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Nucleotide exchange factors (NEFs) trigger substrate release from molecular chaperone Hsp70. The authors found that armadillo-type NEFs (yeast Fes1, human HspBP1) competitively prevent rebinding of released substrate.

Climate warming increases evapotranspiration (ET) more in boreal peatlands than in forests. Observations show that peatland ET can exceed forest ET by up to 30%, indicating a stronger warming response in peatlands. Earth system models do not fully account for peatlands and hence may underestimate future boreal ET.

The molecular genetic landscape of leiomyosarcoma (LMS) is largely unknown. Here, the authors identify frequent DNA copy number alterations, whole-genome duplication, TP53 and RB1 inactivation, alternative telomere lengthening, and genomic imprints of defective DNA repair via homologous recombination as a potential therapeutic target in LMS patients.

PWWP2A is a chromatin-binding transcriptional regulator that mediates mitosis-progression. Here, the authors provide evidence that PWWP2A directly interacts with H2A.Z nucleosomes, DNA and H3K36me3, binds to an MTA1-specific subcomplex of the NuRD complex (M1HR) and promotes changes to histone acetylation.

NFAT nuclear translocation has been shown to be required for CD8⁺ T cell cytokine production in response to viral infection. Here the authors show NFATc1 controls the cytotoxicity and metabolic switching of activated CD8⁺ T cells required for optimal response to bacteria and tumor cells.

Nanocatalysts made up of Co₃O₄ surrounded by nitrogen-doped graphene layers are excellent activators of H₂ and O₂ for the hydrogenation and oxidation of organic compounds. They are environmentally benign, as water is the only reaction by-product.

NASA’s Cold Atom Lab has operated on the International Space Station since 2018 to study quantum gases and mature quantum technologies in Earth’s orbit. Here, Williams et al., report on a series of pathfinding experiments exploring the first quantum sensor using atom interferometry in space.

Viewing behavior is a key variable of interest but also a confound in fMRI studies. This paper presents a deep learning framework to decode gaze position from the magnetic resonance signal of the eyeballs, which enables eye tracking in fMRI data without a camera.

In patients with Crohn’s disease, CD4⁺ T cells with cytotoxic T_H1 cell-like effector functions reactive against dietary and commensal yeasts are increased in blood and inflamed tissue compared with patients with ulcerative colitis and healthy controls.

The success of targeting KRAS for cancer therapy is limited by resistance due to compensatory mechanism, making combinatorial approaches attractive. Here, the authors use a KRAS signature drug repurposing screen and identify the multityrosine kinase PKC inhibitor Midostaurin as synergistic with MEK and KRAS inhibitors in KRAS-mutated lung adenocarcinoma.

Type 2 diabetes (T2D) is characterized by hyperglycemia caused by insufficient insulin release from pancreatic islets, often in combination with insulin resistance. Here the authors present an epigenetic case-control study in human pancreatic islets revealing changes that contribute to type 2 diabetes development, e.g., epigenetic downregulation of RHOT1.

A cascaded hard X-ray self-seeding system is demonstrated at the European X-ray free-electron laser. The setup enables millijoule-level pulses in the photon energy range of 6–14 keV at the rate of ten trains per second, with each train including hundreds of pulses arriving at a megahertz repetition rate.

TMAO is known to be atherothrombotic. Here the authors show that i) kidney function is the main determinant of serum TMAO, ii) TMAO increases kidney scarring with TGF-β1 signalling and iii) anti-diabetic drugs with reno-protective properties such as GLP1R agonists reduce plasma TMAO.

The Pharma Proteomics Project generates the largest open-access plasma proteomics dataset to date, offering insights into trans protein quantitative trait loci across multiple biological domains, and highlighting genetic influences on ligand–receptor interactions and pathway perturbations across a diverse collection of cytokines and complement networks.

The α-cardiac actin M305L hypertrophic cardiomyopathy-causing mutation is located near residues that help confine tropomyosin to an inhibitory position along thin filaments. Here the authors assessed M305L actin in vivo, in vitro, and in silico to characterize emergent pathological properties and define the mechanistic basis of disease.

