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MicroRNAs (miRNAs) regulate most human messenger RNAs and play essential roles in diverse developmental and physiological processes. Correctly predicting the function of each miRNA requires a better understanding of miRNA targeting efficacy. McGeary et al. measured binding affinities between six miRNAs and synthetic targets, built a biochemical model of miRNA-mediated repression, and expanded it to all miRNAs using a convolutional neural network. This approach offers insights into miRNA targeting and enables more accurate prediction of intracellular miRNA repression efficacy than previous algorithms. Science , this issue p. eaav1741 Millions of affinity measurements reveal microRNA-specific preferences and other insights that advance microRNA target prediction. MicroRNAs (miRNAs) act within Argonaute proteins to guide repression of messenger RNA targets. Although various approaches have provided insight into target recognition, the sparsity of miRNA-target affinity measurements has limited understanding and prediction of targeting efficacy. Here, we adapted RNA bind-n-seq to enable measurement of relative binding affinities between Argonaute-miRNA complexes and all sequences ≤12 nucleotides in length. This approach revealed noncanonical target sites specific to each miRNA, miRNA-specific differences in canonical target-site affinities, and a 100-fold impact of dinucleotides flanking each site. These data enabled construction of a biochemical model of miRNA-mediated repression, which was extended to all miRNA sequences using a convolutional neural network. This model substantially improved prediction of cellular repression, thereby providing a biochemical basis for quantitatively integrating miRNAs into gene-regulatory networks.

From recent developments on how roots affect soil organic carbon (SOC) an apparent paradox has emerged where roots drive SOC stabilization causing SOC accrual, but also SOC destabilization causing SOC loss. We synthesize current results and propose the new Rhizo-Engine framework consisting of two linked components: microbial turnover and the soil physicochemical matrix. The Rhizo-Engine is driven by rhizodeposition, root turnover, and plant uptake of nutrients and water, thereby accelerating SOC turnover through both stabilization and destabilization mechanisms. This Rhizo-Engine framework emphasizes the need for a more holistic approach to study root-driven SOC dynamics. This framework would provide better understanding of plant root effects on soil carbon sequestration and the sensitivity of SOC stocks to climate and land-use changes.

In this paper, we develop an algebraic K-stability theory (e.g. special test configuration theory and optimal destabilization theory) for log Fano \\(\\mathbb R\\)-pairs, and construct a proper K-moduli space to parametrize K-polystable log Fano \\(\\mathbb R\\)-pairs with some fixed invariants (e.g. dimension, volume, coefficients). All of these are well-known for log Fano \\(\\mathbb Q\\)-pairs, and the strategy in this paper is trying to reduce the problems (in many cases) to \\(\\mathbb Q\\)-coefficients case rather than rebuilding the whole program as in \\(\\mathbb Q\\)-coefficients case.

Limiting metabolic competition in the tumour microenvironment may increase the effectiveness of immunotherapy. Owing to its crucial role in the glucose metabolism of activated T cells, CD28 signalling has been proposed as a metabolic biosensor of T cells 1 . By contrast, the engagement of CTLA-4 has been shown to downregulate T cell glycolysis 1 . Here we investigate the effect of CTLA-4 blockade on the metabolic fitness of intra-tumour T cells in relation to the glycolytic capacity of tumour cells. We found that CTLA-4 blockade promotes metabolic fitness and the infiltration of immune cells, especially in glycolysis-low tumours. Accordingly, treatment with anti-CTLA-4 antibodies improved the therapeutic outcomes of mice bearing glycolysis-defective tumours. Notably, tumour-specific CD8 + T cell responses correlated with phenotypic and functional destabilization of tumour-infiltrating regulatory T (T reg ) cells towards IFNγ- and TNF-producing cells in glycolysis-defective tumours. By mimicking the highly and poorly glycolytic tumour microenvironments in vitro, we show that the effect of CTLA-4 blockade on the destabilization of T reg cells is dependent on T reg cell glycolysis and CD28 signalling. These findings indicate that decreasing tumour competition for glucose may facilitate the therapeutic activity of CTLA-4 blockade, thus supporting its combination with inhibitors of tumour glycolysis. Moreover, these results reveal a mechanism by which anti-CTLA-4 treatment interferes with T reg cell function in the presence of glucose. CTLA-4 promotes glucose uptake by tumour-infiltrating regulatory T cells, making them unstable.

A bstract Analog condensed matter systems present an exciting opportunity to simulate early Universe models in table-top experiments. We consider a recent proposal for an analog condensed matter experiment to simulate the relativistic quantum decay of the false vacuum. In the proposed experiment, two ultra-cold condensates are coupled via a time-varying radio-frequency field. The relative phase of the two condensates in this system is approximately described by a relativistic scalar field with a potential possessing a series of false and true vacuum local minima. If the system is set up in a false vacuum, it would then decay to a true vacuum via quantum mechanical tunnelling. Should such an experiment be realized, it would be possible to answer a number of open questions regarding non-perturbative phenomena in quantum field theory and early Universe cosmology. In this paper, we illustrate a possible obstruction: the time-varying coupling that is invoked to create a false vacuum for the long-wavelength modes of the condensate leads to a destabilization of shorter wavelength modes within the system via parametric resonance. We focus on an idealized setup in which the two condensates have identical properties and identical background densities. Describing the system by the coupled Gross-Pitaevskii equations (GPE), we use the machinery of Floquet theory to perform a linear stability analysis, calculating the wavenumber associated with the first instability band for a variety of experimental parameters. However, we demonstrate that, by tuning the frequency of the time-varying coupling, it may be possible to push the first instability band outside the validity of the GPE, where dissipative effects are expected to damp any instabilities. This provides a viable range of experimental parameters to perform analog experiments of false vacuum decay.

