bluuebunny/crossref_metadata_2025 huggingface dataset:
Affective bodily responses in monkeys predict subsequent pessimism, but not vice versa
Authors: Iki Sakumi , Adachi Ikuma
Published: February 2025

Affect is a complex interplay of behaviour, physiology, cognition and subjective feelings. The James–Lange theory, which posits that affective bodily responses occur first and subsequently shape our affective experiences, has been extensively studied in humans but remains underexplored in non-human animals. This study employs a judgement bias test to explore the relationship between peripheral bodily responses, specifically self-scratching associated with negative affect, and shifts in cognitive information-processing modes (i.e. a ‘pessimistic’ judgement bias characterized by heightened anticipation of undesirable outcomes) in Japanese macaques (
Macaca fuscata
). Our findings support the hypothesis that bodily responses precede and influence changes in cognitive modes, demonstrating that self-scratching predicts subsequent pessimistic judgements, but not vice versa. This study provides comparative insights into the biological underpinnings of affect, highlighting that peripheral behaviours can shape cognitive processes in non-human primates. These results have broader implications for understanding the evolutionary continuity and adaptive significance of affective response systems across species.
Landscape management can foster pollinator richness in fragmented high-value habitats
Authors: Biegerl Carolin , Holzschuh Andrea , Tanner Benjamin , Sponsler Douglas , Krauss Jochen , Zhang Jie , Steffan-Dewenter Ingolf
Published: February 2025

Pollinator diversity is declining due to habitat loss, low habitat quality, limited habitat connectivity and intensification of agriculture in remaining high-value habitats within human-dominated landscapes, such as calcareous grasslands. Options to increase the local area of protected habitats are often limited. Therefore, we asked how local habitat quality as well as agri-environmental schemes (AES) and configuration of the surrounding landscape can contribute to the preservation of pollinator diversity. We sampled bees, butterflies and hoverflies in 40 calcareous grasslands in Germany, and assessed the effects of calcareous grassland area, quality and connectivity, agricultural configuration, and AES on species richness and abundance. While calcareous grassland area was an important predictor for bee and butterfly species richness, with strongest effects sizes for endangered species, local flower resources and nesting sites and landscape characteristics such as small field size, high proportion of organic fields and connectivity with other grasslands significantly enhanced pollinator richness with responses differing among the three studied taxa. In contrast to expectations, AES flowering fields did not benefit pollinator communities in grasslands. We conclude that improving local habitat quality in combination with targeted landscape management are effective measures to promote pollinator richness in highly fragmented protected grassland.
Utilising multi-modal data-driven network analysis to identify monotherapy and combinational therapy targets in SOX2-dependent squamous cell lung cancer
Authors: Hwang Woochang , Kottmann Daniel , Guo Wenrui , MacMahon Méabh , Correia Lucia , Harris Rebecca , McCaughan Frank , Han Namshik
Published: February 2025

Drug discovery requires a deep understanding of disease mechanisms, making the integration and analysis of diverse, multi-modal data types essential. These data types, spanning omics types, disease- associated, and biological pathway information, often originate from disparate sources and must be combined to uncover critical insights. We have developed iPANDDA (in-silico Pipeline for Agnostic Network-based Drug Discovery Analysis), a computational pipeline that integrates multi-modal data through a network-based approach to predict candidate drug target proteins for specific diseases.

We applied iPANDDA to lung squamous cell carcinoma (LUSC), a subtype of non-small cell lung cancer (NSCLC) that accounts for approximately 25% of all lung cancer cases globally. Despite advances in cancer therapeutics, targeted therapies specifically approved for LUSC remain lacking, exacerbated by the shortage of robust models for studying LUSC carcinogenesis and therapeutic responses. The SOX2 gene, amplified in about 50% of LUSC patients, plays a critical role in driving and maintaining the cancer phenotype. Using iPANDDA, we identified relevant therapeutic targets for SOX2-dependent LUSC.

Selected candidate drug targets were validated in vitro using cell-based models. We conducted target inhibition studies in both SOX2-dependent and non-SOX2-dependent cell lines, evaluating the effects of inhibition and knockout through cell viability assays.

Our findings confirmed key monotherapy and combination therapy targets for SOX2-focused models. Specifically, we validated the AKT and mTOR complexes as promising therapeutic targets for LUSC. Additionally, we identified potential pathways for developing novel combination therapies targeting SOX2-dependent LUSC. iPANDDA offers a robust approach to refining and focusing therapeutic strategies for diseases with unmet clinical needs.
Quantifying phenology in the deciduous tree and phytophagous insect system: a methodological comparison
Authors: Morley Lucy M. , Crofts Sam J. , Cole Ella F. , Sheldon Ben C.
Published: February 2025