Caveolae are spherical nanodomains of the plasma membrane generated by assembly of caveolin and cavin proteins. Here, the authors show that fuzzy electrostatic interactions between caveolin-1 and Cavin1 proteins, combined with membrane lipid interactions, are required to generate membrane curvature and a metastable caveola coat.

Analyses of expression profiles from whole blood of 31,684 individuals identify cis-expression quantitative trait loci (eQTL) effects for 88% of genes and trans-eQTL effects for 37% of trait-associated variants.

Elucidating specific effects of protein kinase Akt isoforms remains challenging. Here, the authors establish an Akt isoform-dependent cellular model system and use it, together with X-ray crystallography and structure-based ligand design, to develop isoform-selective covalent-allosteric Akt inhibitors

Spreading depression is a prolonged depolarization in the CNS associated with several neurological diseases. Here the authors demonstrate a reciprocal relationship between spreading depression and seizures in an animal model.

This study uses calcium imaging to show that T4 and T5 neurons are divided in specific subpopulations responding to motion in four cardinal directions, and are specific to ON versus OFF edges, respectively; when either T4 or T5 neurons were genetically blocked, tethered flies walking on air-suspended beads failed to respond to the corresponding visual stimuli.

Lafont et al. uncover a checkpoint mediated by TBK1 and IKKε, which phosphorylate RIPK1 in the TNFR1-SC. TBK1 and IKKε recruitment depends on M1 ubiquitylation and NEMO to restrict TNF-induced cell death.

Path integration abilities, important for spatial navigation, vary widely across individuals and deteriorate in old age. This work shows that path integration errors in general, as well as age-related path integration deficits, are mainly caused by accumulating noise in people’s velocity estimation.

This genome-wide study of age at first sexual intercourse and first birth identifies 371 signals driven by reproductive biology, externalising behaviour and environmental effects, with later onset associated with lower incidence of some diseases.

The brown fat-derived neuregulin 4 regulates hepatic lipid homeostasis and whole-body insulin sensitivity

Systemic AL amyloidosis is a protein misfolding disease caused by the aggregation and fibrillation of immunoglobulin light chains (LCs). Here, the authors present the cryo-EM structures of λ3 LC-derived amyloid fibrils that were isolated from patient tissue and they observe structural breaks, where the two different fibril structures co-exist at different z-axial positions within the same fibril.

In this longitudinal study of an incident (new infections) and chronic (asymptomatic infections) cohort of Plasmodium falciparum infection in children in Burkina Faso, the authors show higher gametocyte production and mosquito infectivity in chronic infections.

There is a growing interest in performing time-resolved cryo-EM studies. Here, the authors present a time-resolved sample preparation method for cryo-EM called trEM, which uses a microfluidic device to initiate the biochemical reaction by rapid mixing of the components and then spraying the sample onto a cryo-EM grid to snap-freeze it in a blot-free, automated manner within several milliseconds.

Post transcriptional modification of RNAs represents an important layer of gene regulation. Here the authors describe NAIL-MS—a method for monoisotopic RNA labeling in cell culture—demonstrating its capabilities by analyzing the modification kinetics of total tRNA, 18S rRNA and tRNA^Phe as models.

Cryo-EM photosystem I structure reveals adaptation mechanisms to extreme high light in Chlorella ohadii.

Fatty liver is one of the major features of metabolic syndrome and its development is associated with deregulation of systemic lipid and glucose homeostasis. Here Heidenreich et al. show that retinol saturase is implicated in hepatic lipid metabolism by regulating the activity of the transcription factor ChREBP.

Identifying Neanderthal and Denisovan bone fragments using collagen peptide mass fingerprinting and mitochondrial DNA analysis at Denisova Cave, the authors are able to date the earliest secure Denisovan presence at the cave to c. 200 ka. The stratigraphic association with lithics and faunal remains allows the authors to explore the behavioural and environmental adaptations of these elusive hominins.

A genome assembly of the sterlet, Acipenser ruthenus, reveals a whole-genome duplication early in the evolution of the entire sturgeon lineage and provides details about the rediploidization of the genome.

Uhlmann et al. show that the preclinical phase of Alzheimer’s disease may in fact be a relatively late manifestation of a much earlier pathogenic and targetable process of seed formation and propagation.