Estimated millions of tons of plastic are dumped annually into oceans. Plastic has been produced only for 70 y, but the exponential rise of mass production leads to its widespread proliferation in all environments. As a consequence of their large abundance globally, microplastics are also found in many living organisms including humans. While the health impact of digested microplastics on living organisms is debatable, we reveal a physical mechanism of mechanical stretching of model cell lipid membranes induced by adsorbed micrometer-sized microplastic particles most commonly found in oceans. Combining experimental and theoretical approaches, we demonstrate that microplastic particles adsorbed on lipid membranes considerably increase membrane tension even at low particle concentrations. Each particle adsorbed at the membrane consumes surface area that is proportional to the contact area between particle and the membrane. Although lipid membranes are liquid and able to accommodate mechanical stress, the relaxation time is much slower than the rate of adsorption; thus, the cumulative effect from arriving microplastic particles to the membrane leads to the global reduction of the membrane area and increase of membrane tension. This, in turn, leads to a strong reduction of membrane lifetime. The effect of mechanical stretching of microplastics on living cells membranes was demonstrated by using the aspiration micropipette technique on red blood cells. The described mechanical stretching mechanism on lipid bilayers may provide better understanding of the impact of microplastic particles in living systems.

The traditional cable AC withstand voltage test device has poor control accuracy and slow protection performance, and the inverter based on power switching devices can be applied to the test device to effectively solve the above problems. However, the LCL-type inverter contains resonance, which tends to cause system destabilization and reduces current quality, affecting the effectiveness of the device for testing. Differential feedback filter capacitor voltage can solve the problem and can save a high-accuracy sensor, but the differential limits its application. This paper proposes to use the negative-band pass filter (NBPF) connected to lag correction (LC) link to equivalent the differential, and it can not only effectively suppress the resonance, but also can significantly suppress high-frequency noise. An experimental platform is built for validation.

Hydrogen is the ultimate vector for a carbon-free, sustainable green-energy. While being the most promising candidate to serve this purpose, hydrogen inherits a series of characteristics making it particularly difficult to handle, store, transport and use in a safe manner. The researchers’ attention has thus shifted to storing hydrogen in its more manageable forms: the light metal hydrides and related derivatives (ammonia-borane, tetrahydridoborates/borohydrides, tetrahydridoaluminates/alanates or reactive hydride composites). Even then, the thermodynamic and kinetic behavior faces either too high energy barriers or sluggish kinetics (or both), and an efficient tool to overcome these issues is through nanoconfinement. Nanoconfined energy storage materials are the current state-of-the-art approach regarding hydrogen storage field, and the current review aims to summarize the most recent progress in this intriguing field. The latest reviews concerning H2 production and storage are discussed, and the shift from bulk to nanomaterials is described in the context of physical and chemical aspects of nanoconfinement effects in the obtained nanocomposites. The types of hosts used for hydrogen materials are divided in classes of substances, the mean of hydride inclusion in said hosts and the classes of hydrogen storage materials are presented with their most recent trends and future prospects.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is initiated by virus binding to the ACE2 cell-surface receptors 1 – 4 , followed by fusion of the virus and cell membranes to release the virus genome into the cell. Both receptor binding and membrane fusion activities are mediated by the virus spike glycoprotein 5 – 7 . As with other class-I membrane-fusion proteins, the spike protein is post-translationally cleaved, in this case by furin, into the S1 and S2 components that remain associated after cleavage 8 – 10 . Fusion activation after receptor binding is proposed to involve the exposure of a second proteolytic site (S2′), cleavage of which is required for the release of the fusion peptide 11 , 12 . Here we analyse the binding of ACE2 to the furin-cleaved form of the SARS-CoV-2 spike protein using cryo-electron microscopy. We classify ten different molecular species, including the unbound, closed spike trimer, the fully open ACE2-bound trimer and dissociated monomeric S1 bound to ACE2. The ten structures describe ACE2-binding events that destabilize the spike trimer, progressively opening up, and out, the individual S1 components. The opening process reduces S1 contacts and unshields the trimeric S2 core, priming the protein for fusion activation and dissociation of ACE2-bound S1 monomers. The structures also reveal refolding of an S1 subdomain after ACE2 binding that disrupts interactions with S2, which involves Asp614 13 – 15 and leads to the destabilization of the structure of S2 proximal to the secondary (S2′) cleavage site. Cryo-electron microscopy structures of consecutive binding events of ACE2 in complex with the spike protein of SARS-CoV-2 reveal the mechanisms of receptor binding by the spike protein and activation for membrane fusion by the spike protein of SARS-CoV-2.

Transition-metal dissolution from cathode materials, manganese in particular, has been held responsible for severe capacity fading in lithium-ion batteries, with the deposition of the transition-metal cations on anode surface, in elemental form or as chelated-complexes, as the main contributor for such degradations. In this work we demonstrate with diverse experiments and calculations that, besides interfacial manganese species on anode, manganese(II) in bulk electrolyte also significantly destabilizes electrolyte components with its unique solvation-sheath structure, where the decompositions of carbonate molecules and hexafluorophosphate anion are catalyzed via their interactions with manganese(II). The manganese(II)-species eventually deposited on anode surface resists reduction to its elemental form because of its lower electrophilicity than carbonate molecule or anion, whose destabilization leads to sustained consumption. The reveal understanding of the once-overlooked role of manganese-dissolution in electrolytes provides fresh insight into the failure mechanism of manganese-based cathode chemistries, which serves as better guideline to electrolyte design for future batteries. Mn dissolution is dominantly responsible for capacity fading of most Mn-rich cathodes. Here the authors reveal that soluble Mn 2+ species significantly destabilizes solvent and anion via its unique solvation sheath structure, providing insight into the failure mechanism of related cathode chemistries.