bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of the Dorsolateral Prefrontal Cortex in Ego Dissolution and Emotional Arousal During the Psychedelic State
Authors: Coleman Clayton R. , Shinozuka Kenneth , Tromm Robert , Dipasquale Ottavia , Kaelen Mendel , Roseman Leor , Muthukumaraswamy Suresh , Nutt David J. , Barnett Lionel , Carhart-Harris Robin
Published: January 2025

Lysergic acid diethylamide (LSD) is a classic serotonergic psychedelic that induces a profoundly altered conscious state. In conjunction with psychological support, it is currently being explored as a treatment for generalized anxiety disorder and depression. The dorsolateral prefrontal cortex (DLPFC) is a brain region that is known to be involved in mood regulation and disorders; hypofunction in the left DLPFC is associated with depression. This study investigated the role of the DLPFC in the psycho-emotional effects of LSD with functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) data of healthy human participants during the acute LSD experience. In the fMRI data, we measured the correlation between changes in resting-state functional connectivity (RSFC) of the DLPFC and post-scan subjective ratings of positive mood, emotional arousal, and ego dissolution. We found significant, positive correlations between ego dissolution and functional connectivity between the left & right DLPFC, thalamus, and a higher-order visual area, the fusiform face area (FFA). Additionally, emotional arousal was significantly associated with increased connectivity between the right DLPFC, intraparietal sulcus (IPS), and the salience network (SN). A confirmational “reverse” analysis, in which the outputs of the original RSFC analysis were used as input seeds, substantiated the role of the right DLPFC and the aforementioned regions in both ego dissolution and emotional arousal. Subsequently, we measured the effects of LSD on directed functional connectivity in MEG data that was source-localized to the input and output regions of both the original and reverse analyses. The Granger causality (GC) analysis revealed that LSD increased information flow between two nodes of the ‘ego dissolution network’, the thalamus and the DLPFC, in the theta band, substantiating the hypothesis that disruptions in thalamic gating underlie the experience of ego dissolution. Overall, this multimodal study elucidates a role for the DLPFC in LSD-induced states of consciousness and sheds more light on the brain basis of ego dissolution.
A compact protein panel for organ-specific age and chronic disease prediction
Authors: Vladimirova Anastasiya , Goeminne Ludger J.E. , Tyshkovskiy Alexander , Gladyshev Vadim N.
Published: January 2025

Recent advances in plasma proteomics have led to a surge of computational models that accurately predict chronological age, mortality, and diseases from a simple blood draw. We leverage the data of ∼50,000 participants in the UK Biobank to investigate the predictive power of such models compared to individual proteins and metabolites by assessing disease risk and organ aging. We find that, with the exception of brain-related diseases, individual protein levels often match or surpass the predictive power of elaborate clocks trained on chronological age or mortality risk. Certain proteins effectively predict multiple diseases affecting specific organs. We show that in most cases, proteins predict diseases better than polygenic risk scores, and identify novel associations between human plasma protein levels and diseases, including LAMP3 and COPD, CHHR2 and liver disease, FAMC3 and kidney disease, and TMED1 and gout. We present a focused panel of 21 protein biomarkers that reveals the health state of the six organs associated with major age-related diseases. Our panel predicts common age-related diseases, including liver cirrhosis and fibrosis, dementia, kidney failure, and type II diabetes better than established blood panels and aging models. Through its vast coverage of age-related diseases, our compact panel offers a cost-effective alternative to full-scale proteomic analyses, making it a prime candidate for the non-invasive clinical detection and management of numerous age-related diseases simultaneously.
Angiogenic mechanisms governing the segregation of blood-brain barrier and fenestrated capillaries derived from a multipotent cerebrovascular niche
Authors: Lee Nathanael J. , Parab Sweta , Lam Amanda E. , Leong Jun Xiong , Matsuoka Ryota L.
Published: January 2025

Cerebrovascular endothelial cell (EC) subtypes characterized by blood-brain barrier (BBB) properties or fenestrated pores are essential components of brain-blood interfaces, supporting brain function and homeostasis. To date, the origins and developmental mechanisms underlying this heterogeneous EC network remain largely unclear. Using single-cell-resolution lineage tracing in zebrafish, we discover a multipotent vascular niche at embryonic capillary borders that generates ECs with BBB or fenestrated molecular identity. RNAscope analysis demonstrates restricted expression offlt4in sprouting ECs contributing to fenestrated choroid plexus (CP) vasculature, identifying an early molecular distinction from adjacent BBB vessels. Mechanistically,flt4null and cytoplasmic-domain-deletion mutants exhibit CP vascularization defects when combined withvegfr2zebrafish paralog deletion. Pharmacological results support this co-requirement of Flt4 and Vegfr2 signaling and suggest the PI3K and ERK pathways as downstream effectors. These findings reveal a specialized developmental origin for BBB and fenestrated EC subtypes, and establish Flt4 as a crucial guidance receptor mediating their angiogenic segregation.
Assessment of DNA methylation from a single genomic region of ELOV2 is sufficient to predict chronological age
Authors: Zhu Bowen , Li Dean , Han Guojing , Yao Xue , Gu Hongqin , Liu Tao , Liu Linghua , Dai Jie , Liu Isabella Zhaotong , Liang Yanlin , Zheng Jian , Sun Zheming , Lin He , Wang Wenyuan , Liu Nan , Yu Haidong , Shi Meifang , Shen Gaofang , Qu Lefeng
Published: January 2025