The extent to which phenological synchrony between trophic levels may be disrupted by environmental change has been a topic of increased focus in recent years. Phenological associations between deciduous trees, phytophagous insects and their consumers (passerine birds) have become one of the model systems for understanding this process. However, most existing research reports population-level associations rather than examining the smaller spatial scales at which these trophic interactions occur. Furthermore, a variety of methods have been used to measure phenology, particularly on producers and primary consumers, with little formal comparison. To investigate how different methods of measuring producer and primary consumer phenology influence our understanding of these biological relationships at the appropriate scale, we quantified phenological metrics for individual host trees and the phytophagous insects that depend on them in a deciduous woodland during spring 2023. We sampled 170 trees from six deciduous species in Wytham Woods, UK, deriving nine metrics of phenology from five distinct field methods: multispectral drone imaging (NDVI), hemispherical canopy photography, and bud-scoring observations to track tree phenology, as well as water traps and frass traps to monitor insect herbivore phenology. We assessed the reliability of these methods within both trophic levels and across tree species. We further evaluated the extent to which tree phenology metrics best correlated with herbivore phenology, at the level of individual trees and links to variation in subsequent herbivory rates across a subsample of 72 oak (Quercus robur) trees. Our results illustrate how methodological choices can affect our ability to study the timing of trophic interactions and reveal fine-scale spatiotemporal variation in phenology across both trophic levels. We discuss the implications of these results for considering how the scale-dependence of trophic interactions may stabilise populations and shape broader-scale responses to environmental change.
SPECTRE-Plex: an automated, fast, high-resolution-enabled approach for multiplexed cyclic imaging and tissue spatial analysis
Authors: Anderson Michael D. , Plone Abigail , La Jeffrey , Wong Madison , Raghunathan Krishnan , Silvester Jocelyn A. , Thiagarajah Jay R.
Published: February 2025

Mapping the spatial organization of tissues is critical to understanding organ biology in health and disease. Developments in multiplexed antibody-based, fluorescence labelling methods have provided unique insights into tissue microenvironments. However, many current methods have a variety of limitations that reduce their practical utilization. To address this, we developed SPECTRE-Plex; an end-to-end solution based on a series of methods that significantly improve speed, automation, and resolution of cyclic multiplex immunofluorescence imaging.
Reconstructing Sordida subcomplex (Hemiptera, Reduviidae, Triatominae) phylogeny across species distribution range
Authors: Burgueño-Rodríguez Gabriela , Nattero Julieta , Ríos Néstor , Piccinali Romina Valeria , Carbajal-de-la-Fuente Ana L. , Panzera Francisco , Lopes Catarina Macedo , Lobbia Patricia A. , de Arias Antonieta Rojas , Cavallo María J. , Rodríguez Claudia S. , Lorite Pedro , Vega-Gómez María C. , Rolon Miriam , Pita Sebastián
Published: February 2025

The conformation of the Sordida subcomplex has been a topic of prolonged debate, with diverse methodological approaches employed to discern its constituent species. Up to now,Triatoma sordida,T. garciabesiandT. rosaicomprise part of this subcomplex. Distinguishing and identifying these three species pose significant challenges due to their pronounced morphological similarity, overlapping distributions, and presence of natural hybrids. This study aims to uncover the genetic diversity and geographic spread of these three species by analyzing a mitochondrialcytochrome bgene fragment and complementing it with chromosomal studies across natural populations from an extensive geographical range, including Argentina, Bolivia, Brazil, and Paraguay. Phylogenetic analyses revealed genetic distances that suggest the presence of at least six putative species, rather than the three currently recognized. The present findings underscore the potency and significance of molecular analyses from natural populations for species identification and highlight the limitations of morphology in classifying Triatominae species.
The methyl-CpG-binding protein 2 inhibits cGAS-associated signaling
Authors: Chamma Hanane , Guha Soumyabrata , Schüssler Moritz , Messaoud-Nacer Yasmine , Le Hars Pierre , Salma Mohammad , McKellar Joe , Re Joanna , Chemarin Morgane , Carrier Arnaud , Disyak Michael A. , Taffoni Clara , Charpentier Robin , Husson Zoé , Valjent Emmanuel , Andrieu-Soler Charlotte , Soler Eric , Majzoub Karim , Vila Isabelle K. , Laguette Nadine
Published: February 2025

The detection of cytosolic dsDNA is tightly regulated to avoid pathological inflammatory responses. A major pathway involved in their detection relies on the cyclic GMP-AMP synthase (cGAS) that triggers activation of the Stimulator of interferon genes (STING) which subsequently drives the expression of inflammatory genes and type I Interferons (IFNs). Here, we show that the methyl-CpG-binding protein 2 (MECP2), a major transcriptional regulator, controls dsDNA-associated inflammatory responses. We show that the presence of cytosolic dsDNA promotes MECP2 export from the nucleus to the cytosol where it interacts with dsDNA, dampening cGAS activation. Our data also indicate that MECP2 export from the nucleus partially phenocopies MECP2 deficiency, leading to the expression of inflammatory and interferon stimulated genes, enforcing an antiviral state. Finally, we also show that MECP2 displacement from the nucleus following dsDNA stimulation is sufficient to disrupt its canonical function, leading to the reactivation of otherwise repressed genes, such endogenous retroelements of the Long interspersed nuclear element-1 (LINE-1) family. Re-expression of the latter led to the accumulation of DNA species feeding cGAS-dependent signaling and can be dampened by reverse transcriptase inhibitors. We thus establish a previously unforeseen direct role of MECP2 in the regulation of the breadth and nature of dsDNA-associated inflammatory responses. Furthermore, our results suggest that targeting dsDNA-associated pathways or pharmacological inhibition of LINE-1 may bear therapeutic hopes for Rett syndrome (RTT) patients that present with MECP2 deficiency.
Reliability of self-reported catch and effort data via smartphone applications in a multi-species recreational fishery
Authors: Morro Bernat , Riera Inmaculada , Mira Antoni , Mecinas Clara , Grau Antoni Maria , Alos Josep
Published: February 2025

