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Wigger, Barovic and Brunner et al. perform a multidimensional analysis of islets from metabolically characterized patients who had undergone pancreatectomy, observing remarkable heterogeneity between samples from individuals with type 2 diabetes, thus arguing against models of linear beta-cell dedifferentiation in diabetes.

The understanding of nucleation and growth of nanostructures plays a key role in complex materials design. Here, the authors illustrate how X-ray in situ studies link transformation at the molecular- and macro- length scales during the emergence of cobalt oxide assemblies.

To refold client proteins, HSP90 chaperone undergoes large structural rearrangements. Here the authors use NMR and molecular simulation and reveal structure and dynamics of a key functionally relevant metastable state of human HSP90α N-terminal domain.

Experimental microsurgery techniques are powerful for studying embryonic development but require highly trained operators to achieve reproducible results. Here they develop a high precision robotic micromanipulation platform to systematically perturb the physical structure of the developing zebrafish embryo, revealing key insights on the mechanics of body axis morphogenesis.

Oxidized lipids are prominent bioactive agents, and yet their molecular repertoire remains largely unknown. Here, the authors apply bioinformatics and LC-MS/MS to uncover the diversity and specificity of modified lipids in human blood plasma of lean and obese individuals.

Chemotherapy-induced death of colon cancer cells causes ATP release triggering P2X4 to mediate an mTOR-dependent pro-survival program in neighbouring cancer cells, which renders them sensitive to mTOR inhibition.

Rho-family GTPase Rac1 activates the WAVE complex (WRC) to promote Arp2/3-mediated actin assembly in various processes. Here, the authors determined cryo-EM structures of WRC bound to Rac1 in different states, revealing how Rac1 binding activates WRC.

Water availability is a major control of vegetation dynamics and terrestrial carbon cycling. Here, the authors show that vegetation sensitivity to soil moisture has been increasing in the last 36 years, especially in (semi)arid areas, and that state-of-the-art land surface models fail to capture this trend.

Approximately 40 percent of people with type 1 diabetes develop kidney disease, but the risk factors are not well understood. Here, the authors identify DNA methylation signatures associated with diabetic kidney disease, of which 21 biomarkers predict the development of kidney failure.

Genome-wide data of 16 ancient human individuals from islands of the North Moluccas, Sulawesi and East Nusa Tenggara reveal diverse sources of admixture and support a scenario of multiple dispersals into Wallacea.

Continuous-variable QKD protocols are usually easier to implement than discrete-variables ones, but their security analyses are less developed. Here, the authors propose and demonstrate in the lab a CVQKD protocol that can generate composable keys secure against collective attacks.

A number of human African trypanosomiasis, or sleeping sickness, patients suffer from respiratory symptoms commonly attributed to cardiac insufficiency. Here, the authors characterise the role of pulmonary Trypanosoma brucei in respiratory infection.

The poor correlation between brain Aβ deposition and clinical symptoms in Alzheimer´s disease remains puzzling. Here, the authors show a temporal dissociation of Aβ deposition and neurodegeneration.

Basophils are associated mainly with allergy and immune responses to parasites. Mack and colleagues now show that 'antigen-specific' basophils contribute to the humoral memory response by supplying interleukins 4 and 6.

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.

Genome assemblies of four filamentous Zygnematophyceae and co-expression network analyses shed light on the evolutionary roots of the mechanism for balancing environmental responses and multicellular growth.

Fluorescent in situ hybridization is used to identify the subcellular location of mRNAs encoding core photosystem subunits in cyanobacteria. They are clustered at thylakoid surfaces, near the central cytoplasm and nucleoid, by mRNA-binding proteins.

The structure of the GABA_B receptor in an inactive state reveals, amongst other features, a latch between the two subunits that locks the transmembrane domain interface, and the presence of large phospholipids that may modulate receptor function.

Chronic obstructive pulmonary disease is a severe inflammatory lung disease characterized by obstructed airflow from the lungs. Here, Seimetz et al. show that NADPH oxidase subunit 1 (NOXO1) is responsible for peroxynitrite formation from nitric oxide and superoxide and drives the development of smoke-induced emphysema and pulmonary hypertension.

The helical bundle structure of the CC1 domain of STIM1 of the store-activated calcium channel CRAC is crucial to maintaining the channel resting state, and helix–helix interactions can be manipulated to normalize a disease-linked STIM1 mutant.

Analysis with alleles encoding pharmacologically degradable Mediator subunits shows that Mediator acts as a global coactivator that facilitates transcription globally but is acutely required for cell-type-specific gene regulatory circuits.

SARS-CoV-2-specific CD4⁺ and CD8⁺ T cell epitopes are found in both convalescent patients and virus-naive volunteers and are indicative of heterologous recognition shared with seasonal cold viruses.

Guide RNA selection plays an essential role in CRISPR screens, the Vienna Bioactivity CRISPR (VBC) scoring system provides an improved selection for sgRNAs that generate loss-of-function alleles.

Mildner and colleagues characterize two subsets (Cxcl10⁺ and Saa3⁺) of monocytes with pathogenic potential in the central nervous system of mice with experimentally induced autoimmune encephalomyelitis and show these pathogenic cells are not derived from Ly6C⁺ monocytes, but from early myeloid cell progenitors.

By employing a Doppler cancellation technique, optical frequency synthesis is achieved with stability and accuracy in the 10⁻²⁰ range within 100 s. An offset between two optical frequency combs phase-locked at 1,542 nm is obtained as 5.4 × 10⁻²¹ at 1,063 nm within 10⁵ s.

Analysis of satellite stereo imagery uncovers two decades of mass change for all of Earth’s glaciers, revealing accelerated glacier shrinkage and regionally contrasting changes consistent with decadal climate variability.

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.

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.

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

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.

Elucidating the gastroesophageal junction’s development is key to comprehending its disease susceptibility. Here, the authors mapped its development, uncovering cellular diversity and interaction dynamics using advanced spatiotemporal single-cell analysis.

Ding et al. find a mechanism coordinating fatty acid and glucose supply. Glucose-driven Golgi phosphatidylinositol 4-phosphate levels impact the assembly of E3 ligase complex CUL7–FBXW8, controlling adipose triglyceride lipase levels and lipolysis.

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.

Thieben et al report a 3D human-scale magnetic particle imaging scanner, which allows for real-time 3D, multi-contrast imaging with compelling sensitivity and spatial resolution. The use of a medical tracer with appropriate dosages facilitates potential clinical usage.

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.

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.

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.

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.

Inhibition of the Notch pathway reverses damage in a mouse model of kidney disease (pages 290–298). The findings suggest that blockade of the Notch pathway through inhibition of γ-secretase activity may be an approach to combating glomerular failure.

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 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.

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.

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.