Search

Abstract The visceral organ-brain axis, mediated by vagal sensory neurons, is essential for maintaining various physiological functions. Here, we investigate the impact of liver-projecting vagal sensory neurons on energy balance, hepatic steatosis, and anxiety-like behavior in mice under obesogenic conditions. A small subset of vagal sensory neurons innervate the liver and project centrally to the nucleus of the tractus solitarius, area postrema, and dorsal motor nucleus of the vagus, and peripherally to the periportal areas in the liver. The loss of these neurons prevents diet-induced obesity, and these outcomes are associated with increased energy expenditure. Although males and females exhibit improved glucose homeostasis following disruption of liver-projecting vagal sensory neurons, only male mice display increased insulin sensitivity. Furthermore, the loss of liver-projecting vagal sensory neurons limits the progression of hepatic steatosis. Intriguingly, mice lacking liver-innervating vagal sensory neurons also exhibit less anxiety-like behavior compared to control mice. Modulation of the liver-brain axis may aid in designing effective treatments for both psychiatric and metabolic disorders associated with obesity and MAFLD.

Abstract Genetic effects on changes in human traits over time are understudied and may have important pathophysiological impact. We propose a framework that enables data quality control, implements mixed models to evaluate trajectories of change in traits, and estimates phenotypes to identify age-varying genetic effects in GWAS. Using childhood BMI as an example trait, we included 71,336 participants from six cohorts and estimated the slope and area under the BMI curve within four time periods (infancy, early childhood, late childhood and adolescence) for each participant, in addition to the age and BMI at the adiposity peak and the adiposity rebound. GWAS of the 12 estimated phenotypes identified 28 genome-wide significant variants at 13 loci, one of which (in DAOA) has not been previously associated with childhood or adult BMI. Genetic studies of changes in human traits over time could uncover unique biological mechanisms influencing quantitative traits.

Abstract Jaundice affects almost all neonates in their first days of life and is caused by the accumulation of bilirubin. Although the core biochemistry of bilirubin metabolism is well understood, it is not clear why some neonates experience more severe jaundice and require treatment with phototherapy. Here, we present the first genome-wide association study of neonatal jaundice to date in nearly 30,000 parent-offspring trios from Norway (cases ≈ 2000). The alternate allele of a common missense variant affecting the sequence of UGT1A4 reduces the susceptibility to jaundice five-fold, which replicated in separate cohorts of neonates of African American and European ancestries. eQTL colocalization analyses indicate that the association may be driven by regulation of UGT1A1 in the intestines, but not in the liver. Our results reveal marked differences in the genetic variants involved in neonatal jaundice compared to those regulating bilirubin levels in adults, suggesting distinct genetic mechanisms for the same biological pathways.

Abstract SARS-CoV-2 clearance requires adaptive immunity but the contribution of neutralizing antibodies and T cells in different immune states is unclear. Here we ask which adaptive immune responses associate with clearance of long-term SARS-CoV-2 infection in HIV-mediated immunosuppression after suppressive antiretroviral therapy (ART) initiation. We assembled a cohort of SARS-CoV-2 infected people in South Africa (n = 994) including participants with advanced HIV disease characterized by immunosuppression due to T cell depletion. Fifty-four percent of participants with advanced HIV disease had prolonged SARS-CoV-2 infection (>1 month). In the five vaccinated participants with advanced HIV disease tested, SARS-CoV-2 clearance associates with emergence of neutralizing antibodies but not SARS-CoV-2 specific CD8 T cells, while CD4 T cell responses were not determined due to low cell numbers. Further, complete HIV suppression is not required for clearance, although it is necessary for an effective vaccine response. Persistent SARS-CoV-2 infection led to SARS-CoV-2 evolution, including virus with extensive neutralization escape in a Delta variant infected participant. The results provide evidence that neutralizing antibodies are required for SARS-CoV-2 clearance in HIV-mediated immunosuppression recovery, and that suppressive ART is necessary to curtail evolution of co-infecting pathogens to reduce individual health consequences as well as public health risk linked with generation of escape mutants.

Abstract Under climate change, model ensembles suggest that declines in phytoplankton biomass amplify into greater reductions at higher trophic levels, with serious implications for fisheries and carbon storage. However, the extent and mechanisms of this trophic amplification vary greatly among models, and validation is problematic. In situ size spectra offer a novel alternative, comparing biomass of small and larger organisms to quantify the net efficiency of energy transfer through natural food webs that are already challenged with multiple climate change stressors. Our global compilation of pelagic size spectrum slopes supports trophic amplification empirically, independently from model simulations. Thus, even a modest (16%) decline in phytoplankton this century would magnify into a 38% decline in supportable biomass of fish within the intensively-fished mid-latitude ocean. We also show that this amplification stems not from thermal controls on consumers, but mainly from temperature or nutrient controls that structure the phytoplankton baseline of the food web. The lack of evidence for direct thermal effects on size structure contrasts with most current thinking, based often on more acute stress experiments or shorter-timescale responses. Our synthesis of size spectra integrates these short-term dynamics, revealing the net efficiency of food webs acclimating and adapting to climatic stressors.

