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Aging alters DNA structure–induced genetic instability in mice

Repetitive DNA sequences can adopt alternative (i.e., non-B) DNA structures, which represent an endogenous source of genetic instability. Z-DNA, a non-B-DNA structure, has been implicated in the development of age-related genetic disorders such as cancer and Alzheimer’s disease. Previously, we found that Z-DNA is mutagenic in mammals; however, the impact of age on Z-DNA-induced genetic instability has not yet been explored. Here, we investigated the effects of aging on Z-DNA-induced genetic instability using a transgenic mutation reporter mouse model. We found that Z-DNA was more mutagenic than control B-DNA in all tissues tested. Contrary to initial expectations, Z-DNA-induced deletions decreased with age, whereas the point mutation frequencies remained unchanged. Our results suggest that while the cleavage activities on Z-DNA were similar in both age groups, the reduction of Z-DNA-induced deletion mutants in aged mice was due to attenuated DNA end-joining efficiency, which is required for the mutagenic processing of Z-DNA, and increased apoptosis. These results provide mechanistic insight into age-associated genetic instability and the aging-cancer link.

Simultaneous Pi2 pulsation detected by CSES-01, Swarm, RBSP and Arase satellites

Tanycyte-derived lactate activates astrocytic HCAR1 to modulate glutamatergic signaling and POMC neuron excitability

Astrocytes and tanycytes play essential roles in hypothalamic metabolic sensing, yet how glial–glial communication translates metabolic cues into neuronal activity remains poorly understood. We previously demonstrated that tanycytes release lactate and that this metabolite modulates the activity of arcuate pro-opiomelanocortin (POMC) neurons. Here, we identify the lactate receptor, HCAR1, as a key mediator of tanycytes-astrocyte-neuron signaling in the arcuate nucleus. We show that HCAR1 is highly expressed in hypothalamic astrocytes and present in a subset of NPY neurons. In primary hypothalamic cultures, L-lactate, the endogenous agonist of HCAR1, elicited increases in astrocytic cytosolic Ca 2+ and stimulated glutamate release; both effects were abolished by HCAR1 silencing using siRNA. In parallel, L-lactate and 3Cl-HBA increased connexin hemichannel activity, and hemichannel inhibition reduced glutamate release. Consistent with these in vitro observations, focal intracellular glucose delivery to a single tanycyte in acute hypothalamic slices triggered rapid Ca 2+ elevations in neighboring astrocytes, revealing functional glial–glial communication in situ. Importantly, activation of astrocytic HCAR1 enhanced NMDA receptor-dependent slow inward currents and excitability in POMC neurons, an effect reproduced by pharmacological HCAR1 agonists and abolished by astrocytic HCAR1 silencing. Together, these findings uncover a glial metabolic relay in which tanycyte-derived lactate activates astrocytic HCAR1, promotes glutamate release, and enhances POMC neuron excitability, providing a mechanistic link between cerebrospinal fluid-borne glucose fluctuations and hypothalamic control of feeding.

Structure-aware fusion learning and intelligent decision support based on dynamic flight parameter hypergraphs in flight test

A C-degron regulates Chk1 kinase by allowing stability of inactive Chk1 and by making it short- lived upon activation

The Arg/N-degron pathway of Saccharomyces cerevisiae is mediated by two interacting E3 ubiquitin ligases, Ubr1 and Ufd4. We show here that the mitotic checkpoint kinase Chk1 bears a C-degron that can be recognized by both Ubr1 and Ufd4. Ubr1 is an E3 that can target both N-degrons and C-degrons. Deleting 4 residues from the C terminus of full-length Chk1 1-527 abrogates the bulk of Ubr1/Ufd4 affinity for the resulting Chk1 1-523 , inhibits its polyubiquitylation and degradation, and arrests cell growth. Toxicity of the 4-residue C-terminally (Ct)-deleted Chk1 1-523 was traced to its kinase activity, since the kinase-inactive C h k 1 D 142 A 1 - 523 was nontoxic. The L506R mutation is known to activate Chk1 kinase in a way that bypasses other Chk1 activation pathways. Both kinase-active and kinase-inactive Chk1 proteins that contained the L506R mutation ( C h k 1 L 506 R 1 - 527 and C h k 1 D 142 A , L 506 R 1 - 527 ) were short-lived in vivo, in contrast to wildtype Chk1 1-527 . Furthermore, the catalytic N-terminal (Nt) domain of Chk1 physically interacted with its Ct-domain. These and other results strongly suggested the following mechanism of Chk1 regulation. Ct-residues of Chk1 1-527 are a part of its C-degron, targeted by Ubr1/Ufd4 E3s. But the Ct-domain of Chk1 1-527 (including its C-degron) can also bind to the catalytic Nt-domain. The resulting conformation of Chk1 1-527 is inactive as a kinase and relatively long-lived, since the catalytic Nt-domain sterically sequesters C-degron. An induced (e.g., through a regulatory phosphorylation) dissociation of Ct-domain from Nt-domain activates the catalytic Nt-domain and also exposes the C-degron of Chk1. Thus, activation of Chk1 kinase would make it, simultaneously, a short-lived protein.

