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Abstract RNA modifications play a pivotal role in the regulation of RNA chemistry within cells. Several technologies have been developed with the goal of using RNA modifications to regulate cellular biochemistry selectively, but achieving selective and precise modifications remains a challenge. Here, we show that by using designer organelles, we can modify mRNA with pseudouridine in a highly selective and guide-RNA-dependent manner. We use designer organelles inspired by concepts of phase separation, a central tenet in developing artificial membraneless organelles in living mammalian cells. In addition, we use circular guide RNAs to markedly enhance the effectiveness of targeted pseudouridinylation. Our studies introduce spatial engineering through optimized RNA editing organelles (OREO) as a complementary tool for targeted RNA modification, providing new avenues to enhance RNA modification specificity.

Abstract Linking clinical multi-omics with mechanistic studies may improve the understanding of rare cancers. We leverage two precision oncology programs to investigate rhabdomyosarcoma with FUS/EWSR1-TFCP2 fusions, an orphan malignancy without effective therapies. All tumors exhibit outlier ALK expression, partly accompanied by intragenic deletions and aberrant splicing resulting in ALK variants that are oncogenic and sensitive to ALK inhibitors. Additionally, recurrent CKDN2A/MTAP co-deletions provide a rationale for PRMT5-targeted therapies. Functional studies show that FUS-TFCP2 blocks myogenic differentiation, induces transcription of ALK and truncated TERT, and inhibits DNA repair. Unlike other fusion-driven sarcomas, TFCP2-rearranged tumors exhibit genomic instability and signs of defective homologous recombination. DNA methylation profiling demonstrates a close relationship with undifferentiated sarcomas. In two patients, sarcoma was preceded by benign lesions carrying FUS-TFCP2, indicating stepwise sarcomagenesis. This study illustrates the potential of linking precision oncology with preclinical research to gain insight into the classification, pathogenesis, and therapeutic vulnerabilities of rare cancers.

Abstract The potential spin-triplet heavy-fermion superconductor UTe2 exhibits signatures of multiple distinct superconducting phases. For field aligned along the b axis, a metamagnetic transition occurs at μ 0 H m ≈ 35 T. It is associated with magnetic fluctuations that may be beneficial for the field-reinforced superconductivity surviving up to H m. Once the field is tilted away from the b towards the c axis, a reentrant superconducting phase emerges just above H m. In order to better understand this remarkably field-resistant superconducting phase, we conducted magnetic-torque and magnetotransport measurements in pulsed magnetic fields. We determine the record-breaking upper critical field of μ 0 H c2 ≈ 73 T and its evolution with angle. Furthermore, the normal-state Hall effect experiences a drastic suppression indicative of a reduced band polarization above H m in the angular range around 30° caused by a partial compensation between the applied field and an exchange field. This promotes the Jaccarino-Peter effect as a likely mechanism for the reentrant superconductivity above H m.

Abstract Negatively-charged boron vacancy centers ( $${{V}_{B}}^{-}$$ V B − ) in hexagonal Boron Nitride (hBN) are attracting increasing interest since they represent optically-addressable qubits in a van der Waals material. In particular, these spin defects have shown promise as sensors for temperature, pressure, and static magnetic fields. However, their short spin coherence time limits their scope for quantum technology. Here, we apply dynamical decoupling techniques to suppress magnetic noise and extend the spin coherence time by two orders of magnitude, approaching the fundamental T 1 relaxation limit. Based on this improvement, we demonstrate advanced spin control and a set of quantum sensing protocols to detect radiofrequency signals with sub-Hz resolution. The corresponding sensitivity is benchmarked against that of state-of-the-art NV-diamond quantum sensors. This work lays the foundation for nanoscale sensing using spin defects in an exfoliable material and opens a promising path to quantum sensors and quantum networks integrated into ultra-thin structures.

Abstract The dynamic mass loss of ice sheets constitutes one of the biggest uncertainties in projections of ice-sheet evolution. One central, understudied aspect of ice flow is how the bulk orientation of the crystal orientation fabric translates to the mechanical anisotropy of ice. Here we show the spatial distribution of the depth-averaged horizontal anisotropy and corresponding directional flow-enhancement factors covering a large area of the Northeast Greenland Ice Stream onset. Our results are based on airborne and ground-based radar surveys, ice-core observations, and numerical ice-flow modelling. They show a strong spatial variability of the horizontal anisotropy and a rapid crystal reorganisation on the order of hundreds of years coinciding with the ice-stream geometry. Compared to isotropic ice, parts of the ice stream are found to be more than one order of magnitude harder for along-flow extension/compression while the shear margins are potentially softened by a factor of two for horizontal-shear deformation.

