the irresistible hunger pangs known as the munchies? Paradoxically, the answer seems to involve an unusual mode of activation of a brain circuit best known for suppressing appetite. See Article p.45
Signal sequences on messenger RNA that initiate protein synthesis are not thought to be interchangeable between life's domains. The finding that a signal from an arthropod virus can function in bacteria questions this idea. See Letter p.110
Liquid-filled pores in membranes have been designed to reversibly open and close, allowing only particular fluids through at given pressures. This enables tunable and gated separations of mixtures of immiscible fluids. See Letter p.70
A combination of two catalysts — one of which is light-activated — has been used to promote new chemical reactivity, opening up fresh opportunities for the synthesis of structurally complex organic molecules. See Letter p.74
Cannabinoid-induced feeding signals are shown to enhance pro-opiomelanocortin (POMC) neuronal activity in mice, causing an enhancement of β-endorphin release, which is crucial in causing this cannabinoid-induced response; these results uncover an overlooked role of hypothalamic POMC neurons in the promotion of feeding by cannabinoids.
During movement preparation, motor cortical neuronal subpopulations that project to downstream motor areas are more selective for the direction of upcoming movement than those that project to other cortical targets, especially immediately before movement, emphasizing the need to interpret complex neuronal responses measured during behaviour in the context of hierarchically organized cortical circuits.
This study demonstrates the activation of a STAT3-independent healing pathway in response to mucosal injury which involves the co-receptor for IL-6 cytokines gp130 and downstream effectors Src, Yes, YAP and Notch.
The probable evolution of the planetary nebula Henize 2-428 is examined, from a close binary system in which both stars ejected their envelopes to the white dwarf stage with a short orbital period and combined mass above the Chandrasekhar limit, suggesting that the system should merge in about 700 million years and trigger a type Ia supernova.
A quantum error correction scheme is demonstrated in a system of superconducting qubits, and repeated quantum non-demolition measurements are used to track errors and reduce the failure rate; increasing the system size from five to nine qubits improves the failure rate further.
A rapid, reversible, non-fouling gating mechanism is created by infusing a porous membrane with a capillary-stabilized liquid that reconfigures under pressure to form a liquid-lined pathway, enabling selective multiphase transport with rationally tunable differential response profiles for a variety of liquids and gases.
The direct functionalization of unactivated sp3 C–H bonds is still one of the most challenging problems facing synthetic organic chemists. The appeal of such transformations derives from their capacity to facilitate the construction of complex organic molecules via the coupling of simple and otherwise inert building blocks, without introducing extraneous functional groups. Despite notable recent efforts, the establishment of general and mild strategies for the engagement of sp3 C–H bonds in C–C bond forming reactions has proved difficult. Within this context, the discovery of chemical transformations that are able to directly functionalize allylic methyl, methylene and methine carbons in a catalytic manner is a priority. Although protocols for direct oxidation and amination of allylic C–H bonds (that is, C–H bonds where an adjacent carbon is involved in a C = C bond) have become widely established, the engagement of allylic substrates in C–C bond forming reactions has thus far required the use of pre-functionalized coupling partners. In particular, the direct arylation of non-functionalized allylic systems would enable access to a series of known pharmacophores (molecular features responsible for a drug’s action), though a general solution to this long-standing challenge remains elusive. Here we report the use of both photoredox and organic catalysis to accomplish a mild, broadly effective direct allylic C–H arylation. This C–C bond forming reaction readily accommodates a broad range of alkene and electron-deficient arene reactants, and has been used in the direct arylation of benzylic C–H bonds.
Severe drought in a tropical forest ecosystem suppresses photosynthetic carbon uptake and plant maintenance respiration, but growth is maintained, suggesting that, overall, less carbon is available for tree tissue maintenance and defence, which may cause the subsequent observed increase in tree mortality.
Virtually reconstructing the jaw of OH 7 reveals a remarkably primitive shape, suggesting that the Homo habilis lineage originated before 2.3 million years ago; marking deep-rooted species diversity in the genus Homo.
The new entry inhibitor eCD4-Ig, consisting of the immunoadhesin form of CD4 (CD4-Ig) fused to a small CCR5-mimetic sulfopeptide, avidly binds two highly conserved sites of the HIV-1 Env protein; the inhibitor has high potency and breadth and can neutralize 100% of a diverse panel of neutralization-resistant HIV-1 viruses, and when delivered to macaques using an adeno-associated virus vector, it can provide effective long-term protection from multiple challenges with simian/human immunodeficiency virus.