The spatial and temporal heterogeneity of recreational anglers and the challenges associated with monitoring their activities often complicate their effective management. Angler smartphone applications (apps) offer a promising digital tool for self-reporting fishing effort (E) and captures per unit of effort (CPUE). However, despite their growing use for data collection in recreational fisheries, the existing literature on their performance remains limited, raising concerns about potential biases in the collected data. Since 2019, self-reporting of E and CPUE has been mandatory for recreational fishing trips within the network of partially-protected Marine Protected Areas (MPAs) in the Balearic Islands (Spain). A regional-scale App (Diari de Pesca Recreativa) was developed to streamline data collection. This study aimed to evaluate the App's performance in reporting recreational fisheries data over a six-year period. Data obtained via the App (3,672 trip self-reports) were compared to data collected through a traditional method (360 on-site creel surveys). Estimates of E and CPUE were compared across datasets overall, as well as by month, fishing modality, MPA, and for key target species. Significant differences were observed for E (hours x angler x trip, p < 0.001) and CPUE (captures / E, p = 0.001) across datasets. However, when stratified by species, month, fishing modality, and MPA, most groups showed no statistically significant differences in E and CPUE estimates. Data from the App tended to overestimate E compared to creel surveys, likely due to inaccuracies in self-reported trip durations. Conversely, creel surveys appeared to underestimate E, reflecting intrinsic biases in trip duration collection. Assuming that the true values of E and CPUE lie between the estimates derived from the App and creel surveys, integrating both methods is recommended to improve the accuracy and reliability of data. The App not only generates a higher volume of trip data but also provides a user-friendly platform for self-reporting. Moreover, it digitizes data collection, enabling automation and advanced analytics for fisheries monitoring and management of recreational fisheries.
NoisyFlow: Differentially Private Optimal Transport Using Neural Networks for Secure Biomedical Data Sharing
Authors: Li Yunyang , Khandekar Nikhil , Wang Skylar , Khanna Varada , Sanker Julian , Gerstein Mark B.
Published: February 2025

Motivation

Advancing data sharing in biomedical research, particularly for sensitive genomic and clinical datasets, is crucial for improving model performance across diverse patient populations. However, stringent privacy concerns hinder collaboration and limit insights derived from multi-institutional datasets. Current approaches to privacy-preserving data sharing fail to address gaps between data distributions.

Results

We introduce NoisyFlow, a differentially private neural network-based optimal transport framework designed to enable secure and unbiased biomedical data sharing. By integrating optimal transport theory with neural networks and differential privacy mechanisms, our framework aligns data distributions across institutions while preserving individual privacy. NoisyFlow eliminates the need for direct data sharing and reduces distribution shifts caused by covariate and batch effects. Empirical evaluations demonstrate the framework’s effectiveness in handling high-dimensional single-cell genomic data and histopathology images, achieving superior privacy guarantees while maintaining high utility in downstream tasks such as disease classification.

Availability and implementation

The implementation of NoisyFlow is available athttps://github.com/liyy2/NoisyFlow.

Contact

mark@gersteinlab.org.

Supplementary information

Supplementary data are available online.
adabmDCA 2.0 – a flexible but easy-to-use package for Direct Coupling Analysis
Authors: Rosset Lorenzo , Netti Roberto , Muntoni Anna Paola , Weigt Martin , Zamponi Francesco
Published: February 2025

In this methods article, we provide a flexible but easy-to-use implementation of Direct Coupling Analysis (DCA) based on Boltzmann machine learning, together with a tutorial on how to use it. The packageadabmDCA 2.0is available in different programming languages (C++, Julia, Python) usable on different architectures (single-core and multi-core CPU, GPU) using a common front-end interface. In addition to several learning protocols for dense and sparse generative DCA models, it allows to directly address common downstream tasks like residue-residue contact prediction, mutational-effect prediction, scoring of sequence libraries and generation of artificial sequences for sequence design. It is readily applicable to protein and RNA sequence data.
Viral-mediated fluorescent labeling of hyaluronan reveals extracellular matrix dynamics in the mouse brain in vivo
Authors: Fernández-Ballester Mario , Ardaya María , Dutheil Nathalie , Largitte Leslie-Ann , Martín Abraham , Soria Federico N.
Published: February 2025