Estimation of chronological age is particularly informative in forensic contexts. Assessment of DNA methylation status allows for the prediction of age, though the accuracy and ease of manipulation may vary across different models. In this study, we started with a carefully designed discovery cohort recruiting more elderly subjects than other age categories, to diminish the effect of epigenetic drifting. We analyzed DNA methylation from a single genomic region of ELOV2, which was sufficient to construct an age-prediction model comprising 15 CpG sites. This model is further validated by an independent cohort as well as a multi-center test using trace dried bloodstains. The nature of our analytical pipeline, when combined the assessment of a single genomic locus with high-throughput sequencing, can easily be scaled up with low cost. Taken together, we propose a new age-prediction model featuring accuracy, ease of manipulation, high-throughput, and low cost. This model can be readily applied in both classic and newly emergent forensic contexts that require age estimation.
Assembly of a functional neuronal circuit in embryos of an ancestral metazoan is influenced by environmental signals including the microbiome
Authors: Noack Christopher , Jenderny Sebastian , Giez Christoph , Merza Ornina , Hofacker Lisa-Marie , Wittlieb Jörg , Repnik Urska , Bramkamp Marc , Ochs Karlheinz , Bosch Thomas C. G.
Published: January 2025

Understanding how neural populations evolve to give rise to behavior is a major goal in neuroscience. However, the complexity of the nervous system in most invertebrates and vertebrates complicates the deciphering of underlying fundamental processes. Here, we explore the self-assembly of neural circuits inHydra, an organism with a simple nervous system but no centralized information processing, to improve the understanding of nervous system evolution. The N4 neuronal circuit in embryos develops through activity-driven self-assembly, where neurons in distinct regions increase connectivity and synchronization. Gap junctions and vesicle-mediated communication between neuronal and non-neuronal cells drive rapid assembly, with the embryo’s prospective oral region exhibiting the highest neuronal density. An artificial electrical circuit-based model demonstrates dynamic increases in synchronization over time, along with predictions for selective dynamic adaptions of connections. Environmental factors, like temperature and an absent microbiome, modify neural architecture, suggesting the existence of a certain plasticity in neural development. We propose that these fundamental features originated in the last common bilaterian ancestor, supporting the hypothesis that the basic architecture of the nervous system is universal.
Two divergent haploid nuclei shaped the landscape of population diversity in wheat stripe rust
Authors: Wang Yibo , Yin Mou , He Fei
Published: January 2025

Heterozygosity is a measure of allelic diversity within individuals.Puccinia striiformisf. sp.tritici(Pst) is a highly heterozygous dikaryotic crop pathogen. Its source of heterozygosity variation and the contribution to adaptability are still unknown. By analyzing resequencing data of 266 worldwidePstisolates, we found thatPstmay have undergone an important historical hybridization event, introducing substantial diversity and leading to the divergence of its haploid genomes into two distinct haplotypes. Strains with both haplotypes exhibit higher individual allele diversity and wider geographical distribution. Between the two haploid genomes, 16% of the genome had diverged, scattered as mosaic blocks within the genome. These regions are enriched with genes displaying critical roles during infection of the plant host, and exhibit higher expression levels. In these regions, 8.0 Mb shows recombination fingerprints associated with virulence, while 4.9 Mb displays linkage across the entire genome. We demonstrated that sexual recombination inPstis extensive and significant.Pstcan gain genetic diversity and adaptability due to intra- and inter-species hybridization. Our study resolved the debate over the sources of individual allele diversity inPstand expands the understanding of pathogen virulence evolution. These findings also suggest that interrupting the sexual reproduction of pathogens can be an effective strategy for controlling wheat stripe rust.
Genetic silencing of KCa3.1 inhibits atherosclerosis in ApoE null mice
Authors: Alam P. , Tharp D.L. , Bowles H.J. , Grisanti L. , Bui H. , Bender S.B. , Bowles D.K.
Published: January 2025

Increased expression of KCa3.1 has been found in vascular smooth muscle (SMC), macrophages, and T cells in atherosclerotic lesions from humans and mice. Proliferating SMC cells increase the expression of KCa3.1, such that it becomes a dominant K+channel and contributes to SMC cell migration. The efficacy of pharmacological inhibition of KCa3.1 in limiting atherosclerosis progression has been demonstrated in mice and pigs, however direct, loss-of-function, i.e. gene silencing, studies are absent. To investigate the role of KCa3.1, we used CRISPR/Cas9 to generate KCa3.1-/-Apoe-/-(DKO) mice and assessed lesion development in the brachiocephalic artery (BCA) of DKO versus Apoe-/-mice on a Western diet for 3 months. Notably, the loss of KCa3.1 did not affect serum total cholesterol or body weight. In BCAs of DKO mice, lesion size (0.036 mm² vs. 0.118 mm², p<0.05) and relative stenosis (13.9% vs. 43.0%, p<0.05) were reduced by 70% compared to Apoe-/-mice, with no effect on medial or lumen area. Additionally, DKO mice exhibited a significant reduction in macrophage content within atherosclerotic plaques compared to Apoe-/-mice, independent of sex.In vitromigration assays further showed a significant reduction in migration of bone marrow-derived macrophages (BMDMs) from DKO mice compared to those from Apoe-/-mice. Furthermore,in vitroexperiments using rat aortic smooth muscle cells (RAOSMCs) revealed significant inhibition of PDGF-BB-induced MCP1/Ccl21 expression upon KCa3.1 inhibition, while activation of KCa3.1 further enhanced MCP1/Ccl21 expression. Bothin vivoandin vitroanalyses showed that silencing KCa3.1 and sex had no significant effect on the collagen content of plaque. RNAseq analysis of BCA samples from DKO and Apoe-/-mice revealed PPAR-dependent signaling as a potential key mediator of the reduction in atherosclerosis due to KCa3.1 silencing. Overall, this study provides the first genetic evidence that KCa3.1 is a critical regulator of atherosclerotic lesion development and composition and provides novel mechanistic insight into the link between KCa3.1 and atherosclerosis.
Therx3gene contributes to the evolution of eye loss in the cavefishAstyanax mexicanus
Authors: Shennard Devin , Sifuentes-Romero Itzel , Ambosie Rianna , Abdelaziz Jennah , Duboue Erik R. , Kowalko Johanna E.
Published: January 2025