Abstract Genes act in concert with each other in specific contexts to perform their functions. Determining how these genes influence complex traits requires a mechanistic understanding of expression regulation across different conditions. It has been shown that this insight is critical for developing new therapies. Transcriptome-wide association studies have helped uncover the role of individual genes in disease-relevant mechanisms. However, modern models of the architecture of complex traits predict that gene-gene interactions play a crucial role in disease origin and progression. Here we introduce PhenoPLIER, a computational approach that maps gene-trait associations and pharmacological perturbation data into a common latent representation for a joint analysis. This representation is based on modules of genes with similar expression patterns across the same conditions. We observe that diseases are significantly associated with gene modules expressed in relevant cell types, and our approach is accurate in predicting known drug-disease pairs and inferring mechanisms of action. Furthermore, using a CRISPR screen to analyze lipid regulation, we find that functionally important players lack associations but are prioritized in trait-associated modules by PhenoPLIER. By incorporating groups of co-expressed genes, PhenoPLIER can contextualize genetic associations and reveal potential targets missed by single-gene strategies.

Understanding the genetic regulation of hypothalamic function could yield insights into disease pathogenesis, but its inaccessibility has made this challenging. Here the authors present a high-resolution chromatin atlas of a hypothalamic-like neuron model across three stages of differentiation.

Testicular germ cell tumors are highly heritable, and the authors present the largest genome association study, identifying 22 novel loci, which account for a third of those identified to date. Implicated pathways include male germ cell development and differentiation, and chromosomal segregation.

The in vivo firing patterns of ventral midbrain dopamine neurons are controlled by afferent and intrinsic activity. The authors identified biophysical membrane potential signatures associated with distinct in vivo firing patterns in whole-cell recordings of spontaneously active midbrain dopamine neurons.

Hypothalamic melanocortin neurons regulate systemic glucose homeostasis through incompletely understood pathways. Here, the authors show that a subset of pro-opiomelanocortin neurons innervate the liver via preganglionic parasympathetic cholinergic neurons in the dorsal motor nucleus of the vagus and that stimulation of this pathway elevates blood glucose levels

T cells are a major cell type involved in systemic lupus erythematosus (SLE). Here, the authors use promoter capture-C and ATAC-seq in human follicular T helper cells to identify SLE genes distant from GWAS loci (via 3D interaction) and validate the function of key regulatory elements and genes in vitro.

Associations of copy number variations (CNVs) with complex traits are challenging to study because of their low frequency. Here, the authors analyse SNP array and array comparative genomic hybridization data of 100,028 individuals and report their associations with immune-related, cardiometabolic and neuropsychiatric diseases as well as cancer.

Newly acquired plasmids are frequently lost due to fitness costs. Here, Zhang et al. show that the evolution of satellite plasmids with gene deletions can reduce fitness costs by driving down the copy number of full plasmids and thus favor maintenance of the full plasmid and its novel accessory genes.

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

Gestational duration depends on both maternal and fetal genetic influences. Here, the authors perform a fetal genome-wide association meta-analysis and find that a locus on 2q13 is associated with pregnancy duration and further show that the lead SNP rs7594852 changes the binding properties of transcriptional repressor HIC1.

GWAS have identified numerous genetic loci for bone mineral density (BMD) and fracture risk. Here, the authors map these variants to putative target genes using ATAC-seq and Capture C of human osteoblasts and confirm ING3 and EPDR1 as BMD genes in in vitro osteoblast differentiation experiments.

Apoptotic cells display surface signals such as phosphatidlyserines that are recognized by phagocytes via engulfment signal receptors. Here, the authors show how one such receptor, transthyretin-like protein 11, plays a role in initiating axon regeneration in the peripheral nervous system.

Author summary Bone mineral density and lean skeletal mass are heritable traits. Here, Medina-Gomez and colleagues perform bivariate GWAS analyses of total body lean mass and bone mass density in children, and show genetic loci with pleiotropic effects on both traits.

Spectral corruption impedes imaging of blood oxygen saturation. Here Tzoumas et al.describe light fluence in the spectral domain and introduce eigenspectra Multispectral Optoacoustic Tomography to account for wavelength-dependent light attenuation and estimate blood oxygen saturation within deep tissue.

