bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractEstimation 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

AbstractUnderstanding 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

AbstractHeterozygosity 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

AbstractIncreased 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

AbstractUncovering 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

ABSTRACTThe 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 & NOTEWORTHYChronic 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

AbstractStandard 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

AbstractCurrent 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 StatementWith 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

AbstractAnimals 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

AbstractThe 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

AbstractCopious 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

AbstractThe 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.HighlightsTaqCad1 converts ATP to ITP in a magnesium- and cOA-dependent mannerCryo-EM structures reveal TaqCad1 forms a homohexamerCryo-EM structures reveal how cA4is degraded and modulates the ADA active site