Uncovering mechanisms by which sensory systems evolve is critical for understanding how organisms adapt to a novel environment.Astyanax mexicanusis a species of fish with populations of surface fish that inhabit rivers and streams and cavefish that have adapted to life within caves. Cavefish have evolved sensory system changes relative to their surface fish counterparts, providing an opportunity to investigate mechanisms underlying sensory system evolution. Here, we report the role of the generetinal homeobox 3(rx3) in cavefish eye evolution. We generated surface fish with putative loss-of-function mutations in therx3gene using CRISPR-Cas9 to determine the role of this gene in eye development in this species. Theserx3mutant surface fish fail to develop eyes, demonstrating thatrx3is required for surface fish eye development. Further,rx3mutant surface fish exhibit altered behaviors relative to wild-type surface fish, suggesting that the loss of eyes impacts sensory-dependent behaviors. Finally, eye development is altered in cave-surface hybrid fish that inherit the mutant allele ofrx3from surface fish relative to siblings that inherit a wild-type surface fishrx3allele, suggesting that cis-regulatory variation at therx3locus contributes to eye size evolution in cavefish. Together, these findings demonstrate that, as in other species,rx3is required for eye development inA. mexicanus. Moreover, they suggest that variation at therx3locus plays a role in the evolved reduction of eye size in cavefish, shedding light on the genetic mechanisms underlying sensory system evolution in response to extreme environmental changes.
Predicted Effect of Circadian Regulation of Renal Transporters in a Hypertensive Rat
Authors: Zheng Kaixin , Layton Anita T.
Published: January 2025

The kidney regulates extracellular fluid and electrolyte homeostasis. Its function is modulated by the renin-angiotensin-aldosterone system (RAAS). Overactivation of the RAAS, such as in chronic Ang II infusion, promotes vasoconstriction, anti-natriuresis, and hypertension. Kidney function is also modulated by circadian clocks. Indeed, glomerular filtration rate, filtered electrolyte loads, urine volume, and urinary excretion all exhibit notable diurnal rhythms, which reflect, in part, the regulation of renal transporter proteins by circadian clock genes. Key renal transporters that are regulated by clock gene proteins include sodium-hydrogen exchanger 3 (NHE3), sodium-glucose cotransporter 1 (SGLT1), Na+-K+-2Cl−cotransporter (NKCC2), Na+-Cl−cotransporter (NCC), and epithelial sodium channel (ENaC), which are targeted by diuretics used to treat hypertension. The objective of the present study was to assess the effect of administration time on the natriuretic and diuretic effects of loop, thiazide, and K+-sparing diuretics, which are common treatments for hypertension, and how those effects differ between a normotensive and hypertensive kidney. Loop diuretics inhibit NKCC2 on the apical membrane of the thick ascending limb; notably, In Ang II-induced hypertension, NKCC2 is differentially regulated along the medullary versus cortical thick ascending limb. Thiazide diuretics inhibit NCC on the distal convoluted tubule, and K+-sparing diuretics inhibit ENaC on the connecting tubule and collecting duct. We simulated Na+transporter inhibition using computational models of kidney function at different times of day. The simulation results predicted qualitatively similar diurnal oscillations in segmental transport in the normotensive and hypertensive kidneys, and highlighted significant time-of-day differences in the natriuresis, diuresis, and kaliuresis responses.

NEW & NOTEWORTHY

Chronic infusion of angiotensin II promotes vasoconstriction, salt retention, and hypertension. Blood pressure and kidney function exhibit circadian rhythms. Given the diurnal variations in the expression levels of key renal electrolyte transporters, how do the natriuretic and diuretic effects of diuretics, a common treatment for hypertension that targets renal transporters, vary during the day? To answer this question, we simulated Na+transporter inhibition using computational models of kidney function at different times of day.
Specificity, length, and luck: How genes are prioritized by rare and common variant association studies
Authors: Spence Jeffrey P. , Mostafavi Hakhamanesh , Ota Mineto , Milind Nikhil , Gjorgjieva Tamara , Smith Courtney J. , Simons Yuval B. , Sella Guy , Pritchard Jonathan K.
Published: January 2025