The molecular mechanism of axon regeneration after injury is poorly understood. Here the authors show that in C. elegans, the HIF-1 transcription factor induces ectopic synthesis of serotonin in severed ‘non-serotonergic’ neurons and that serotonin activates downstream signaling pathways leading to axon regeneration.

To ensure their survival, animals must be able to respond adaptively to threats within their environment. However, the precise neural circuit mechanisms that underlie flexible defensive behaviors remain poorly understood. Using neuronal manipulations, machine learning-based behavioral detection, electron microscopy (EM) connectomics and calcium imaging in Drosophila larvae, we map second-order interneurons that are differentially involved in the competition between defensive actions in response to competing aversive cues. We find that mechanosensory stimulation inhibits escape behaviors in favor of startle behaviors by influencing the activity of escape-promoting second-order interneurons. Stronger activation of those neurons inhibits startle-like behaviors. This suggests that competition between startle and escape behaviors occurs at the level of second-order interneurons. Finally, we identify a pair of descending neurons that promote startle behaviors and could modulate the escape sequence. Taken together, these results characterize the pathways involved in startle and escape competition, which is modulated by the sensory context., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

The surface chemistry of the Fischer-Tropsch catalytic reaction over Co has still several unknows. Here, we report an in-situ X-ray photoelectron spectroscopy study of Co 0001 and Co( 10 1 ¯ 4 ), and in-situ high energy surface X-ray diffraction of Co 0001 , during the Fischer-Tropsch reaction at 0.15 bar - 1 bar and 406 K - 548 K in a H 2 /CO gas mixture. We find that these Co surfaces remain metallic under all conditions and that the coverage of chemisorbed species ranges from 0.4-1.7 monolayers depending on pressure and temperature. The adsorbates include CO on-top, C/-C x H y and various longer hydrocarbon molecules, indicating a rate-limiting direct CO dissociation pathway and that only hydrocarbon species participate in the chain growth. The accumulation of hydrocarbon species points to the termination step being rate-limiting also. Furthermore, we demonstrate that the intermediate surface species are highly dynamic, appearing and disappearing with time delays after rapid changes in the reactants' composition., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Reducing green hydrogen production cost is critical for its widespread application. Proton-exchange-membrane water electrolyzers are among the most promising technologies, and significant research has been focused on developing more active, durable, and cost-effective catalysts to replace expensive iridium in the anode. Ruthenium oxide is a leading alternative while its stability is inadequate. While considerable progress has been made in designing doped Ru oxides and composites to improve stability, the uncertainty in true failure mechanism in acidic oxygen evolution reaction inhibits their further optimization. This study reveals that proton participation capability within Ru oxides is a critical factor contributing to their instability, which can induce catalyst pulverization and the collapse of the electrode structure. By restricting proton participation in the bulk phase and stabilizing the reaction interface, we demonstrate that the stability of Ru-oxide anodes can be notably improved, even under a high current density of 4 A cm ‒2 for over 100 h. This work provides some insights into designing Ru oxide-based catalysts and anodes for practical water electrolyzer applications., Competing Interests: Competing interests: The authors declare no conflict of interest., (© 2025. The Author(s).)

Charge-carrier compensation in topological semimetals amplifies the Nernst signal and simultaneously degrades the Seebeck coefficient. In this study, we report the simultaneous achievement of both a large Nernst signal and an unsaturating magneto-Seebeck coefficient in a topological nodal-line semimetal TaAs 2 single crystal. The unique dual-high transverse and longitudinal thermopowers are attributed to multipocket synergy effects: the combination of a strong phonon-drag effect and the two overlapping highly dispersive conduction and valence bands with electron-hole compensation and high mobility, promising a large Nernst effect; the third Dirac band causes a large magneto-Seebeck effect. High transverse and longitudinal power factors of ~3100 and ~50 μW cm -1 K -2 , respectively, are achieved, surpassing those of other topological semimetals and mainstream semiconductors. Our study presents a feasible approach for optimizing the longitudinal and transverse thermopowers in topological semimetals simultaneously and demonstrates the potential of TaAs 2 for low temperature solid-state cooling., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Small registers of spin qubits in silicon can exhibit hour-long coherence times and exceeded error-correction thresholds. However, their connection to larger quantum processors is an outstanding challenge. To this end, spin qubits with optical interfaces offer key advantages: they can minimize the heat load and give access to modular quantum computing architectures that eliminate cross-talk and offer a large connectivity. Here, we implement such an efficient spin-photon interface based on erbium dopants in a nanophotonic resonator. We demonstrate optical single-shot readout of a spin in silicon whose coherence exceeds the Purcell-enhanced optical lifetime, paving the way for entangling remote spins via photon interference. As erbium dopants can emit coherent photons in the minimal-loss band of optical fibers, and tens of such qubits can be spectrally multiplexed in each resonator, the demonstrated hardware platform offers unique promise for distributed quantum information processing based on scalable, integrated silicon devices., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Hydroxyl (OH) is the atmosphere's main oxidant removing most pollutants including methane. Its short lifetime prevents large-scale direct observational quantification. Abundances inferred using anthropogenic trace gas measurements and models yield conflicting trend estimates. By contrast, radiocarbon monoxide ( 14 CO), produced naturally by cosmic rays and almost exclusively removed by OH, is a tracer with a well-understood source. Here we show that Southern-Hemisphere 14 CO measurements indicate increasing OH. New Zealand 14 CO data exhibit an annual-mean decrease of 12 ± 2% since 1997, whereas Antarctic measurements show a December-January decrease of 43 ± 24%. Both imply similar OH increases, corroborating our own and other model results suggesting that OH has been globally increasing during recent decades. Model sensitivity simulations illustrate the roles of methane, nitrogen oxides, stratospheric ozone depletion, and global warming driving these trends. They have substantial implications for the budgets of pollutants removed by OH, and especially imply larger than documented methane emission increases., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