Feasibility and utility of a tablet-based digital neurocognitive assessment following radiosurgery for brain metastases

Chemputer and chemputation—A universal chemical compound synthesis machine

Chemputation treats chemical synthesis as the execution of reaction code on programmable hardware. We show that a Chemputer, equipped with an extensible set of reagents, catalysts, and process conditions, together with a compiler that maps reaction and hardware graphs, is universal. This means it can produce any stable, isolable molecule in finite time and detectable quantity, provided real-time error correction maintains sufficient step fidelity relative to the number of steps in the synthesis. We formalize this into a Chemical Synthesis Turing Machine (CSTM), which defines chemical execution through a unified description of reagents, process variables, and catalysts. The framework introduces the Universal Chemputation Principle and a dynamic error-correction scheme that enables fault-tolerant synthesis. Linking this framework to assembly theory strengthens the definition of a molecule by demanding practical synthesizability and error correction becomes a prerequisite for universality. We demonstrate the abstraction is universal with more than 100 χDL programs executed on modular Chemputers, from single-step reactions to multistep syntheses. In each case, the number of unit operations scales linearly with synthetic depth. These results establish programmable chemical synthesis, chemputation, as a subset of general computation where χDL programs are compiled to hardware, executed with closed-loop control, and yield verifiable molecular outputs. This formalization enables shareable chemical code, interoperable hardware, and a machine-verifiable, executable foundation for a searchable and formally provable map of chemical space.

The effect of social media information on college major choices in China: a difference-in-differences analysis

Multimetric analysis uncovers time-dependent climate forcings from China’s 2.3-fold cropland reactive nitrogen emissions

China is the largest emitter of cropland gaseous reactive nitrogen (Ngr, including NH 3 , N 2 O, and NOx), which greatly affects regional air quality, climate change, and human health. Despite the substantial spatial and temporal variations in cropland Ngr emissions, their driving mechanisms and net climate change forcings (either cooling or warming) remain unclear. Using revised emission estimates and bottom–up mass flow-based approaches, we evaluated the spatiotemporal changes in and key drivers of China’s cropland Ngr emissions from 1978 to 2023. We assessed the relative contribution of China’s cropland Ngr emissions to climate change via multiple metrics (global warming and temperature potentials). China’s cropland Ngr emissions increased by approximately 2.3-fold from 1978 to 2023. The pace of this increase decelerated over time, from 0.17 Tg N·y −2 before 1996 to 0.15 Tg N·y −2 during 1997–2005 and −0.05 Tg N·y −2 after 2005. Population growth and N-intensive animal-sourced food production accounted for 31.7% and 23.2% of this historical emission change, respectively. The net climate change forcing of Ngr varies with scale. Currently, China’s cropland Ngr emissions in 2017 at the county level impart a net cooling effect ascribed to short-lived NH 3 and NOx emissions, but this forcing shifts in sign and magnitude to a warming effect over a one-hundred-year time horizon, primarily through long-lived N 2 O emissions. Our findings suggest that a combination of metrics can comprehensively and adequately capture short-, medium-, and long-term climate impacts and that achieving climate targets will conspire against Ngr mitigation efforts for environmental protection goals.

Correlation between neuropathy severity and neurofilament light chain levels in Brazilian patients with hereditary transthyretin amyloidosis

Whole-genome combinatorial gene fusions generate novel genes for advanced microbial trait development