Standard genome-wide association studies (GWAS) and rare variant burden tests are essential tools for identifying trait-relevant genes. Although these methods are conceptually similar, we show by analyzing association studies of 209 quantitative traits in the UK Biobank that they systematically prioritize different genes. This raises the question of how genes should ideally be prioritized. We propose two prioritization criteria: 1) trait importance — how much a gene quantitatively affects a trait; and 2) trait specificity — a gene’s importance for the trait under study relative to its importance across all traits. We find that GWAS prioritize genes near trait-specificvariants, while burden tests prioritize trait-specificgenes. Because non-coding variants can be context specific, GWAS can prioritize highly pleiotropic genes, while burden tests generally cannot. Both study designs are also affected by distinct trait-irrelevant factors, complicating their interpretation. Our results illustrate that burden tests and GWAS reveal different aspects of trait biology and suggest ways to improve their interpretation and usage.
Investigating saccade-onset locked EEG signatures of face perception during free-viewing in a naturalistic virtual environment
Authors: Nolte Debora , Schmidt Vincent , Grasso-Cladera Aitana , König Peter
Published: January 2025

Current research strives to investigate cognitive processes under natural conditions. Virtual reality and EEG are promising techniques combining naturalistic settings with close experimental control. However, many questions and technical challenges remain, e.g., are fixation or saccade onsets a suitable replacement as key events in continuous gaze trajectories (Amme et al., 2024), and can VR effectively capture differences across experimental conditions (Rossion & Jacques, 2008)? To address both questions, we investigate the N170 face effect in a free-viewing immersive VR study that contained houses, various background stimuli, and, notably, static and moving pedestrians to study face perception under naturalistic conditions. Our results show that aligning trials to saccade-onset leads to more well-defined ERPs, especially for the P100 component, and support that saccade-onset ERPs are the better-suited analysis method than fixation-onset ERPs for this type of experiment. Further, we observe an evolution of condition-based differences, i.e., face vs. background fixations, compatible with previous reports but extending in a large temporal window and including all electrode sites at different points in time. In summary, experiments combining VR, EEG, and eye-tracking provide further insights into the processing of faces and the relevance of saccadic onsets as event triggers under natural conditions.

Significance Statement

With the effort of investigating and understanding cognitive processes under naturalistic conditions, combining virtual reality and EEG can be fruitful to implement free-viewing studies. The current work combines these technologies to explore key challenges in the context of face perception in an immersive virtual environment. Our results show that saccade-onset ERPs yield more precise measurements when analyzing continuous eye-tracking data than fixation onsets. Furthermore, when processing face compared to background stimuli, distinct temporal patterns encompassing all electrode sites can be observed, offering new insights into face perception. Overall, this work highlights the potential of integrating VR and EEG to advance our understanding of cognitive processes in naturalistic settings.
Magellanic penguins balance navigation with foraging opportunities in complex current regimes
Authors: Gunner Richard M. , Quintana Flavio , Tonini Mariano H. , Holton Mark D. , Yoda Ken , Crofoot Margaret C. , Wilson Rory P.
Published: January 2025

Animals navigating in fluid environments often face lateral forces from wind or water currents that challenge travel efficiency and route accuracy. We investigated how 27 Magellanic penguins (Spheniscus magellanicus) adapt their navigation strategies to return to their colony amid regional tidal ocean currents. Using GPS-enhanced dead-reckoning loggers and high-resolution ocean current data, we reconstructed penguin travel vectors during foraging trips to assess their responses to variable currents during their colony-bound movements. By integrating estimates of energy costs and prey pursuits, we found that birds balanced direct navigation with current-driven drift: in calm currents, they maintained precise line-of-sight headings to their colony. In stronger currents, they aligned their return with lateral flows, which increased travel distance, but at minimal energy costs, and provided them with increased foraging opportunities. Since the lateral tidal currents always reversed direction over the course of return paths, the penguins’ return paths were consistently S-shaped but still resulted in the birds returning efficiently to their colonies. These findings suggest that Magellanic penguins can sense current drift and use it to optimize energy expenditure by maintaining overall directional accuracy while capitalizing on foraging opportunities.
Cannabinoid agonist WIN55,212-2 prevents scopolamine-induced impairment of spatial memory
Authors: Moreno-Rodríguez Marta , Bengoetxea de Tena Iker , Martínez-Gardeazabal Jonatan , Pereira-Castelo Gorka , Llorente-Ovejero Alberto , Manuel Iván , Rodríguez-Puertas Rafael
Published: January 2025