The extracellular matrix (ECM) of the brain is primarily composed of the glycan polymer hyaluronan (HA), a core scaffold that nucleates proteoglycans forming a self-assembled matrix that acts as structural framework and signaling hub. Since most of the neural matrix is composed of sugars, development of genetically encoded tags has been limited. Therefore, although several staining protocols exist for ECM in fixed tissue, there are no reliable matrix labels for live imaging. Here we report a viral-mediated fluorescent probe that binds to HA and labels the mouse brain ECM. The vector encodes the HA binding domain from neurocan fused to GFP and an externalization tag (AAV-Ncan-GFP), enabling transduced cells to secrete the fluorescent hyalectan into the extracellular space, thereby labeling HA. We demonstrate stable probe expression in organotypic brain slices, as well as in vivo in the mouse cortex, where it labels both perineuronal nets and interstitial matrix. We validate HA labeling through colocalization with HABP and sensitivity to hyaluronidase, and confirm the probe’s extracellular localization by shadow imaging. As a proof of concept, we combine AAV-Ncan-GFP with dendritic spine imagingex vivoand calcium transient imagingin vivo, providing a real-time map of local ECM alongside neural function. The probe enables time-lapse imaging of ECM dynamics in live mice, facilitating longitudinal studies across a wide range of timescales, from minutes to days. The results establish AAV-Ncan-GFP as a valuable tool for real-time observation of brain ECM and a promising resource to explore ECM dynamics and brain function in vivo.
Subjective sleep quality in healthy young adults moderates associations of sensitivity to punishment and reward with functional connectivity of regions relevant for insomnia disorder
Authors: Zareba Michal Rafal , Davydova Tatiana , Palomar-García María-Ángeles , Adrián-Ventura Jesús , Costumero Victor , Visser Maya
Published: February 2025

Chronic unhealthy sleeping behaviours are a major risk factor for the emergence of mood and anxiety disorders. Nevertheless, we are still lacking understanding why some individuals are more prone than others to affective dysregulation caused by sleep disruption. With preliminary evidence suggesting that brain activity during positive and negative emotional processing might play an important modulating role, we conducted whole-brain resting-state functional connectivity analyses in a large cohort of healthy young adults (N = 155). Using regions consistently affected in insomnia disorder as seeds, we investigated sleep quality-related neural connectivity patterns that were both insensitive and sensitive to the interactions with individual measures of reward and punishment processing, additionally assessing the links with indices of emotional health. Majority of the findings reflected interactions between sleep quality and reinforcement sensitivity, with the opposite associations reported in the good and poor sleepers. One of such connections, the coupling between precentral gyrus and posterior insula, was additionally negatively linked to trait anxiety, with the lowest connectivity values observed in poor sleepers with higher sensitivity to punishment. In turn, the only finding associated solely with sleep quality, i.e. coupling between subgenual anterior cingulate cortex and thalamus, was also related to the habitual use of emotion suppression strategies. As such, the present study provides evidence that affective functioning plays an essential role in determining the effects of poor sleep quality on brain connectivity and emotional health, providing a plausible mechanism for why certain individuals are more susceptible to sleep-related affective dysregulation than others.

Highlights

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Functional connectivity of insomnia-related brain regions is altered in poor sleepers

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Sleep quality interacts with reinforcement sensitivity for most of such effects

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Distinct sleep-related mechanisms are linked to trait anxiety and emotion suppression

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Poor sleep and high punishment sensitivity increase the risk of affect dysregulation.
Genetic diversity and conservation insights for the baobabAdansonia suarezensisin northern Madagascar: a whole genome SNP analysis
Authors: Razanamaro Onja Hariveloniaina Morilline , La Montagna Dario , Attorre Fabio , Rondoni Elisa , Buttarazzi Francesco , Andriaharimalala Tahiana , Ishikawa Naoko , Suyama Yoshihisa , Parducci Laura
Published: February 2025

Madagascar is home to seven unique baobab species in the genusAdansonia, all threatened by climate change, habitat destruction, and deforestation. Previous studies have highlighted the vulnerability of baobabs, particularlyA. suarezensis, without delving into the specific genetic structure of its populations. In this paper we examine the genetic structure, diversity, and connectivity of seven populations ofA. suarezensis, using genome-wide Single Nucleotide Polymorphism (SNP) data. The results revealed significant genetic differentiation between inland and coastal populations, with the Mahory population forming a distinct genetic cluster characterized by high heterozygosity but low polymorphism, indicative of historical bottlenecks. In contrast, northern populations showed greater admixture and gene flow but higher inbreeding coefficients in coastal regions, such as Ambilo and Cap d’Ambre, suggesting localized inbreeding depression. Additionally, historical climatic shifts and potential anthropogenic dispersal are explored as contributing factors to the current genetic patterns. This study highlights the importance of understanding genetic dynamics for conservation, emphasizing habitat restoration and targeted management strategies to preserve the evolutionary potential ofA. suarezensisand ensure its long-term survival.
Identification of Viral Variants from Functional Genomics Data
Authors: Röckl Florian , Friedel Caroline C.
Published: February 2025

The analysis of virus knockout mutants is a common approach for studying the role of individual viral genes in viral infections and is increasingly performed using functional genomics sequencing experiments, e.g. RNA-seq or ATAC-seq, of infected cells. Identifying viral variants directly in these experiments avoids additional genome sequencing and allows confirming the presence of particular mutations directly in the experiment of interest. Here, we present a pipeline to directly identify viral variants from these functional genomics data. This combines existing SNP callers with novel methods for identifying deletions, insertions, and corresponding inserted sequences. The latter address the problem that existing structural variant callers performed poorly on functional genomics data with large variations in coverage. We evaluated the pipeline on RNA-seq data for infection with wild-type Herpes simplex virus 1 (HSV-1) and null mutants of important HSV-1 proteins. Comparison of variants identified by our pipeline with the descriptions of the original publications showed that we could correctly recover the introduced mutations. Thus, our pipeline offers researchers a fast and easy way to verify the existence of variants in the viral genome without additional genome sequencing experiments.