High-velocity stars and peculiar G objects orbit the central supermassive black hole (SMBH) Sagittarius A* (Sgr A*). Together, the G objects and high-velocity stars constitute the S cluster. In contrast with theoretical predictions, no binary system near Sgr A* has been identified. Here, we report the detection of a spectroscopic binary system in the S cluster with the masses of the components of 2.80  ±  0.50 M ⊙ and 0.73  ±  0.14 M ⊙ , assuming an edge-on configuration. Based on periodic changes in the radial velocity, we find an orbital period of 372±3 days for the two components. The binary system is stable against the disruption by Sgr A* due to the semi-major axis of the secondary being 1.59±0.01 AU, which is well below its tidal disruption radius of approximately 42.4 AU. The system, known as D9, shows similarities to the G objects. We estimate an age for D9 of 2 . 7 - 0.3 + 1.9 × 1 0 6 yr that is comparable to the timescale of the SMBH-induced von Zeipel-Lidov-Kozai cycle period of about 10 6 yr, causing the system to merge in the near future. Consequently, the population of G objects may consist of pre-merger binaries and post-merger products. The detection of D9 implies that binary systems in the S cluster have the potential to reside in the vicinity of the supermassive black hole Sgr A* for approximately 10 6 years., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Iron-sulfur (FeS) protein biogenesis in eukaryotes begins with the de novo assembly of [2Fe-2S] clusters by the mitochondrial core iron-sulfur cluster assembly (ISC) complex. This complex comprises the scaffold protein ISCU2, the cysteine desulfurase subcomplex NFS1-ISD11-ACP1, the allosteric activator frataxin (FXN) and the electron donor ferredoxin-2 (FDX2). The structural interaction of FDX2 with the complex remains unclear. Here, we present cryo-EM structures of the human FDX2-bound core ISC complex showing that FDX2 and FXN compete for overlapping binding sites. FDX2 binds in either a 'distal' conformation, where its helix F interacts electrostatically with an arginine patch of NFS1, or a 'proximal' conformation, where this interaction tightens and the FDX2-specific C terminus binds to NFS1, facilitating the movement of the [2Fe-2S] cluster of FDX2 closer to the ISCU2 FeS cluster assembly site for rapid electron transfer. Structure-based mutational studies verify the contact areas of FDX2 within the core ISC complex., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Neoantigen-specific T cell receptors (neoTCRs) promise safe, personalized anti-tumor immunotherapy. However, detailed assessment of neoTCR-characteristics affecting therapeutic efficacy is mostly missing. Previously, we identified diverse neoTCRs restricted to different neoantigens in a melanoma patient. In this work, we now combine single-cell TCR-sequencing and RNA-sequencing after neoantigen-specific restimulation of peripheral blood-derived CD8 + T cells of this patient. We detect neoTCRs with specificity for the previously detected neoantigens and perform fine-characterization of neoTCR-transgenic (tg) T cells in vitro and in vivo. We describe a heterogeneous spectrum of TCR-intrinsic activation patterns in response to a shared neoepitope ranging from previously detected more highly frequent neoTCRs with moderate activation to rare ones with initially stronger activation. Experimental restimulation of adoptively transferred neoTCR-tg T cells in a xenogeneic rechallenge tumor model demonstrates superior anti-tumor responses of moderate neoTCR-tg T cells upon repeated tumor contact. These insights have significant implications for the selection of TCRs for therapeutic engineering of TCR-tg T cells., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Many enzymes assemble into homomeric protein complexes comprising multiple copies of one protein. Because structural form is usually assumed to follow function in biochemistry, these assemblies are thought to evolve because they provide some functional advantage. In many cases, however, no specific advantage is known and, in some cases, quaternary structure varies among orthologs. This has led to the proposition that self-assembly may instead vary neutrally within protein families. The extent of such variation has been difficult to ascertain because quaternary structure has until recently been difficult to measure on large scales. Here, we employ mass photometry, phylogenetics, and structural biology to interrogate the evolution of homo-oligomeric assembly across the entire phylogeny of prokaryotic citrate synthases - an enzyme with a highly conserved function. We discover a menagerie of different assembly types that come and go over the course of evolution, including cases of parallel evolution and reversions from complex to simple assemblies. Functional experiments in vitro and in vivo indicate that evolutionary transitions between different assemblies do not strongly influence enzyme catalysis. Our work suggests that enzymes can wander relatively freely through a large space of possible assembly states and demonstrates the power of characterizing