The endocannabinoid system is involved in diverse processes, like learning and memory, governed by cholinergic neurotransmission. Recent research demonstrates that in a model of dementia derived from basal forebrain cholinergic degeneration, WIN55,212-2 improves cognition through increased cortical choline levels. However, the effect of cannabinoids on cholinergic deficits is still under investigation. In this work, we studied the effect of this treatment in a pharmacological model of transient cholinergic hypofunction by the acute administration of the muscarinic antagonist, scopolamine, in spatial, recognition and aversive memory tests. Scopolamine induced memory impairment was observed in the three tests and, importantly, the cannabinoid subchronic treatment with low doses of WIN55,212-2 prevented this deleterious effect in spatial memory when evaluated in spatial Barnes maze test. Autoradiographic studies indicate that, following the WIN55,212-2 treatment, cannabinoid receptor density increased in the motor and somatosensory cortices. In layers I-V of the motor cortex, the activity of cannabinoid and muscarinic receptors also increased. These results suggest that WIN55,212-2, through the activation of CB1receptors, indirectly elevates the muscarinic tone in key cortical areas for learning and memory, preventing the memory deficits induced by scopolamine specifically in spatial memory. This highlights the importance of the crosstalk between the endocannabinoid and the cholinergic system for learning and memory processes and suggest that cannabinoid agonists might be an alternative for the treatment of cognitive deficits associated with cholinergic dysfunction.
PRMT1-Mediated Metabolic Reprogramming Promotes Leukemogenesis
Authors: Su Hairui , Sun Yong , Guo Han , Sun Chiao-Wang , Chen Qiuying , Liu Szumam , Li Anlun , Gao Min , Zhao Rui , Raffel Glen , Jin Jian , Qu Cheng-qui , Yu Michael , Klug Christopher A. , Zheng George Y. , Ballinger Scott , Kutny Matthew , Zheng X.Long , Chong Zechen , Senevirathne Chamara , Gross Steve , Chen Yabing , Luo Minkui , Zhao Xinyang
Published: January 2025

Copious expression of protein arginine methyltransferase 1 (PRMT1) is associated with poor survival in many types of cancers, including acute myeloid leukemia. We observed that a specific acute megakaryocytic leukemia (AMKL) cell line (6133) derived from RBM15-MKL1 knock-in mice exhibited heterogeneity in Prmt1 expression levels. Interestingly, only a subpopulation of 6133 cells expressing high levels of Prmt1 caused leukemia when transplanted into congenic mice. The PRMT1 inhibitor, MS023, effectively cured this PRMT1-driven leukemia. Seahorse analysis revealed that PRMT1 increased the extracellular acidification rate (ECAR) and decreased the oxygen consumption rate (OCR). Consistently, PRMT1 accelerated glucose consumption and led to the accumulation of lactic acid in the leukemia cells. The metabolomic analysis supported that PRMT1 stimulated the intracellular accumulation of lipids, which was further validated by FACS analysis with BODIPY 493/503. In line with fatty acid accumulation, PRMT1 downregulated the protein level of CPT1A, which is involved in the rate-limiting step of fatty acid oxidation. Furthermore, administering the glucose analogue 2-deoxy-glucose (2-DG) delayed AMKL progression and promoted cell differentiation. Ectopic expression of Cpt1a rescued the proliferation of 6133 cells ectopically expressing PRMT1 in the glucose-minus medium. In conclusion, PRMT1 upregulates glycolysis and downregulates fatty acid oxidation to enhance the proliferation capability of AMKL cells.
A CRISPR-associated Rossman-fold Ring Nuclease and Adenosine Deaminase Fusion Allosterically Converts ATP to ITP
Authors: Whyms Charlisa , Zhao Yu , Addo-Yobo Doreen , He Huan , Whittington Arthur Carl , Trasanidou Despoina , Salazar Carl Raymund P. , Staals Raymond H.J. , Li Hong
Published: January 2025

The recently identified CARF (CRISPR-associated Rossman-fold) family of proteins play a critical role in prokaryotic defense, mediating cOA (cyclic oligoadenylate)-stimulated ancillary immune responses in the type III CRISPR-Cas systems. Whereas most previously characterized CARF proteins contain nucleic acids or protein degradation effectors, a subset comprisesCARF-fusedadenosinedeaminase (ADA) (Cad1) and has a yet to be determined function. Here we present biochemical and structural analyses of a ring nuclease Cad1, revealing its unexpected role in deaminating adenosine-5′-triphosphate to inosine-5′-triphosphate in a cOA-dependent manner. Despite an overall structural similarity to canonical ADA enzymes, the ADA domain of Cad1 possesses unique structural features underlying its specificity for ATP. Supported by mutational analysis, we demonstrate an allosteric link between the cOA-binding CARF and the ADA domain, suggesting that Cad1 is a cOA-stimulated effector that influences cellular metabolic processes.

Highlights

TaqCad1 converts ATP to ITP in a magnesium- and cOA-dependent manner

Cryo-EM structures reveal TaqCad1 forms a homohexamer

Cryo-EM structures reveal how cA4is degraded and modulates the ADA active site
EEG-based Assessment of Long-Term Vigilance and Lapses of Attention using a User- Centered Frequency-Tagging Approach
Authors: Ladouce S , Tresols J. J. Torre , Goff K. Le , Dehais F
Published: January 2025

Sustaining vigilance over extended periods is crucial for many critical operations but remains challenging due to the cognitive resources required. Fatigue and other factors contribute to fluctuations in vigilance, causing attentional focus to drift from task-relevant information. Such lapses of attention, common in prolonged tasks, lead to decreased performance and missed critical information, with potentially serious consequences. Identifying physiological markers that predict inattention is key to developing preventive strategies. Previous research has established electroencephalography (EEG) responses to periodic visual stimuli, known as steady-state visual evoked potentials (SSVEP), as sensitive markers of attention. In this study, we evaluated a minimally intrusive SSVEP-based approach for tracking vigilance in healthy participants (N = 16) during two sessions of a 45-minute sustained visual attention task (Mackworth’s clock task). A 14 Hz frequency-tagging flicker was either superimposed on the task or absent. Results revealed that SSVEP responses were lower prior to lapses of attention, while other spectral EEG markers, such as frontal theta and parietal alpha activity, did not reliably distinguish between detected and missed attention probes. Importantly, the flicker did not affect task performance or participant experience. This non-intrusive frequency-tagging method provides a continuous measure of vigilance, effectively detecting attention lapses in prolonged tasks. It holds promise for integration into passive brain-computer interfaces, offering a practical solution for real-time vigilance monitoring in high-stakes settings like air traffic control or driving.