Availability

The pipeline is implemented as a workflow for the workflow management system Watchdog and is available athttps://github.com/watchdog-wms/watchdog-wms-workflows/(Variant-CallerPipeline).
Generalizable Prediction of Alzheimer Disease Pathologies with a Scalable Annotation Tool and an High-Accuracy Model
Authors: Gopal Ramaswamy Vivek , Ahirwar Monika , Ryan Gennadi , Dugger Brittany N. , Al Dalahmah Osama , Signaevsky Maxim , Purohit Dushyant P. , Haroutunian Vahram , Finkbeiner Steven
Published: February 2025

Characterizing the cardinal neuropathologies in Alzheimer disease (AD) can be laborious, time consuming, and susceptible to intra- and inter-observer variability. The lack of high throughput unbiased approaches to reliably assess neuropathology hampers efforts to use pathology as a means to link clinical features of AD to molecular pathogenesis in the ever-growing datasets of persons with AD. To remove this roadblock, we designed an annotation tool in addition to a computational pipeline to analyze digital microscopic images of postmortem tissue from persons with AD in a fully automated and unbiased manner in only a fraction of the time taken with conventional approaches and allows neuropathological analyses and lesion quantification at multiple scales. The pipeline includes a Mask Regional-Convolutional Neural Network (Mask R-CNN) we trained to detect, classify, and segment different types of amyloid. To establish ground truth for training and validation, we utilized an existing open source platform, QuPath, and developed a tool to collect consensus annotations of neuropathology experts. The Mask R-CNN identified amyloid pathology in samples (with accuracy: 94.6%, F1: 87.7%, Dice: 81.8%) unrelated to the training dataset, indicating that it detects generalizable pathology features. Its quantitative measurements of amyloid pathology on 298 samples correlated with the severity of AD neuropathology assessed by experts and neuropathologists (CERAD ratings) and estimates of cognitive compromise (Clinical Dementia Ratings (CDR)). Our computational pipeline should enable rapid, unbiased, inexpensive, quantitative, and comprehensive neuropathological analysis of large tissue collections and integration with orthogonal clinical and multi-omic measurements.
Structural mutations set an equilibrium non-coding genome fraction
Authors: Luiselli Juliette , Banse Paul , Mazet Olivier , Lartillot Nicolas , Beslon Guillaume
Published: February 2025

Non-coding genome size evolution is poorly understood. While some fraction of non-coding DNA has arguably a regulatory function, a large part does not seem to have a detectable impact on any phenotypic trait. The abundance of non-functional DNA in genomes, observed across the Tree of Life, challenges a purely adaptationist explanation. Several non-adaptive theories have been proposed to explain its presence and identify its determinants, emphasizing either the mutational processes or the mutational hazard entailed by non-coding and non-functional DNA. However, those theories have not yet been integrated into a single framework, and the exact nature of the mutational hazard is not yet fully understood. In this work, we propose a simple mathematical model of genome size evolution. The model shows how the non-coding fraction of the genome is shaped by two factors: unavoidable biases in the neutrality of the different mutation types (adding base pairs is more likely to be neutral than removing some), and the robustness selection imposed by the mere existence of structural mutations (larger genomes are more prone to double-strand breaks that can initiate structural mutations, imposing a second-order selection on robustness). Together, these two factors ensure the existence of an equilibrium non-coding fraction. We show that this equilibrium depends solely on mutation biases and the product of population size and mutation rate.
Epithelial miR-149-5p up-regulation is associated with immune evasion in progressive bronchial premalignant lesions
Authors: Ning B , Chiu DJ , Pfefferkorn RM , Kefella Y , Kane E , Reyes-Ortiz V , Liu G , Zhang S , Liu H , Sultan L , Green E , Constant M , Spira AE , Campbell JD , Reid ME , Varelas X , Burks EJ , Lenburg ME , Mazzilli SA , Beane JE
Published: February 2025