Emulsifying agents, which are common food additives in the human diet, induce low-grade inflammation and obesity/metabolic syndrome in mice, suggesting that further investigation into the potential impact of dietary emulsifiers on the gut microbiota and human heath are warranted.
In Caenorhabditis elegant, reduced insulin/IGF-1 signalling can promote longevity through a program that is genetically distinct from the dauer developmental pathway, and requires SKN-1-dependent collagen remodelling that is a broadly essential feature of longevity assurance pathways.
The BCR-ABL1 fusion gene is a driver oncogene in chronic myeloid leukaemia and 30–50% of cases of adult acute lymphoblastic leukaemia. Introduction of ABL1 kinase inhibitors (for example, imatinib) has markedly improved patient survival, but acquired drug resistance remains a challenge. Point mutations in the ABL1 kinase domain weaken inhibitor binding and represent the most common clinical resistance mechanism. The BCR–ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) confers resistance to all approved ABL1 inhibitors except ponatinib, which has toxicity limitations. Here we combine comprehensive drug sensitivity and resistance profiling of patient cells ex vivo with structural analysis to establish the VEGFR tyrosine kinase inhibitor axitinib as a selective and effective inhibitor for T315I-mutant BCR–ABL1-driven leukaemia. Axitinib potently inhibited BCR–ABL1(T315I), at both biochemical and cellular levels, by binding to the active form of ABL1(T315I) in a mutation-selective binding mode. These findings suggest that the T315I mutation shifts the conformational equilibrium of the kinase in favour of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib. Treatment of a T315I chronic myeloid leukaemia patient with axitinib resulted in a rapid reduction of T315I-positive cells from bone marrow. Taken together, our findings demonstrate an unexpected opportunity to repurpose axitinib, an anti-angiogenic drug approved for renal cancer, as an inhibitor for ABL1 gatekeeper mutant drug-resistant leukaemia patients. This study shows that wild-type proteins do not always sample the conformations available to disease-relevant mutant proteins and that comprehensive drug testing of patient-derived cells can identify unpredictable, clinically significant drug-repositioning opportunities.
The structural polymorphism of intrinsically disordered protein 4E-BP2 allows it to regulate translation initiation through post-translational modification-mediated folding, exemplifying a new and potentially general mechanism of biological regulation mediated by intrinsically disordered proteins.
A eukaryotic viral internal ribosome entry site (IRES) element is described that binds both bacterial and eukaryotic ribosomes and initiates translation in both, demonstrating that RNA structure-based initiation can occur in both these domains of life, although in bacteria the element uses a mechanism that differs from that in eukaryotes.
Filamentous actin (F-actin) is the major protein of muscle thin filaments, and actin microfilaments are the main component of the eukaryotic cytoskeleton. Mutations in different actin isoforms lead to early-onset autosomal dominant non-syndromic hearing loss, familial thoracic aortic aneurysms and dissections, and multiple variations of myopathies. In striated muscle fibres, the binding of myosin motors to actin filaments is mainly regulated by tropomyosin and troponin. Tropomyosin also binds to F-actin in smooth muscle and in non-muscle cells and stabilizes and regulates the filaments there in the absence of troponin. Although crystal structures for monomeric actin (G-actin) are available, a high-resolution structure of F-actin is still missing, hampering our understanding of how disease-causing mutations affect the function of thin muscle filaments and microfilaments. Here we report the three-dimensional structure of F-actin at a resolution of 3.7 Å in complex with tropomyosin at a resolution of 6.5 Å, determined by electron cryomicroscopy. The structure reveals that the D-loop is ordered and acts as a central region for hydrophobic and electrostatic interactions that stabilize the F-actin filament. We clearly identify map density corresponding to ADP and Mg2+ and explain the possible effect of prominent disease-causing mutants. A comparison of F-actin with G-actin reveals the conformational changes during filament formation and identifies the D-loop as their key mediator. We also confirm that negatively charged tropomyosin interacts with a positively charged groove on F-actin. Comparison of the position of tropomyosin in F-actin–tropomyosin with its position in our previously determined F-actin–tropomyosin–myosin structure reveals a myosin-induced transition of tropomyosin. Our results allow us to understand the role of individual mutations in the genesis of actin- and tropomyosin-related diseases and will serve as a strong foundation for the targeted development of drugs.