Highlights

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Fluctuations in the SSVEP response to a continuous frequency-tagging flicker presented throughout a 45-minutes long vigilance task was used to characterize lapses of attention

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The frequency-tagging flicker superimposed to the task was designed to be minimally intrusive thanks to its low luminance and low contrast

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Neither the user experience nor the task performance were altered by the presence of the frequency-tagging flicker

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The SSVEP response outperformed measures of individual alpha peak and theta band activity in the distinction of attentional lapses (missed events) from successful target event identification

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The present findings have implications for the design of Human-Computer Interfaces aimed at monitoring (in)attention during the performance of monotonous routines (e.g., surveillance, driving,…)
Deep functional profiling of gene sets using Large Language Models: A blueprint for tailored, context-aware functional annotation
Authors: Khan Taushif , Yurieva Marina , Kabeer Basirudeen Syed Ahamed , Toufiq Mohammed , Rinchai Darawan , Palucka Karolina , Chaussabel Damien
Published: January 2025

In this study, we present a proof-of-concept approach leveraging Large Language Models (LLMs) for the deep functional profiling of gene sets, addressing the limitations of traditional functional annotation tools. By employing a stepwise prompting strategy with OpenAI’s GPT-4, we systematically retrieve, consolidate, and score immune functions associated with each gene in a module, generating ranked lists of functions with detailed justifications and supporting literature evidence. As a blueprint for this approach, we demonstrate how this in-depth, context-aware analysis can characterize Module M10.4 from the BloodGen3 transcriptional module repertoire, confirming its central role in neutrophil-mediated innate immunity and antimicrobial defense while uncovering a nuanced network of immune functions overlooked by conventional methods. The LLM-based workflow identifies cell types and transcriptional programs driving these functions, offering a more granular and quantitative assessment of the gene set’s functional associations compared to direct LLM prompting or pathway enrichment analysis. Our results showcase the potential of LLMs in providing biologically meaningful interpretations of gene expression signatures, accounting for cellular composition changes and transcriptional regulation. This initial proof-of-concept study establishes a foundation for the automated, high-throughput functional profiling of transcriptional signatures. By integrating advanced language models with traditional literature-based validation, we present a powerful strategy for unraveling the complex biology of gene sets and transcriptional modules, ultimately facilitating the translation of systems-level molecular data into actionable knowledge.
Effects of Environmental Salinity on Global and Endocrine-Specific Transcriptomic Profiles in the Caudal Neurosecretory System of Salmonid Fishes
Authors: Culbert Brett M. , McCormick Stephen D. , Bernier Nicholas J.
Published: January 2025

The caudal neurosecretory system (CNSS) is a fish-specific neuroendocrine complex whose function(s) remain uncertain despite 60+ years of research. Osmoregulatory roles for the CNSS have been hypothesized, but molecular regulation of the CNSS following changes in environmental salinity remains poorly characterized. Therefore, we performed transcriptomics on the CNSS of rainbow trout (Oncorhynchus mykiss) to establish: 1) how the CNSS responds following seawater (SW) transfer, and 2) which endocrine systems contribute to osmoregulatory responses in the CNSS. Responses following SW transfer varied at 24 h versus 168 h, with changes primarily affecting membrane transport and transcriptional processes at 24 h and neuronal processes at 168 h. Components of several osmoregulation-associated endocrine systems were affected (e.g., corticosteroid receptors), including some which have not previously been identified in the CNSS (e.g., calcitonin). Additionally, transcript levels of corticotropin-releasing factor (CRF) peptides—which have osmoregulatory functions and were highly abundant in the CNSS—were ∼2-fold higher after 24 h in SW. Therefore, we performed additional experiments investigating CRF peptides in a more euryhaline salmonid, Atlantic salmon (Salmo salar). Smolts had up to 12-fold higher levels of CRF peptide transcripts than parr, but abundance declined following SW transfer. Additionally, CRF transcripts were lower 24 h following freshwater transfer of SW-acclimated salmon. These results suggest that CRF peptides acutely aid in coordinating physiological responses following fluctuations in environmental salinity via anticipatory and/or responsive mechanisms. Collectively, our data indicate that CNSS-mediated production of CRF peptides has osmoregulatory functions and provide a resource for investigations of novel CNSS functions.
Integrated multi-omics highlights alterations of gut microbiome functions in prodromal and idiopathic Parkinson’s disease
Authors: Villette Remy , Ortís Sunyer Júlia , Novikova Polina V. , Aho Velma T. E. , Petrov Viacheslav A. , Hickl Oskar , Busi Susheel Bhanu , De Rudder Charlotte , Kunath Benoit , Heintz-Buschart Anna , Trezzi Jean-Pierre , Halder Rashi , Jäger Christian , Lebrun Laura A. , Daujeumont Annegrät , Schade Sebastian , Janzen Annette , Jehmlich Nico , von Bergen Martin , Laczny Cédric C. , May Patrick , Trenkwalder Claudia , Oertel Wolfgang , Mollenhauer Brit , Wilmes Paul
Published: January 2025