structure-function relationships across entire phylogenies., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Veins have emerged as the origin of all other endothelial cell subtypes needed to expand vascular networks during developmental and pathological neoangiogenesis. Here, we uncover the role of the angioneurin Fibronectin Leucine Rich Transmembrane protein (FLRT) 2 in central nervous system (CNS) vascular development in the mouse. Early postnatal FLRT2 deletion reveals specific defects in retinal veins, impacting endothelial cell proliferation, sprouting and polarity that result in reduced tip cells at the vascular front. FLRT2 interacts with VE-cadherin and together with the endocytic adaptor protein Numb contribute to the modulation of adherens junction morphology in both retina and cerebral cortex in vivo. Utilizing expansion microscopy, we visualize the altered dynamic distribution of VE-cadherin in tissue of FLRT2 endothelial mutants. Additionally, FLRT2 in cortical vessels regulates the crosstalk between adherens and tight junctions, influencing blood-brain barrier development. Our findings position FLRT2 as a vein-specific regulator of CNS vascular development., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Acetyl-CoA is a key metabolic intermediate and the product of various natural and synthetic one-carbon (C1) assimilation pathways. While an efficient conversion of acetyl-CoA into other central metabolites, such as pyruvate, is imperative for high biomass yields, available aerobic pathways typically release previously fixed carbon in the form of CO 2 . To overcome this loss of carbon, we develop a new-to-nature pathway, the Lcm module, in this study. The Lcm module provides a direct link between acetyl-CoA and pyruvate, is shorter than any other oxygen-tolerant route and notably fixes CO 2 , instead of releasing it. The Lcm module relies on the new-to-nature activity of a coenzyme B 12 -dependent mutase for the conversion of 3-hydroxypropionyl-CoA into lactyl-CoA. We demonstrate Lcm activity of the scaffold enzyme 2-hydroxyisobutyryl-CoA mutase from Bacillus massiliosenegalensis, and further improve catalytic efficiency 10-fold by combining in vivo targeted hypermutation and adaptive evolution in an engineered Escherichia coli selection strain. Finally, in a proof-of-principle, we demonstrate the complete Lcm module in vitro. Overall, our work demonstrates a synthetic CO 2 -incorporating acetyl-CoA assimilation route that expands the metabolic solution space of central carbon metabolism, providing options for synthetic biology and metabolic engineering., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The attractive interaction in conventional BCS superconductors is provided by a bosonic mode. However, the pairing glue of most unconventional superconductors is unknown. The effect of electron-boson coupling is therefore extensively studied in these materials. A key signature is dispersion kinks that can be observed in the spectral function as abrupt changes in velocity and lifetime of quasiparticles. Here, we show the existence of two kinks in the unconventional iron-based superconductor RbFe 2 As 2 using angle-resolved photoemission spectroscopy (ARPES) and dynamical mean field theory (DMFT). In addition, we observe the formation of a Hubbard band multiplet due to the combination of Coulomb interaction and Hund's rule coupling in this multiorbital system. We demonstrate that the two dispersion kinks are a consequence of these strong many-body interactions. This interpretation is in line with a growing number of theoretical predictions for kinks in various general models of correlated materials. Our results provide a unifying link between iron-based superconductors and different classes of correlated, unconventional superconductors such as cuprates and heavy-fermion materials., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility in men. The non-synonymous KLK3 single nucleotide polymorphism (SNP), rs17632542 (c.536 T > C; Ile163Thr-substitution in PSA) is associated with reduced prostate cancer risk, however, the functional relevance is unknown. Here, we identify that the SNP variant-induced change in PSA biochemical activity mediates prostate cancer pathogenesis. The 'Thr' PSA variant leads to small subcutaneous tumours, supporting reduced prostate cancer risk. However, 'Thr' PSA also displays higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterisation of this PSA variant demonstrates markedly reduced proteolytic activity that correlates with differences in in-vivo tumour burden. The SNP is associated with increased risk for aggressive disease and prostate cancer-specific mortality in three independent cohorts, highlighting its critical function in mediating metastasis. Carriers of this SNP allele have reduced serum total PSA and a higher free/total PSA ratio that could contribute to late biopsy decisions and delay in diagnosis. Our results provide a molecular explanation for the prominent 19q13.3 KLK locus, rs17632542 SNP, association with a spectrum of prostate cancer clinical outcomes., (© 2024. The Author(s).)