The Greenland Ice Sheet is the largest land ice contributor to sea level rise. This will continue in the future but at an uncertain rate and observational estimates are limited to the last few decades. Understanding the long-term glacier response to external forcing is key to improving projections. Here we use historical photographs to calculate ice loss from 1880-2012 for Jakobshavn, Helheim, and Kangerlussuaq glacier. We estimate ice loss corresponding to a sea level rise of 8.1 ± 1.1 millimetres from these three glaciers. Projections of mass loss for these glaciers, using the worst-case scenario, Representative Concentration Pathways 8.5, suggest a sea level contribution of 9.1-14.9 mm by 2100. RCP8.5 implies an additional global temperature increase of 3.7 °C by 2100, approximately four times larger than that which has taken place since 1880. We infer that projections forced by RCP8.5 underestimate glacier mass loss which could exceed this worst-case scenario.

The recently demonstrated approaches to fabrication of quantum emitters in silicon result in their random positioning, hindering applications in quantum photonic integrated circuits. Here the authors demonstrate controlled fabrication of telecom-wavelength quantum emitters in silicon wafers by focused ion beams.

mTORC1 blocks lysosomal nutrient generation. Here, the authors show that mTORC1 inactivation triggers V-ATPase assembly, which rapidly initiates lysosomal acidification and degradation of protein contents throughout the lysosomal population.

Flexible thermoelectrics are of great interest with increasing demand of flexible and wearable electronics. Here, the authors demonstrate that the Weyl semimetal, WTe2, has a high Nernst power factor and great mechanical flexibility.

While rare, SARS-CoV-2-infected children can develop severe COVID-19 (ARDS) or inflammatory syndrome (MIS-C). Here, the authors use proteomics to characterize hundreds of blood proteins and identify key biological pathways that differentiate MIS-C and ARDS.

‘Archaeogenetic analysis of black rat remains reveals that this species was introduced into temperate Europe twice, in the Roman and medieval periods. This population turnover was likely associated with multiple historical and environmental factors.’

Semiconductor nanowires are promising candidates for the realization of novel transistor concepts. Here, the authors demonstrate that electron mobility in strained coaxial nanowire heterostructures can be higher than in the corresponding bulk crystals.

The acidic tumour microenvironment in melanoma drives immune evasion by cAMP in tumor-infiltrating monocytes. Here, the authors show that the release of an adenylate cyclase inhibitor from micelles restores antitumor immunity and, when combined with regulatory T cell depletion, leads to remission of established B16-F10-OVA tumors.

Regulatory T (Treg) cells are important modulators of the tumor microenvironment. Here the authors perform transcriptome profiling of immune cells from patients with renal clear cell carcinoma to find a Treg signature that correlates with poorer prognosis, with CD177 being implicated as the main mediator for related alterations in Treg activity and tumor outcome.

Natural Killer cell development is controlled by two related transcription factors, Eomes and T-bet. Authors show here that while the two factors share a large proportion of their target genes, they regulate distinct developmental processes by differing in their pattern of expression and in their associated co-factors.

Ferromagnetic systems rarely display a large or non-saturating magnetoresistance, due to the low Fermi velocity of the predominant charge carrier. Here, the authors show that MnBi, a ferromagnet, bucks this trend, showing both large and non-saturating magnetoresistance, and high charge carrier motilities.

The E3 ligase Hakai can interact with the m6A methylation machinery but its function is still unclear. Here, the authors show that Hakai is a conserved component of the m6A methyltransferase complex and provide functional and molecular insights into its role in regulating m6A levels in Drosophila.

Honeycomb iridates are thought to have strongly spin-anisotropic exchangeinteractions that could lead to an extraordinary state of matter known as theKitaev quantum spin liquid. The realization of this state requires almostperfectly frustrated interactions between the magnetic Ir$^{4+}$ ions, butsmall imbalances in energy make other ordered states more favorable. Indeed,the closeness in energy of these ordered states is itself a signature of theintrinsic frustration in the system. In this work, we illustrate that smallmagnetic fields can be employed to drive the frustrated quantum magnet$\beta-$Li$_2$IrO$_3$,between different broken symmetry states, but withoutcausing a true thermodynamic phase transition. This field-induced brokensymmetry phase has all the signatures of a thermodynamic order parameter, butit is never truly formed in zero field. Rather, it is summoned when the scalesof frustration are appropriately tipped, intertwined with other nearby quantumstates.