Parkinson’s disease (PD) is associated with gut microbiome shifts, but the functional consequences remain unclear. Here, we use an integrated multi-omics approach to compare the gut microbiomes of individuals with PD and prodromal PD as well as healthy individuals. After analyzing each omics, meta-metabolomic was selected to inform the analysis as it represents the most discriminatory and robust ome. We identified 11 metabolites that were differentially abundant between the groups, amongst which β-glutamate was increased in PD and prodromal PD, and correlated with the transcriptional activities ofMethanobrevibacter smithiiandClostridiumspp. We identified decreases in transcripts, but not in gene abundances, related to glutamate metabolism, bile acids, chemotaxis and flagellar assembly in PD, particularly in keystone genera such asRoseburia, AgathobacterandBlautia. Our findings, integrated into the Expobiome map, reveal multifactorial microbiome alterations which converge with PD pathways. Our study highlights the importance of investigating the gut microbiome’s functional dimensions to better resolve microbiome-host interactions in health and disease.
Sex Differences in Auditory Brainstem Responses in the Hispid Pocket Mouse (Chaetodipus hispidus)
Authors: Joseph Luberson , Joseph Desi M. , Hobbs Sarah , Rivera Naleyshka Colon , McCullagh Elizabeth A.
Published: January 2025

The hispid pocket mouse (C. hispidus) is a solitary semi-fossorial rodent that has been the subject of various ecological and genetic studies. However, no previous studies have characterized its hearing ability, which is important for its survival and fitness. We collected auditory brainstem responses (ABRs) fromC. hispidusand measured craniofacial and pinna morphological features to assess hearing ability and test differences in hearing thresholds, monaural and binaural ABR amplitudes and latencies between the sexes. ABR recordings revealed that similar to other small mammals,C. hispidusdisplayed the lowest threshold to sounds between 8-16 kHz, indicating best hearing across those frequencies. We found significant differences in auditory thresholds of the ABRs between the sexes, with females showing lower frequency hearing compared to males. However, no significant differences were detected in monaural and binaural ABR amplitudes and latencies between the sexes. We also found no significant differences in craniofacial and pinna dimensions between the sexes. These findings shed novel insights into the auditory systems across species and highlighted for the first time sex differences in auditory thresholds for this rodent species.
Maizerough endosperm6is a predicted RNA helicase required for miRNA processing and endosperm cell patterning
Authors: Yang Tianxiao , Suzuki Masaharu , Hannah L. Curtis , Settles A. Mark
Published: January 2025

Maizerough endospermmutants have defective kernels with a rough, etched, or pitted endosperm surface. Molecular genetic analysis of this mutant class has identified multiple RNA processing proteins critical to endosperm development. Here, we report thatrough endosperm6(rgh6) encodes a predicted DEAD-box RNA helicase required for miRNA processing. Mutantrgh6kernels reduce grain fill and increase relative transcript levels of markers specific to epidermal endosperm cell types. B-A translocation crosses revealed thatrgh6mutant endosperm inhibits normal embryo development. We mapped thergh6locus to a three gene interval and confirmed it encodes a predicted DEAD-box RNA helicase with two independent transposon-tagged alleles. Transient expression of a RGH6-green fluorescent protein (GFP) fusion is localized to nucleolus and nuclear speckles consistent with a function in nuclear RNA processing. Mutantrgh6endosperms have increased precursor miRNA and decreased mature miRNA levels indicating thatrgh6impacts miRNA processing. Our study demonstrates that precursor miRNA processing and miRNA target regulation are required for normal endosperm development.
Origins and Implications of Intron Retention Quantitative Trait Loci in Human Tissues
Authors: Park Eddie , Xing Yi
Published: January 2025

Intron retention is a type of alternative splicing in which introns remain unspliced in mature RNA transcripts. In order to explore the landscape and consequences of genetically regulated intron retention, we perform an intron retention quantitative trait loci (irQTL) analysis in 49 human tissues across 838 individuals. We identify 8,624 unique intron retention events associated with genetic polymorphisms. 1,369 irQTLs (16%) are also associated with genome-wide association study (GWAS) traits, suggesting that genetically regulated intron retention may play a causal role in the regulation of these GWAS traits. 1,999 irQTLs (23%) colocalize with eQTLs to their respective gene, suggesting that intron retention and steady-state gene expression levels are regulated by shared sets of genetic variants. Through a colocalization analysis of irQTL:eQTL events, we demonstrate that irQTLs are sufficient to generate eQTLs when one of the alternatively spliced transcripts is preferentially targeted by the nonsense mediated decay (NMD) pathway. Surprisingly, for intron retention events whose potential NMD effects can be confidently predicted based on their positions within known gene annotations, we find that 58.8% (923/1570) of the colocalized irQTL and eQTL pairs show effect size directions that are discordant with the NMD model. Moreover, we find that irQTLs are significantly more likely to occur in the same gene with the same effect size direction as compared to exon skipping QTLs. Through mathematical modeling and analysis of experimental perturbation data, we provide evidence that eQTLs are able to generate irQTLs by altering the steady state ratios of spliced and unspliced transcripts, and we postulate that this mechanism may partially underlie the widespread intron retention observed previously in various biological conditions. Taken together, these results show that intron retention and steady state gene expression levels are closely intertwined to regulate phenotypic traits.
Landscape and regulation of new protein translation in the earlyC. elegansembryo
Authors: Shukla Yash , Ghatpande Vighnesh , Hu Cindy F. , Dickinson Daniel J. , Cenik Can
Published: January 2025