Understanding of Late Devonian mass extinction mechanisms is poor due to imprecise stratigraphies. Here, using cyclostratigraphic techniques, the authors present a global orbitally-calibrated chronology and reveal the key role of astronomically-forced Milankovitch climate change.

Gephyrin is an adaptor molecule that binds to both GABA_A receptors and glycine receptors. Here Maric et al. present the structure between gephyrin and a peptide from GABA_Areceptor and identify key residues dictating the preference of gephyrin for glycine receptor.

Classifying crystal structures using their space group is important to understand material properties, but the process currently requires user input. Here, the authors use machine learning to automatically classify more than 100,000 simulated perfect and defective crystal structures.

By time-sharing optical forces, researchers show that it is possible to adapt the shape of a trapping potential to the shape of an elongated helical bacterium. This approach allows the bacterium to be held and stably oriented for several minutes, which will aid investigations into the nanomechanics of single wall-less bacteria reacting to external stimuli.

The barrel-shaped 20S proteasome core particle assembles via 15S intermediates through the action of Ump1 and Pba1–Pba2 chaperones. Using structural approaches, Kock et al. reveal conformational changes occurring upon formation of the nascent 20S particle leading to ejection of Pba1–Pba2.

Creeping subduction zones are unlikely to generate tsunamigenic earthquakes. Analysis of a creeping part of the Alaskan subduction zone reveals fault structures similar to those in Tohoku, suggesting it may host large earthquakes and tsunamis.

Moderate consumption of alcohol is associated with protection from some autoimmune diseases. Here the authors show that ethanol and its metabolite acetate can protect mice from collagen-induced arthritis and provide evidence that the mechanism of this effect might be via inhibition of the effector function of T follicular helper cells.

Nematodes define a new role for sirtuins in lifespan extension, in which the sirtuin product nicotinamide is converted to a substrate for aldehyde oxidase; turnover of this enzyme generates hydrogen peroxide, causing upregulation of defense mechanisms that promote longevity.

Sulfonylureas are widely used anti-diabetic drugs, which promote insulin release by blocking a pancreatic ion channel. Here the authors create a photoswitchable sulfonylurea derivative and use it to control insulin release from cultured cells and isolated pancreatic islets by illumination with blue light.

Protein kinase A (PKA) is a key mediator of cyclic AMP signalling. Here, Eccles et al. show that ARHGAP36 antagonizes PKA by acting as a kinase inhibitor and targeting the catalytic subunit for endolysosomal degradation, thus reducing sensitivity of cells to cAMP and promoting Hedgehog signalling.

Calmodulin (CaM) regulates a variety of membrane channels in response to Ca2+, but the precise mechanisms are still unclear. Now a combination of single-particle EM, molecular dynamics simulations and functional assays is used to elucidate the structure of Ca2+–CaM bound to the full-length aquaporin AQP0, revealing a cytoplasmic gate that is closed upon CaM binding to control channel permeability in an allosteric manner.

Visceral and subcutaneous fat are associated with different metabolic risk, but mediators of such depot specific effects are not very well known. Here the authors identify the transcriptional regulator, TRIP-Br2, as a regulator of endoplasmic reticulum (ER) stress-induced inflammatory responses specifically in visceral fat.

GABA receptors are implicated in neuronal postsynaptic long-term potentiation of inhibition (iLTP). Here, Petrini et al. show that iLTP depends on recruitment of the scaffold protein gephyrin at synapses, which is enhanced by CaMKII-dependent phosphorylation of a specific residue on GABA_Areceptors.

The involvement of the sirtuin family of lysine deacylases in disease, metabolism and ageing makes them promising pharmaceutical targets. Rumpf et al.present structures of human Sirt2 in complex with two highly selective drug-like inhibitors, and show that they act by rearranging the enzyme’s active site.

Understanding the heterogeneity of peritoneal macrophages is hampered by controversy over their origin and homeostasis. Here the authors show the embryonic F4/80hi population is replaced over time by self-renewing bone marrow-derived cells transitioning from F4/80lo to F4/80hi in adult mice, and that such turnover is more rapid in male mice.

HMBG1 is a protein expressed in natural killer cells and is important in immunosurveillance. In this study, the authors show that HMGB1 binds to and inhibits PKM2, resulting in a block in aerobic glycolysis and ultimately cell death.