Embedding of cell-surface receptors into a membrane defines their dynamics but also complicates experimental characterization of their signaling complexes. The hepatocyte growth factor receptor MET is a receptor tyrosine kinase involved in cellular processes such as proliferation, migration, and survival. It is also targeted by the pathogen Listeria monocytogenes, whose invasion protein, internalin B (InlB), binds to MET, forming a signaling dimer that triggers pathogen internalization. Here we use an integrative structural biology approach, combining molecular dynamics simulations and single-molecule Förster resonance energy transfer (smFRET) in cells, to investigate the early stages of MET activation. Our simulations show that InlB binding stabilizes MET in a conformation that promotes dimer formation. smFRET reveals that the in situ dimer structure closely resembles one of two previously published crystal structures, though with key differences. This study refines our understanding of MET activation and provides a methodological framework for studying other plasma membrane receptors., (© 2024. The Author(s).)

Synchronization of Bloch oscillations in small Josephson junctions (JJs) under microwave radiation, which leads to current quantization, has been proposed as an effect that is dual to the appearance of Shapiro steps. This current quantization was recently demonstrated in superconducting nanowires in a compact high-impedance environment. Direct observation of current quantization in JJs would confirm the synchronization of Bloch oscillations with microwaves and help with the realisation of the metrological current standard. Here, we place JJs in a high-impedance environment and demonstrate dual Shapiro steps for frequencies up to 24 GHz (I = 7.7 nA). Current quantization exists, however, only in a narrow range of JJ parameters. We carry out a systematic study to explain this by invoking the model of a JJ in the presence of thermal noise. The findings are important for fundamental physics and application in quantum metrology., (© 2024. The Author(s).)

In eukaryotes, topologically associating domains (TADs) organize the genome into functional compartments. While TAD-like structures are common in mammals and many plants, they are challenging to detect in Arabidopsis thaliana. Here, we demonstrate that Arabidopsis PDS5 proteins play a negative role in TAD-like domain formation. Through Hi-C analysis, we show that mutations in PDS5 genes lead to the widespread emergence of enhanced TAD-like domains throughout the Arabidopsis genome, excluding pericentromeric regions. These domains exhibit increased chromatin insulation and enhanced chromatin interactions, without significant changes in gene expression or histone modifications. Our results suggest that PDS5 proteins are key regulators of genome architecture, influencing 3D chromatin organization independently of transcriptional activity. This study provides insights into the unique chromatin structure of Arabidopsis and the broader mechanisms governing plant genome folding., (© 2024. The Author(s).)

H2A.Z-nucleosomes are present in both euchromatin and heterochromatin and it has proven difficult to interpret their disparate roles in the context of their stability features. Using an in situ assay of nucleosome stability and DT40 cells expressing engineered forms of the histone variant we show that native H2A.Z, but not C-terminally truncated H2A.Z (H2A.Z∆C), is released from nucleosomes of peripheral heterochromatin at unusually high salt concentrations. H2A.Z and H3K9me3 landscapes are reorganized in H2A.Z∆C-nuclei and overall sensitivity of chromatin to nucleases is increased. These tail-dependent differences are recapitulated upon treatment of HeLa nuclei with the H2A.Z-tail-peptide (C9), with MNase sensitivity being increased genome-wide. Fluorescence correlation spectroscopy revealed C9 binding to reconstituted nucleosomes. When introduced into live cells, C9 elicited chromatin reorganization, overall nucleosome destabilization and changes in gene expression. Thus, H2A.Z-nucleosomes influence global chromatin architecture in a tail-dependent manner, what can be modulated by introducing the tail-peptide into live cells., (© 2024. The Author(s).)