Translation of maternal mRNAs is crucial for early embryonic development. InC. elegans,cell fates become determined from the first division without new transcription, making this organism ideal for studying post-transcriptional regulation of lineage specification. Using low-input ribosome profiling combined with RNA sequencing on precisely staged embryos, we measured protein translation during the first four cell cycles ofC. elegansdevelopment. We uncovered stage-specific patterns of developmentally coordinated translational regulation. We found that mRNA localization correlates with translational efficiency, though initial translational repression in germline precursors occurs prior to P-granule association. The RNA-binding protein OMA-1 emerged as a key regulator of translational efficiency in a stage-specific manner. These findings illuminate how post-transcriptional mechanisms shape the embryonic proteome to direct cell differentiation, with implications for understanding similar regulation across species where maternal factors guide early development.
Study protocol for the EYEdentify project: An examination of gaze behaviour in autistic adults using a virtual reality-based paradigm
Authors: Jeppesen Alberte C. E. , Andresen Johannes , Parvaiz Rizwan , Clemmensen Lars , Møllegaard Jepsen Jens Richardt , Hansen Dan Witzner , Glenthøj Louise Birkedal
Published: January 2025

Introduction

Autism Spectrum Condition (ASC) is characterised by difficulties in social communication and interaction, which may pose significant challenges to daily functioning throughout life. While current diagnostic methods for ASC often rely on measures based on subjective reports, there is a growing need for objective, quantifiable measures to support current clinical assessment of ASC. Eye-tracking technology records eye and gaze movements in real time and provides a direct and objective method for assessing social attention. Integrating eye-tracking within virtual reality (VR) environments presents a novel approach for capturing gaze behaviour in dynamic, ecologically valid social scenarios. This study aims to investigate whether VR-based eye information can reveal group differences in gaze behaviour between autistic adults and neurotypical controls in simulated social interactions.

Methods

This case-control study will include 140 adults diagnosed with ASC and 50 neurotypical controls, matched by age and gender. Participants will engage in six VR-based social scenarios, which vary in social complexity and the presence of non-social distractors. Eye information will be measured using eye-tracking technology integrated into a head-mounted display. Gaze behaviour will be analysed through fixation-based metrics on parameters including number of fixations, mean fixation time, and dwell time, on predetermined Areas of Interest.

Analysis

Statistical analyses will assess between-group differences in gaze behaviour as well as correlations between gaze metrics and clinical measures of social functioning, social cognition and symptom severity.

Discussion

This study utilises VR-based eye-tracking to investigate novel paradigms for assessing gaze behaviour in ASC in immersive, interactive environments and aims to advance the current understanding of visual social attention in ASC. Positive outcomes from this study may support further research into VR- based eye-tracking to supplement existing clinical assessment methods.
Quantitative Detection of Amyloid Fibrils using Fluorescence Resonance Energy Transfer (FRET) Between Engineered Yellow and Cyan Proteins
Authors: Moustouka Caitlyn , Makhatadze George I.
Published: January 2025

Over 20 human diseases are caused by or associated with amyloid formation. Developing diagnostic tools to understand the process of amyloid fibril formation is essential for creating therapeutic agents to combat these widespread and growing health problems. Here, we capitalize on our recent striking discovery that green fluorescent protein (GFP), one of the most used proteins in molecular and cell biology, has a high intrinsic binding affinity to various structural intermediates along the fibrillation pathway, independent of amyloid sequence. Using engineered GFP with the fluorescence properties of Aquamarine and mCitrine, we developed a FRET-based sensor to quantitatively monitor amyloid fibrils. The proof-of-principle characterization was performed on a test system consisting of PAPf39 fibrils.
Insight into the Thermo-responsive Phase Behavior of P1 Domain ofα-synuclein using Atomistic Simulations
Authors: Chakraborty Sanchari , Biswas Mithun
Published: January 2025

Biomolecular condensate formation driven by intrinsically disordered proteins (IDPs) is regulated by interaction between various domains of the protein. Such condensates are implicated in various neurodegenerative diseases. The presynaptic intrinsically disordered protein,α-Syn is involved in the pathogenesis of Parkinson’s disease. The central non-amyloidβ-component (NAC) domain in the protein is considered to be a major driver of pathogenic aggregation, although recent studies have suggested that the P1 domain from the flanking N-terminal region, can act as a ‘master controller’ forα-Syn function and aggregation. To gain molecular insight into the phase behavior of the P1 domain itself, we investigate how assemblies of P1 (residues 36-42) chains phase separate with varying temperatures using all-atom molecular dynamics simulations. The simulations reveal that P1 is able to phase separate above a lower critical solution temperature. Formation of the condensed phase is driven by exclusion of water molecules by the hydrophobic chains. P1 chain density in the condensate is determined by weak multi-chain interactions between the residues. Moreover, Tyrosine (Y39) is involved in the formation of strongest contacts between residue pairs in the dense phase. These results provide a detailed picture of condensate formation by a key segment of theα-Syn molecule, which may help deciphering the phase behavior of the full-length protein.