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Reduced glucose flux via the hexosamine pathway contributes to lysosomal dysfunction and protein accumulation in Parkinson patient iPSC-neurons. Enhancing the hexosamine pathway rescues lysosome activity and restores proteostasis.

Automated design tools and tailored subunits are beneficial in fine-tuning all components of a complex genetic circuit. Here the authors create E. coli and B. subtilis promoter libraries using FACS and HTS, from which an online promoter design tool has been developed using CNN.

Primary lymphomas of the central nervous system (PCNSL) are defined as diffuse large B-cell lymphomas (DLBCL) confined to the CNS. Here, the authors complete whole genome sequencing and RNA-seq to characterize 51 PCNSLs, and find common mutations in immune pathways and upregulated TERT expression and find distinct pathway differences between DLBCL and other primary CNS lymphomas.

FOXO3 is one of the few established longevity genes. Here, the authors fine-map the FOXO3-longevity association to two intronic SNPs and, using luciferase assays and EMSAs, show that these SNPs affect binding of transcription factors CTCF and SRF and associate with FOXO3 expression.

While the development of weakly coordinating anions received much attention, the progress on weakly coordinating and inert solvents almost stagnated. Here the authors report that strategic F-substitution of fluorobenzene solvents strongly increases the redox potentials of Ag⁺ and NO⁺ salts and tolerates high potentials of perfluorinated radical cations.

Here, the authors show in a cohort of people with HIV, COVID mRNA vaccination is followed by a transient boost in a particular profile of HIV-specific T-cell responses and a corresponding decrease in residual HIV RNA – suggesting productive immune engagement with infected cells.

A study reports single-cell RNA-sequencing profiles for more than 1.6 million cell nuclei from 101 whole mouse embryos including 22 mutant and 4 wild-type genotypes, from one experiment.

The European X-ray free-electron laser (EuXFEL) in Hamburg is the first XFEL with a megahertz repetition rate. Here the authors present the 2.9 Å structure of the large membrane protein complex Photosystem I from T. elongatus that was determined at the EuXFEL.

Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.

Polyunsaturated Fatty Acids (PUFA), such as omega-3 fatty acids, are recognized for their lipid lowering and anti-inflammatory properties. Here, the authors show that endogenous lipid synthesis controls the use of PUFA and thus determine the therapeutic benefit of omega-3 fatty acid supplementation.

The neural mechanisms underlying the beneficial effects of behavioural training in combination with transcranial direct current stimulation (tDCS) are not well understood. Here, the authors combine cognitive training with tDCS, showing a modulation of prefrontal white and grey matter microstructure, and increased prefrontal functional connectivity.

LaNiO₃ is a strange metal, for reasons that are not well understood. Here, Liu et al. report evidence for scattering of charge carriers by antiferromagnetic quantum fluctuations in high-purity epitaxial thin films of LaNiO₃, suggesting it is close to an antiferromagnetic quantum critical point.

Rudloff et al. examine the kinetics of CD8⁺ T cell dysfunction/exhaustion. Tumor-specific CD8⁺ T cells in the tumor environment exhibit epigenetic modifications within hours, before cell division. The findings suggest a temporal relationship between tumor antigen exposure, chromatin remodeling and dysfunction ‘imprinting’.

Optimal control of quantum many-body systems is needed to make use of quantum technologies, but is challenging due to the exponentially large dimension of the Hilbert space as a function of the number of qubits. Metz and Bukov propose a framework combining matrix product states and reinforcement learning that allows control of a larger number of interacting quantum particles than achievable with standard neural-network-based methods.

The United States experienced two of its hottest recorded summers in 1934 and 1936, amplified by drier soils associated with the Dust Bowl drought. A large regional climate model ensemble estimates present-day GHGs would cause similarly extreme, 1-in-100-year heatwaves to occur about every 40 years.

Myelofibrosis is a myeloproliferative neoplasm. Here, the authors show the clonal evolution of myelofibrosis during JAK inhibitor therapy, revealing how the treatment results in an increase in clonal complexity and a gain of RAS pathway mutations.

The mechanism by which adenosine monophosphate modulates dynein ATPase-mediated ciliary and flagellar beating remains obscure. Here the authors identify an axonemal module including cilia and flagella associated protein 45 that supports adenine nucleotide homeostasis and underlies a human ciliopathy

In the 1930s, the US was hit by a severe drought and record-breaking heatwaves in a period known as the Dust Bowl. Here, the authors present model experiments that suggest that warm North Atlantic temperatures and human devegetation played key roles in making these heatwaves particularly strong.

A range of environmental stressors are estimated for farmed and wild capture blue foods, including bivalves, seaweed, crustaceans and finfish, with the potential to inform more sustainable diets.