Dendritic cells (DCs) are crucial for initiating protective immune responses and have also been implicated in the generation and regulation of Foxp3 + regulatory T cells (Treg cells). Here, we show that in the lamina propria of the small intestine, the alternative NF-κB family member RelB is necessary for the differentiation of cryptopatch and isolated lymphoid follicle-associated DCs (CIA-DCs). Moreover, single-cell RNA sequencing reveals a RelB-dependent signature in migratory DCs in mesenteric lymph nodes favoring DC-Treg cell interaction including elevated expression and release of the chemokine CCL22 from RelB-deficient conventional DCs (cDCs). In line with the key role of CCL22 to facilitate DC-Treg cell interaction, RelB-deficient DCs have a selective advantage to interact with Treg cells in an antigen-specific manner. In addition, DC-specific RelB knockout animals show increased total Foxp3 + Treg cell numbers irrespective of inflammatory status. Consequently, DC-specific RelB knockout animals fail to mount protective Th2-dominated immune responses in the intestine after infection with Heligmosomoides polygyrus bakeri. Thus, RelB expression in cDCs acts as a rheostat to establish a tolerogenic set point that is maintained even during strong type 2 immune conditions and thereby is a key regulator of intestinal homeostasis., (© 2024. The Author(s).)

In this community effort, we compare measurements between 34 laboratories from 19 countries, utilizing mixtures of labelled authentic synthetic standards, to quantify by mass spectrometry four clinically used ceramide species in the NIST (National Institute of Standards and Technology) human blood plasma Standard Reference Material (SRM) 1950, as well as a set of candidate plasma reference materials (RM 8231). Participants either utilized a provided validated method and/or their method of choice. Mean concentration values, and intra- and inter-laboratory coefficients of variation (CV) were calculated using single-point and multi-point calibrations, respectively. These results are the most precise (intra-laboratory CVs ≤ 4.2%) and concordant (inter-laboratory CVs < 14%) community-derived absolute concentration values reported to date for four clinically used ceramides in the commonly analyzed SRM 1950. We demonstrate that calibration using authentic labelled standards dramatically reduces data variability. Furthermore, we show how the use of shared RM can correct systematic quantitative biases and help in harmonizing lipidomics. Collectively, the results from the present study provide a significant knowledge base for translation of lipidomic technologies to future clinical applications that might require the determination of reference intervals (RIs) in various human populations or might need to estimate reference change values (RCV), when analytical variability is a key factor for recall during multiple testing of individuals., (© 2024. The Author(s).)

Pythium sensu lato (s.l.) is a genus of parasitic oomycetes that poses a serious threat to agricultural production worldwide, but their severity is often neglected because little knowledge about them is available. Using an internal transcribed spacer (ITS) amplicon-based-metagenomics approach, we investigate the occurrence, abundance, and diversity of Pythium spp. s.l. in 127 corn fields of 11 European countries from the years 2019 to 2021. We also identify 73 species, with up to 20 species in a single soil sample, and the prevalent species, which show high species diversity, varying disease potential, and are widespread in most countries. Further, we show species-species co-occurrence patterns considering all detected species and link species abundance to soil parameter using the LUCAS topsoil dataset. Infection experiments with recovered isolates show that Pythium s.l. differ in disease potential, and that effective interference with plant hormone networks suppressing JA (jasmonate)-mediated defenses is an essential component of the virulence mechanism of Pythium s.l. species. This study provides a valuable dataset that enables deep insights into the structure and species diversity of Pythium s.l. communities in European corn fields and knowledge for better understanding plant-Pythium interactions, facilitating the development of an effective strategy to cope with this pathogen., (© 2024. The Author(s).)

Wildlife tagging provides critical insights into animal movement ecology, physiology, and behavior amid global ecosystem changes. However, the stress induced by capture, handling, and tagging can impact post-release locomotion and activity and, consequently, the interpretation of study results. Here, we analyze post-tagging effects on 1585 individuals of 42 terrestrial mammal species using collar-collected GPS and accelerometer data. Species-specific displacements and overall dynamic body acceleration, as a proxy for activity, were assessed over 20 days post-release to quantify disturbance intensity, recovery duration, and speed. Differences were evaluated, considering species-specific traits and the human footprint of the study region. Over 70% of the analyzed species exhibited significant behavioral changes following collaring events. Herbivores traveled farther with variable activity reactions, while omnivores and carnivores were initially less active and mobile. Recovery duration proved brief, with alterations diminishing within 4-7 tracking days for most species. Herbivores, particularly males, showed quicker displacement recovery (4 days) but slower activity recovery (7 days). Individuals in high human footprint areas displayed faster recovery, indicating adaptation to human disturbance. Our findings emphasize the necessity of extending tracking periods beyond 1 week and particular caution in remote study areas or herbivore-focused research, specifically in smaller mammals., (© 2024. The Author(s).)