Translational fusion of two separate genes into a compound sequence encoding a fusion protein is a key evolutionary mechanism which underpins the emergence of new protein activities, families, and architectures. In biotechnology, gene fusion is a valuable molecular evolution tool for tagging proteins of interest and for combining or altering protein activities. To broadly demonstrate and harness the gain-of-function capabilities of fusion genes in a whole-genome approach, we constructed a “Function Generator™” fusion gene library containing pairwise combinations of 5,019 protein-coding sequences in the Saccharomyces cerevisiae genome. The open reading frames (ORFs) were PCR amplified from the S288C yeast genome and cloned into a centromeric expression vector, with each ORF represented in the 5′ and the 3′ positions of the resulting gene fusions. To illustrate the ability of fusion genes in the library to confer complex phenotypes, a population of yeast library transformants was screened for resistance to four toxic heavy metal ions (Cd +2 , Co +2 , Cu +2 , and Ni +2 ). Active fusion genes were cloned, validated, and sequenced, revealing a multitude of biological functions represented in these genes, including proteins involved in transcription, translation, metal ion binding and transport, and cell cycle control, as well as unknown functions. The gain-of-function principle of gene fusions was confirmed by comparing the activity of selected fusion genes to their constituent single ORFs expressed either individually or in nonfused pairs. Function Generator™ represents a powerful way to approach phenotypic diversity in the laboratory and to bypass a key evolutionary bottleneck for accelerated strain development.

The role of arbuscular mycorrhizal symbiosis in maintaining potassium uptake in bean under drought and ABA stress

Pathogen hijacks focal adhesion signaling by a T3SS effector CteX

Infections by Gram-negative pathogens like Salmonella and Shigella rely on type III secretion system (T3SS) effectors. While the opportunistic pathogen Chromobacterium violaceum encodes a crucial T3SS (Cpi-1/-1a), its full effector repertoire remains undefined. Here, we performed a comprehensive proteomic analysis of the C.v. Cpi-1/-1a T3SS secretome. Our analysis not only confirmed known effectors but also unveiled CteX, an effector with no prior functional annotation. Structural determination revealed that CteX adopts a papain-like fold, and functional studies demonstrated that it acts as a cysteine protease that specifically cleaves the focal adhesion adapter protein Paxillinα. This proteolytic activity triggers the collapse of focal adhesions and actin cytoskeleton. CteX-mediated cytoskeletal remodeling limits excessive invasion of epithelial cells by C. violaceum , which could otherwise lead to widespread cell death and premature bacterial exposure. Further, animal infection models confirm that CteX is essential for the virulence and sustained colonization of C. violaceum . Thus, we identify CteX as a T3SS effector that orchestrates bacterial persistence through the unexpected proteolytic targeting of host focal adhesions.

Attention enhanced hybrid deep learning architecture with PCA-based feature fusion for banana leaf disease detection

A secreted citrus protease cleaves an outer membrane protein of the Huanglongbing pathogen

Plants secrete a variety of proteases as a defense response during infection by microbial pathogens. However, the relationship between their catalytic activities and antimicrobial functions remains largely unknown. Particularly, few biologically relevant substrates of these proteases have been identified. Huanglongbing (HLB) has been a major threat to the citrus industry worldwide. The HLB-associated bacterium, “ Candidatus Liberibacter asiaticus” (Las), was previously shown to deploy an inhibitor of papain-like cysteine proteases (PLCPs) to promote disease in citrus. In this study, we identified an outer membrane protein (OMP) of Las, LasOMP1, as a substrate of the citrus PLCP Cs RD21a. LasOMP1 is one of the most highly expressed genes in Las. Cs RD21a cleaves LasOMP1 and produces cleaved peptide products, which could be detected in vitro and in HLB-diseased citrus plants. We found that Cs RD21a targets the N-terminal portion of LasOMP1, potentially at an extracellular loop region. Importantly, transgenic sweet orange overexpressing Cs RD21a showed reduced Las populations and improved plant growth, highlighting that engineering this protease is a promising strategy to enhance HLB resistance in citrus. Together, our work reveals a pathogen-derived substrate of plant PLCPs and suggests bacterial OMPs may be direct targets of plant defense.

CRAFT: cold-start recommender with attention and federated training

Abstract One of the main challenges in recommender systems is the cold-start problem, in which recommendation systems struggle to recommend new or rarely visited items. The traditional methods usually comprise centralized data merging or collaborative filtering techniques, which are not easily applicable in the decentralized settings. The current federated recommendation techniques like FedMF and FedGN have limited support for cold-start personalization, particularly in situations where the metadata of the items is sparse or non-existent. To overcome these drawbacks, we propose a new federated learning-based model, CRAFT (Cold-start Recommender with Attention and Federated Training), that improves cold-start recommendations without compromising the privacy of the user. CRAFT proposes an attention mechanism to highlight salient user-item interaction patterns to enhance the inference of user preferences. Every client then trains a personalized model locally, where the updates are collectively aggregated through Federated Averaging (FedAvg) so that the collective intelligence is obtained without losing the sensitive information. CRAFT provides very personalized suggestions by adding time-varying dynamics and rich interaction histories. CRAFT can also be scaled to be deployed across distributed environments with the use of NVFlare platform. As indicated by experimental results on three real world datasets, including MovieLens 1M, Amazon Movies & TV and CiteULike, CRAFT is able to achieve nDCG 20 in cold-start scenarios up to 16.8 better than state of the art baselines, with strong privacy guarantees.