The molecular drivers bronchial premalignant lesion progression to invasive lung squamous cell carcinoma are not well defined. Prior work profiling longitudinally collected bronchial premalignant lesion biopsies by RNA sequencing defined a proliferative subtype, enriched with bronchial dysplasia. We found that a gene co-expression module associated with interferon gamma signaling and antigen processing/presentation was down-regulated in progressive/persistent versus regressive lesions within the proliferative subtype, suggesting a functional impact of these genes on immune evasion. RNA from these same premalignant lesions was profiled by microRNA (miRNA) sequencing and a miRNA-gene network analysis identified hsa-miR-149-5p as a potential regulator of this antigen presentation gene co-expression module associated with lesion progression. hsa-miR-149-5p was found to be predominantly expressed in the epithelium and up-regulated in progressive/persistent versus regressive proliferative lesions while targets of this miRNA, the transcriptional coactivator of MHC-I gene expression,NLRC5, and the genes it regulates were down-regulated. MicroRNA in situ hybridization of hsa-miR-149-5p in tissue from adjacent fixed biopsies showed that hsa-miR-149-5p was increased in areas of bronchial dysplasia in progressive/persistent versus regressive lesions. Imaging mass cytometry showed that NLRC5 protein expression was decreased in progressive/persistent versus regressive lesions within areas of hyperplasia, metaplasia, and dysplasia. Additionally, basal cells with high versus low levels of NLRC5 were found to be in close spatial proximity to CD8 T cells, suggesting that these cells exhibit increased functional MHC-I gene expression in lesions with low hsa-miR-149-5p expression. Collectively, our data suggests a functional role for hsa-miR-149-5p in bronchial premalignant lesions and may serve as a therapeutic target for PML immunomodulation.

STATEMENT OF SIGNIFICANCE

Integrative analysis across bronchial premalignant lesions has identified and localized a potential regulator of immune evasion in progressive/persistent lesions that could be a novel therapeutic target.
Transcription start sites experience a high influx of heritable variants fuelled by early development
Authors: Guzmán Miguel Cortés , Castellano David , Colomé Clàudia Serrano , Seplyarskiy Vladimir , Weghorn Donate
Published: February 2025

Mutations drive evolution and genetic diversity, but the impact of transcription on germline mutagenesis remains poorly understood. Here, we identify a hypermutation phenomenon at transcription start sites in the human germline, spanning several hundred base pairs in both directions. We link this TSS mutational hotspot to divergent transcription, RNA polymerase II stalling, R-loops, and mitotic—but not meiotic—double-strand breaks, revealing a recombination-independent mechanism distinct from known processes. Notably, the hotspot is absent inde novomutation data. We reconcile this by showing that TSS mutations are significantly enriched with early mosaic variants often filtered out inde novomutation calls, indicating that the hotspot arises during early embryogenesis. Mutational signature analysis reinforces these findings and implicates alternative non-homologous end joining and maternal mutation clusters. Our study provides the first detailed description of a germline TSS mutation hotspot, with broad evolutionary and biomedical implications.
Dynamic Proximal Interactomics and Chemical Genetic Screening Reveal CCR4-NOT Sequestration in Stress Granules as a Mechanism for Transcript Stabilization
Authors: Tsai Yi-Cheng , Uechi Hiroyuki , Millar Sean R. , Kadijk Eileigh , Schreiber Karl J. , Minkovich Alon , Huang Jie Qi , Kasmaeifar Vesal , Zhang Zhixin , Barsacchi Rico , Möbius Claudia , Janosch Antje , Savage Jonathan C. , Röst Hannes , Hyman Anthony A. , Youn Ji-Young
Published: February 2025

Living cells adapt to stress by protecting essential resources, such as stabilizing transcripts. Stress granules, which form during stress through the coalescence of polyadenylated transcripts released from polysomes and RNA-binding proteins, are implicated in post-transcriptional regulation, although their precise roles remain contested. To address this, we generated dynamic proteomic landscapes of stress granules during assembly and disassembly under oxidative and hyperosmotic stress using multi-bait BioID profiling combined with quantitative mass spectrometry. Our analysis reveals dynamic rewiring of stress granule proximal interaction networks, identifying RNA-binding proteins involved in translation repression and mRNA decay, including the CCR4-NOT deadenylase complex, as universal molecular signatures of condensed stress granules. Using the CCR4-NOT deadenylase complex as a model, we demonstrate the function of dynamic components associated with stress granules. Complementary genome-wide chemical genetic screening identified CCR4-NOT components as regulators of stress granule formation. Reduced CCR4-NOT activity, which lengthens poly(A) tails, enhanced stress granule assembly, while shortened poly(A) tails inhibited it. Furthermore, stress-induced sequestration of the CCR4-NOT complex to stress granules coincided with known global poly(A) tail lengthening. These findings suggest that stress granule condensation promotes transcriptome stabilization by regulating CCR4-NOT localization as part of an adaptive stress response. This work underscores the power of integrating quantitative proteomics with chemical genetics to advance our understanding of biomolecular condensates in diverse biological processes.
Anti-resonance in developmental signaling regulates cell fate decisions
Authors: Rosen Samuel J , Witteveen Olivier , Baxter Naomi , Lach Ryan S , Bauer Marianne , Wilson Maxwell Z
Published: February 2025

Cells process dynamic signaling inputs to regulate fate decisions during development. While oscillations or waves in key developmental pathways, such as Wnt, have been widely observed, the principles governing how cells decode these signals remain unclear. By leveraging optogenetic control of the Wnt signaling pathway in both HEK293T cells and H9 human embryonic stem cells, we systematically map the relationship between signal frequency and downstream pathway activation. We find that cells exhibit a minimal response to Wnt at certain frequencies, a behavior we term anti-resonance. We developed both detailed biochemical and simplified hidden variable models that explain how anti-resonance emerges from the interplay between fast and slow pathway dynamics. Remarkably, we find that frequency directly influences cell fate decisions involved in human gastrulation; signals delivered at anti-resonant frequencies result in dramatically reduced mesoderm differentiation. Our work reveals a previously unknown mechanism of how cells decode dynamic signals and how anti-resonance may filter against spurious activation. These findings establish new insights into how cells decode dynamic signals with implications for tissue engineering, regenerative medicine, and cancer biology.
Photomodulation of Kv Channel Activity
Authors: Yadav Rohit , Pfeffermann Juergen , Goessweiner-Mohr Nikolaus , Glasnov Toma , Akimov Sergey A. , Pohl Peter
Published: February 2025

