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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.

The stability of widespread methane hydrates in shallow subsurface sediments of the marine continental margins is sensitive to temperature increases experienced by upper intermediate waters. Destabilization of methane hydrates and ensuing release of methane would produce climatic feedbacks amplifying and accelerating global warming. Hence, improved assessment of ongoing intermediate water warming is crucially important, especially that resulting from a weakening of Atlantic meridional overturning circulation (AMOC). Our study provides an independent paleoclimatic perspective by reconstructing the thermal structure and imprint of methane oxidation throughout a water column of 1,300 m. We studied a sediment sequence from the eastern equatorial Atlantic (Gulf of Guinea), a region containing abundant shallow subsurface methane hydrates. We focused on the early part of the penultimate interglacial and present a hitherto undocumented and remarkably large intermediate water warming of 6.8 °C in response to a brief episode of meltwater-induced, modest AMOC weakening centered at 126,000 to 125,000 y ago. The warming of intermediate waters to 14 °C significantly exceeds the stability field of methane hydrates. In conjunction with this warming, our study reveals an anomalously low δ13C spike throughout the entire water column, recorded as primary signatures in single and pooled shells of multitaxa foraminifers. This extremely negative δ13C excursion was almost certainly the result of massive destabilization of methane hydrates. This study documents and connects a sequence of climatic events and climatic feedback processes associated with and triggered by the penultimate climate warming that can serve as a paleoanalog for modern ongoing warming.

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.

The CLT code is employed to quantitatively investigate how a single destabilization of the m/n = 3/2 double tearing mode (DTM) and sequential destabilizations of multi-DTMs affect the pressure crash. The focus is on the explosive reconnection process, characterized by kinetic energy bursts and the position exchange of islands on two resonant surfaces. For the first time, it has been demonstrated that pressure crashes related to the 3/2 DTM can be manipulatable by modifying the q-profile. Precursor bursts impact the behavior of the 3/2 DTM but do not significantly contribute to pressure collapse, which mainly occurs during the destabilization of the 3/2 DTM. The sequential reconnecting DTMs of different helicities culminating in a 3/2 DTM with a pressure crash may decrease the overall amplitude of the pressure crash, thereby mitigating the destructive impact of the pressure crash on plasma confinement.

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.

The Mathieu–Duffing equation represents a basic form for a parametrically excited system with cubic nonlinearities. In multi-degree-of-freedom systems, parametric resonances and the associated limit cycles take place at both principal and combination resonance frequencies. Furthermore, using asynchronous parametric excitation of coupling terms leads to a broadband destabilization of the trivial solution and the appearance of limit cycles at non-resonant frequencies. Regarding applications, the utilization of this excitation method has its significant importance in micro- and nanosystems. On the one hand, cubic nonlinearities are found to be abundant in these systems. On the other hand, parametric excitation is preferably utilized in these systems for better amplification leading to an enhanced sensitivity and for squeezing thermal noise, and thus, proved to be significantly useful in mechanical, optical and microwave systems. Therefore, this theoretical investigation should be of relevant importance to those small-scaled systems. Accordingly, a general two-degree-of-freedom Mathieu–Duffing system is studied. The non-trivial solutions are obtained at different parametric resonance conditions. A bifurcation analysis is carried out using the multiple scales method, followed by investigating the effect of the asynchronous parametric excitation on the existence of limit cycles at resonant and non-resonant frequencies.

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

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.

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.