Sender–receiver subdivisions of the default mode network in perceptual and memory-guided cognition

Everyday cognition depends on the brain’s capacity to shift between sensing the external world and constructing it from memory. To achieve this, large-scale cortical systems must flexibly integrate incoming sensory signals with internally generated representations. Here, we show that this flexibility is reflected in the macroscale architecture of the default mode network (DMN). Using convergent analyses across three independent fMRI datasets spanning directional connectivity, intrinsic organization, and task-evoked responses, we identify spatially distinct DMN subregions that are preferentially engaged during perceptual decisions about faces or memory-guided decisions based on previously seen images. These subregions correspond to a microarchitectural distinction, captured via directional and intrinsic connectivity profiles: regions preferentially engaged during face perception align with receiver-like, afferent-biased zones that show strong intrinsic connectivity across the heteromodal cortex, a profile that might support information integration during perceptually guided decision-making. In contrast, memory-guided, perceptually decoupled decisions differentially engage sender-like, efferent-biased zones that show broader connectivity with perceptual-motor and attentional systems beyond the DMN. This double dissociation demonstrates a systematic association between DMN connectivity and engagement during perceptually coupled versus memory-guided cognitive processes, providing an organizational account of how DMN architecture relates to flexible human thought.

A multicentre benchmark dataset for comprehensive landmark-based fetal ultrasound biometry

Abstract Accurate fetal growth assessment from ultrasound (US) relies on precise biometry measured by manually identifying anatomical landmarks in standard planes. Manual annotation of landmarks is time-consuming, operator-dependent, and sensitive to variability across scanners and sites, limiting the reproducibility of automated approaches. There is a need for multi-source, annotated datasets to develop artificial intelligence-assisted fetal growth assessment methods. To address this bottleneck, we present an open-access, multicentre benchmark dataset of fetal US images with expert anatomical landmark annotations for clinically used fetal biometric measurements. These measurements include head biparietal and occipitofrontal diameters, abdominal transverse and anteroposterior diameters, and femoral length. The dataset contains 4,513 de-identified US images from 1,904 subjects acquired at four clinical sites using seven different US devices. We provide subject-disjoint train/test splits, evaluation code, and baseline results to enable fair and reproducible comparisons of methods. Using an automated landmark-based fetal biometry model on pre-selected standard planes, we quantify domain shift and show that training and evaluation confined to a single centre can overestimate performance relative to multicentre testing. To the best of our knowledge, this is the first publicly available multicentre, multi-device, landmark-annotated dataset that covers all primary fetal biometry measures, providing a robust benchmark for studying domain shift and multicentre generalisation and enabling more reliable AI-assisted fetal biometry across centres. All data and annotations are available on the UCL Research Data Repository . Training code and evaluation pipelines are available at https://github.com/surgical-vision/Multicentre-Fetal-Biometry.git .

Humanized extracellular vesicles for efficient RNA delivery

Engineered extracellular vesicles (EVs) are a class of nonviral delivery vectors for RNA-based vaccines and gene therapies. A specialized form of engineered EVs, known as enveloped protein nanocages (EPNs), has been developed to enhance cargo loading and delivery. When EPNs are equipped with a viral fusogen, such as vesicular stomatitis virus glycoprotein (VSV-G), they have been shown to deliver proteins or RNA efficiently into recipient cells. Comparisons across different EPN types and optimization of their different features have been difficult, as assays for their activity have not been reported for single, active units. As we were interested in optimizing EVs, we first developed a biological titration assay inspired by the methods used for infectious viral particles. With this assay, we optimized EVs using a modular platform, creating EVs composed predominantly of human-derived protein components. This system achieved efficient RNA delivery, with functional titers comparable to those of lentiviral vectors. The optimized chimeric proteins comprising the EV particles integrate domains from human epsin 1, human citramalyl-CoA lyase beta-like protein (CLYBL), and human CEP55. The constructs also include a short 21-amino-acid peptide from a nonhuman source for RNA packaging, resulting in an EV-based RNA delivery system with reduced immunogenicity compared with EPNs and retroviral virus-like particles (VLPs).

Synergistic multiscale reinforcement of sand concrete incorporating steel fibers and granulated blast-furnace slag