Voltage-gated potassium (Kv) channels, essential for shaping action potentials, are influenced not only by voltage but also by mechanical stimuli. Membrane tension has been shown to stabilize the open state of the pore, suggesting that pore dilation occurs in a thinner membrane. However, structural studies using cryo-electron microscopy indicate that membrane thinning is associated with pore closure. To clarify the role of local hydrophobic membrane thickness in channel gating, we reconstituted Kv channels fromAeropyrum pernix(KvAP) into planar bilayers containing photoswitchable lipids. Blue light exposure increased membrane thickness and increased the KvAP activity at both single channel and ensemble levels, whereas UV light reversed these effects by decreasing thickness and reducing activity. These results support a model in which the positioning of lipid phosphates in a thicker membrane drives the upward movement of interacting arginine residues in the KvAP voltage sensor and primes the channel for opening. This light-driven regulation of Kv channel activity offers new possibilities for controlling neuronal excitability.
Evolution of developmental bias explains divergent patterns of phenotypic evolution
Authors: Picao-Osorio Joao , Bouleau Charlotte , Gonzalez de la Rosa Pablo M. , Stevens Lewis , Fekonja Nina , Blaxter Mark , Braendle Christian , Félix Marie-Anne
Published: February 2025

Rates of phenotypic evolution vary across traits, and these evolutionary patterns themselves evolve. Understanding how development contributes—or biases—such patterns remains a challenge because it requires large-scale measurement of phenotypic variation resulting from random mutations across multiple species. Using the experimentally tractable system of nematode vulval development, we quantified the mutational sensitivity of six cell fates across two nematode clades. The results show that within each clade, mutational sensitivity is sufficient to explain the observed phenotypic evolution. The difference between clades can be explained by a simple spatial shift across cells of the sensitive region of a Wnt signaling dose-response curve. These findings underscore the importance of integrating the evolving genotype-phenotype map into the understanding of phenotypic change at both micro- and macroevolutionary scales.
Stem cell-specific NF-kB is required for stem cell survival and epithelial regeneration upon intestinal damage.
Authors: Joly Aurelia , Ferguson Meghan , Shin Minjeong , Foley Edan
Published: February 2025

Immune signals coordinate the repair of damaged epithelia by intestinal stem cells. However, it is unclear if immune pathways act autonomously within the stem cell to direct the damage response pathway. We consider this an important question, as stem cell dynamics are essential for formation and maintenance of the entire epithelium. We used Drosophila to determine the impact of stem cell-specific loss of NF-κB on tissue regeneration upon chemical injury. We found that loss of NF-κkB enhanced cell death, impaired enterocyte renewal and increased mortality. Mechanistically, we showed that inhibition of stem cell apoptosis is essential for NF-κB-dependent maintenance of cell viability and tissue repair. Combined, our data demonstrate that stem cell-intrinsic NF-κB activity is essential for an orderly repair of damaged intestinal epithelia.
Continuum architecture dynamics of vesicle tethering in exocytosis
Authors: Puig-Tintó Marta , Ortiz Sebastian , Meek Sasha , Coray Raffaele , Hernández Altair C. , Castellet Anna , Kramer Eric , Betancur Laura I. , Hoess Philipp , Mund Markus , Izquierdo-Serra Mercè , Oliva Baldo , de Marco Alex , Ries Jonas , Castaño-Díez Daniel , Manzo Carlo , Gallego Oriol
Published: February 2025

Essential for eukaryotic organisms, multiple copies of the exocyst complex tether each secretory vesicle to the plasma membrane (PM) in constitutive exocytosis. The exocyst higher-order structure (ExHOS) that coordinates the action of these multiple exocysts remains unexplored. We integrated particle-tracking, super-resolution microscopy and cryo-electron tomography in a model that time-resolves the continuum conformational landscape of the ExHOS and functionally annotates its different conformations. We found that 7 exocysts form flexible ring-shaped ExHOS that tether vesicles at <45 nm from the PM. The ExHOS, initially 19 nm in radius, rapidly expands while it pulls the vesicle towards the PM. Subsequently, the ExHOS stabilizes, securing the vesicle at ∼4 nm from the PM. After fusion, Sec18 mediates the ExHOS disassembly when its radius is 38 nm. By resolving the fundamental biophysical principles of tethering we bridged the gap between static isolated structures and the dynamic and multimeric nature of exocytosis.
Prime editing outperforms homology-directed repair as a tool for CRISPR-mediated variant knock-in in zebrafish
Authors: Vanhooydonck Michiel , De Neef Elyne , De Saffel Hanna , Boel Annekatrien , Willaert Andy , Callewaert Bert , Claes Kathleen BM
Published: February 2025