Mesocosm experiments in different biomes show that future ocean acidification will slow down the dissolution of biogenic silica, decreasing silicic acid availability in the surface ocean and triggering a global decline of diatoms as revealed by Earth system model simulations.

Infection with SARS-CoV-2 in rhesus macaques causes a respiratory disease that recapitulates aspects of COVID-19 in humans, establishing this species as an animal model for investigating the pathogenesis of SARS-CoV-2.

Elevational trends in biodiversity and ecosystem functions across natural and anthropogenic habitats on Mount Kilimanjaro show that the effects of land use are strongly mediated by climate.

The authors provide mechanistic insights into the crosstalk between signalling components of pattern-triggered immunity and effector-triggered immunity and their molecular linkers.

Electron–phonon coupling in a monolayer WSe₂ on a substrate is investigated by femtosecond surface X-ray scattering. Counterintuitively, the absorbed optical photon energy is dominantly coupled to the in-plane lattice vibrations within 1 ps.

A new high-throughput platform to find rare T cells that can recognize shared cancer neoantigens identifies T cell receptors specific for a conserved, immunogenic and therapeutically actionable epitope in mutant PI3Kα, one of the most common driver oncogenes

While current COVID-19 vaccines provide certain protection, more effective vaccination strategies are still desirable. Here the authors show, using mouse vaccination models, that priming with a systemic mRNA and boosting with an intranasal adenoviral vector vaccine induces comprehensive T cell and mucosal immunity.

The gut microbiome composition of the coral-feeding butterflyfish across Caribbean reefs is more variable at degraded reefs. These microbiomes have a lower abundance of Endozoicomonas and a higher diversity of anaerobic fermentative bacteria.

A typology of four perspectives on loss and damage is developed based on the study of actor perspectives, including interviews with stakeholders in research, practice, and policy. This may help with navigation of this necessarily ambiguous territory.

The current prevailing view is that body plans of sponges and other animals cannot be compared. Here, the authors identify developmental regulatory genes in the calcisponge, Sycon ciliatum, and report similar developmental gene expression between sponges and cnidarians, which suggests that their body plans are homologous.

Proton motive forces are central for life but it is not well understood how these pH gradients emerged at the beginning of life. Here the authors show that heat flow across a water-filled chamber forms and sustains stable pH gradients and support their experimental findings with simulations.

The ChAdOx1 nCoV-19 vaccine against SARS-CoV-2 induces an immune response in rhesus macaques and leads to reduced SARS-CoV-2 viral loads in respiratory tissues and an absence of pneumonia, but not to a reduction in nasal virus shedding, compared with unvaccinated animals.

Evaluation of evidence generated to test 19 proposed policy recommendations and guidance for the future.

The phloem tissue is the main transport route for sugars in plant bodies. This study reveals a nuclear protein complex consisting of SMXL5 and OBE3 to be essential for phloem development by establishing a phloem-specific chromatin conformation.

Multiregion sequencing is needed to better capture the heterogeneity of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Here, the authors analyse HCC and iCCA tumours with multiregion single-cell RNA-seq, revealing cellular dynamics and communication networks with immune cells.

Gaining access to medical data to train AI applications can present problems due to patient privacy or proprietary interests. A way forward can be privacy-preserving federated learning schemes. Kaissis, Ziller and colleagues demonstrate here their open source framework for privacy-preserving medical image analysis in a remote inference scenario.

A genome-wide association study including 22,389 cases of multiple sclerosis finds an association with disease progression at the DYSF–ZNF638 and DNM3–PIGC loci and identifies a potential of higher educational attainment in slowing disease progression.

Complex genomic alterations segregate melanoma into different molecular subsets, but for most subsets it is unclear whether they drive a distinct clinical behaviour. Here, the authors use gene-expression data from melanoma patients to search for outlier genes that correlate with survival and identify that MTSS1 is associated with metastasis.

CRISPR screens identify JNK–JUN family genes as repressors of definitive endoderm differentiation in human pluripotent stem cells. JUN co-occupies stem cell enhancers with OCT4, NANOG, SMAD2 and SMAD3 and inhibits the exit from pluripotency.

The contribution of intra-tumour heterogeneity is increasingly associated with resistance to therapy. Here, the authors use genomic analyses to study heterogeneity in colorectal cancer and perform in-depth reconstruction of heterogeneity in one sample.

ACKR3 is a critical regulator of platelet-mediated thrombosis and organ injury following ischemia/reperfusion. Platelet ACKR3 surface expression is independently associated with all-cause mortality in patients with cardiovascular diseases.

Here the authors report that inhibition of de novo fatty acid synthesis by deleting the enzyme Acetyl-CoA-Carboxylase 1 in the intestinal epithelium results in the loss of crypt structures and a specific decline in Lgr5+ intestinal epithelial stem cells.