Magnetic honeycomb iridates are thought to show strongly spin-anisotropic exchange interactions which, when highly frustrated, lead to an exotic state of matter known as the Kitaev quantum spin liquid. However, in all known examples these materials magnetically order at finite temperatures, the scale of which may imply weak frustration. Here we show that the application of a relatively small magnetic field drives the three-dimensional magnet β-Li2IrO3 from its incommensurate ground state into a quantum correlated paramagnet. Interestingly, this paramagnetic state admixes a zig-zag spin mode analogous to the zig-zag order seen in other Mott-Kitaev compounds. The rapid onset of the field-induced correlated state implies the exchange interactions are delicately balanced, leading to strong frustration and a near degeneracy of different ground states.Materials with a Kitaev spin liquid ground state are sought after as models of quantum phases but candidates so far form either zig-zag or incommensurate magnetic order. Ruiz et al. find a crossover between these states in β-Li2IrO3 under weak magnetic fields, indicating strongly frustrated spin interactions.

The genetic architecture underlying rapid adaptive responses to novel environments are poorly understood. A study of great tits from nine European cities finds that urban adaptation in a widespread songbird occurred through unique and shared selective sweeps in a core-set of behaviour-linked genes.

The Greenland Ice Sheet is the largest land ice contributor to sea level rise and understanding the long-term glacier response to external forcing is key to improved projections. Here the authors show Greenland’s three largest outlet glaciers will likely exceed current worst-case scenario

Anderson localization has been previously reported in 1D and 3D but it has remained elusive in 2D environments. Here the authors report probable observation of 2D Anderson localization using ultracold atoms in a weak interaction regime.

The substrate specificity of phosphoprotein phosphatases PP1 and PP2A depends on their catalytic and regulatory subunits. Using proteomics approaches, the authors here provide insights into the sequence specificity of the catalytic subunits and their distinct contributions to PP1 and PP2A selectivity.

Multiple quantum critical behaviors exist in the heavy fermion material CeRhIn5, but their interrelation is less studied. Here, Helm et al. investigate the interrelation of two quantum critical points and other relevant orders, revealing a strongly non-mean-field-like phase diagram.

Proteome activity has a major role in cancer progression and response to drugs. Here, the authors use comprehensive proteomic and phosphoproteomic data, in conjunction with drug-sensitivity screens, to generate a community resource consisting of landscapes of pathway and kinase activity across different cell lines

Here the authors show that a murine norovirus causes self-resolving diarrhea in the absence of systemic disease in wild-type neonatal mice and show that lymphocytes affect disease in a dual manner. The data suggests that neonatal mice are a promising model for further studies.

Most chloroplast proteins are imported from the cytosol and thus transiently exposed to the cytosolic proteasome. Here the authors show that impairment of the cytosolic proteasome can elevate precursor protein abundance and photosynthetic activity suggesting that cytosolic protein turnover is a means to tune plastid function.

A controversial discussion on the occurrence of the RNA modification m1A in mRNA takes a new turn, as an antibody with a central role in modification mapping was shown to also bind mRNA cap structures.

S. cerevisiae encodes two Hsp90 isoforms, the constitutively expressed Hsc82 and stress-inducible Hsp82 that are 97% identical. Here, the authors combine a range of biophysical methods and show that they differ in their enzymatic properties, resilience to stress and client range, which suggests that they evolved to provide fine-tuned chaperone assistance under physiological and stress conditions.

Designing core/shell nanowires with desired optoelectronic properties of III-V semiconductor alloys remains a challenge. Here, the authors report an engineering strategy to surmount strain-induced difficulties in the growth achieving highly strained cores with a sizeable change in their band gap.

ATP can function as a biological hydrotrope, but its global effects on protein solubility have not yet been characterized. Here, the authors quantify the effect of ATP on the thermal stability and solubility of the cellular proteome, providing insights into protein solubility regulation by ATP.

Ubiquitination may control protein stability or function. Here the authors show that an ubiquitination enzyme, Hectd3, ubiquitinates Stat3 and Malt1 to modulate their function but not degradation in T cells, and thereby promoting the differentiation of pathogenic Th17 cells and susceptibility to a mouse model of multiple sclerosis.

Trypanosoma brucei mainly relies on translational regulation to adjust gene expression, but details are unclear. Here the authors show that, under stress conditions, tRNAThr half level increases, associates with ribosomes and polysomes, and stimulates protein synthesis by facilitating mRNA loading.