Zebrafish serve as a valuable model organism for studying human genetic diseases. While generating knockout lines is relatively straightforward, introducing precise disease-specific genetic variants by knock-in (KI) remains challenging. KI lines, however, enable more accurate studies of molecular and physiological consequences of genetic diseases. Their generation is often hampered by low editing efficiencies (EE) and potential off-target effects. In this study, we optimized conventional CRISPR/Cas9-mediated homology-directed repair (HDR) strategies for precise KI of genetic variants in zebrafish and compared their efficacy with prime editing (PE), a recently developed technique that is not yet commonly used. Using next-generation sequencing (NGS), we determined KI EE by HDR for six unique base-pair substitutions in three different zebrafish genes. We assessed the effect of 1) varying Cas9 amounts, 2) HDR templates with chemical modifications to improve integration efficiency, 3) different micro-injection procedures, and 4) synonymous guide-blocking variants in the protospacer sequence. Increasing Cas9 amounts augmented KI EE, with optimal injected amounts of Cas9 between 200 and 800 pg. The use of Alt-R™ HDR templates (IDT) further increased KI EE, while guide-blocking modifications did not. Injecting components directly into the cell was not superior to injections into the yolk. PE, however, increased EE up to fourfold and expanded the F0 founder pool for four targets when compared to conventional HDR editing, with fewer off-target effects. Therefore, PE is a very promising methodology for improving the creation of precise genomic edits in zebrafish, facilitating the modeling of human diseases.
Universal coherent atom-molecule oscillations in the dynamics of the unitary Bose gas near a narrow Feshbach resonance
Authors: Wang Ke , Zhang Zhendong , Nagata Shu , Wang Zhiqiang , Levin K.
Published: February 2025

Quench experiments on a unitary Bose gas around a broad Feshbach resonance have led to the discovery of universal dynamics. This universality manifests in the measured atomic momentum distributions, where, asymptotically, a quasiequilibrated metastable state is found in which both the momentum distribution and the timescales are determined by the particle density. In this Letter we present counterpart studies for the case of a very narrow Feshbach resonance of Cs133 atoms with a width of 8.3 mG. In dramatic contrast to the behavior reported earlier, a rapid quench of an atomic condensate to unitarity is observed to ultimately lead to coherent oscillations involving dynamically produced condensed and noncondensed molecules and atoms. The same characteristic frequency, determined by the Feshbach coupling, is observed in all types of particles. To understand these quench dynamics and how these different particle species are created, we develop a beyond Hartree-Fock-Bogoliubov dynamical framework including a type of cross-correlation between atoms and molecules. This leads to quantitative consistency with the measured frequency. Our results, which can be applied to the general class of bosonic superfluids associated with narrow Feshbach resonances, establish a alternate paradigm for universal dynamics dominated by quantum many-body interactions.

Published by the American Physical Society
2025
Examining generative AI user continuance intention based on the SOR model
Authors: Zhou Tao , Ma Xinjie
Published: February 2025

Purpose

The purpose of this research is to examine generative artificial intelligence (AI) user continuance intention based on the stimulus-organism-response model.

Design/methodology/approach

We adopted a mixed method of structural equation modeling and fuzzy-set qualitative comparative analysis to conduct data analysis.

Findings

The results found that generative AI content quality (perceived personalization, perceived accuracy and perceived credibility) and system quality (perceived interactivity, perceived anthropomorphism and perceived intelligence) affect sense of empowerment and satisfaction, both of which further determine continuance intention.

Originality/value

Extant research has identified the effect of flow, trust and parasocial interaction on generative AI user continuance, but it has seldom disclosed the internal decisional process of generative AI user continuance intention. This research tries to fill this gap, and the results enrich the extant research on generative AI user continuance.
Developing calling to reduce turnover intention through mentoring: a contextualized study in China
Authors: Tan Xiao , Jiang Yangyang , Zhou Abby Jingzi , Zhou Steven Shijin , Wu Daoyou
Published: February 2025

Purpose

Drawing on social information processing theory and work-as-calling theory, this study explores the impact of mentoring within the Chinese context – which encompasses the roles of both mentors and senior mentees – on the calling and turnover intention of junior mentees in the hospitality industry.

Design/methodology/approach

Survey questionnaires were administered to collect 222 valid responses from frontline hotel employees in China. Partial least squares structural equation modeling (PLS-SEM) was adopted to test the hypotheses. We further conducted several post hoc interviews to gain a deeper understanding of the relationships examined.

Findings

Chinese mentoring positively affects mentees’ perceiving and living a calling, which in turn reduces their turnover intention. Junior mentees’ liking of their senior mentees further amplifies the negative effect of living a calling on their turnover intention.

Originality/value

This study enriches the literature on calling by exploring the antecedents of perceiving a calling and the boundary conditions that enhance the effect of living a calling on turnover intention. Additionally, our study highlights the unique aspect of Chinese mentorship as resembling a family-like relationship, a characteristic shaped by the pervasive influence of Confucianism in China, which enriches the existing literature on mentorship studies.