Solid-state Li-ion batteries, based on Ni-rich oxide cathodes and Li-metal anodes, can theoretically reach a high specific energy of 393 Wh kg -1 and hold promise for electrochemical storage. However, Li intercalation-induced dimensional changes can lead to crystal defect formation in these cathodes, and contact mechanics problems between cathode and solid electrolyte. Understanding the interplay between cathode microstructure, operating conditions, micromechanics of battery materials, and capacity decay remains a challenge. Here, we present a microstructure-sensitive chemo-mechanical model to study the impact of grain-level chemo-mechanics on the degradation of composite cathodes. We reveal that crystalline anisotropy, state-of-charge-dependent Li diffusion rates, and lattice dimension changes drive dislocation formation in cathodes and contact loss at the cathode/electrolyte interface. These dislocations induce large lattice strain and trigger oxygen loss and structural degradation preferentially near the surface area of cathode particles. Moreover, contact loss is caused by the micromechanics resulting from the crystalline anisotropy of cathodes and the mechanical properties of solid electrolytes, not just operating conditions. These findings highlight the significance of grain-level cathode microstructures in causing cracking, formation of crystal defects, and chemo-mechanical degradation of solid-state batteries., (© 2024. The Author(s).)

The physical characterization of proteins in terms of their sizes, interactions, and assembly states is key to understanding their biological function and dysfunction. However, this has remained a difficult task because proteins are often highly polydisperse and present as multicomponent mixtures. Here, we address this challenge by introducing single-molecule microfluidic diffusional sizing (smMDS). This approach measures the hydrodynamic radius of single proteins and protein assemblies in microchannels using single-molecule fluorescence detection. smMDS allows for ultrasensitive sizing of proteins down to femtomolar concentrations and enables affinity profiling of protein interactions at the single-molecule level. We show that smMDS is effective in resolving the assembly states of protein oligomers and in characterizing the size of protein species within complex mixtures, including fibrillar protein aggregates and nanoscale condensate clusters. Overall, smMDS is a highly sensitive method for the analysis of proteins in solution, with wide-ranging applications in drug discovery, diagnostics, and nanobiotechnology., (© 2024. The Author(s).)

When porous materials are subjected to compressive loads, localized failure chains, commonly termed anticracks, can occur and cause large-scale structural failure. Similar to tensile and shear cracks, the resistance to anticrack growth is governed by fracture toughness. Yet, nothing is known about the mixed-mode fracture toughness for highly porous materials subjected to shear and compression. We present fracture mechanical field experiments tailored for weak layers in a natural snowpack. Using a mechanical model for interpretation, we calculate the fracture toughness for anticrack growth for the full range of mode interactions, from pure shear to pure collapse. The measurements show that fracture toughness values are significantly larger in shear than in collapse, and suggest a power-law interaction between the anticrack propagation modes. Our results offer insights into the fracture characteristics of anticracks in highly porous materials and provide important benchmarks for computational modeling., (© 2024. The Author(s).)

Interfacial ferroelectricity, prevalent in various parallel-stacked layered materials, allows switching of out-of-plane ferroelectric order by in-plane sliding of adjacent layers. Its resilience against doping potentially enables next-generation storage and logic devices. However, studies have been limited to indirect sensing or visualization of ferroelectricity. For transition metal dichalcogenides, there is little knowledge about the influence of ferroelectric order on their intrinsic valley and excitonic properties. Here, we report direct probing of ferroelectricity in few-layer 3R-MoS 2 using reflectance contrast spectroscopy. Contrary to a simple electrostatic perception, layer-hybridized excitons with out-of-plane electric dipole moment remain decoupled from ferroelectric ordering, while intralayer excitons with in-plane dipole orientation are sensitive to it. Ab initio calculations identify stacking-specific interlayer hybridization leading to this asymmetric response. Exploiting this sensitivity, we demonstrate optical readout and control of multi-state polarization with hysteretic switching in a field-effect device. Time-resolved Kerr ellipticity reveals direct correspondence between spin-valley dynamics and stacking order., (© 2024. The Author(s).)

Implantable devices interfacing with peripheral nerves exhibit limited longevity and resolution. Poor nerve-electrode interface quality, invasive surgical placement and development of foreign body reaction combine to limit research and clinical application of these devices. Here, we develop cuff implants with a conformable design that achieve high-quality and stable interfacing with nerves in chronic implantation scenarios. When implanted in sensorimotor nerves of the arm in awake rats for 21 days, the devices record nerve action potentials with fascicle-specific resolution and extract from these the conduction velocity and direction of propagation. The cuffs exhibit high biocompatibility, producing lower levels of fibrotic scarring than clinically equivalent PDMS silicone cuffs. In addition to recording nerve activity, the devices are able to modulate nerve activity at sub-nerve resolution to produce a wide range of paw movements. When used in a partial nerve ligation rodent model, the cuffs identify and characterise changes in nerve C fibre activity associated with the development of neuropathic pain in freely-moving animals. The developed implantable devices represent a platform enabling new forms of fine nerve signal sensing and modulation, with applications in physiology research and closed-loop therapeutics., (© 2024. The Author(s).)