bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mice-side bias: Deliberative decision making in a model of rule revision reveals ‘myside’ confirmation bias-like cognitive processes in mice
Authors: Stevens Christopher , Lacroix Cathy , Bouchet Mathilde , Marsicano Giovanni , Marighetto Aline 
Published: December 2024

AbstractConfirmation or ‘myside’ bias—over-valuation of novel information which confirms previously internalized cognitive content (prior beliefs, rules of conduct, etc.) and corresponding under-valuation of disconfirming novel information—constitutes a serious obstacle to adaptive revision of our beliefs, especially in ambiguous or complex epistemic environments. Indeed, myside bias has become a particularly pernicious fact of societal cohesion, contributing to the propagation of fake news, to social polarization, and even to the replication crisis in experimental science. By contrast, relatively little is understood about either its neurocognitive underpinnings or its evolution, one reason for this being that the potential presence of myside bias-like tendencies in non-human animals has never been directly tested. Hence, in order to advance research in both of these directions, we designed a novel mouse model of everyday-like rule revision such that the dynamic model environment would be sufficient to call out myside bias-like behaviors providing that mice did indeed possess the particular kind of competing neurocognitive processes necessary for it to manifest. Here, we both validate that model and provide the first behavioral descriptions of myside confirmation bias-like deliberative profiles in a non-human animal. Notably, we observe that this bias does not manifest in a merely unreflective or heuristic/‘system 1’ manner but rather also emerges through and indeed increases deliberative behaviors, especially in contexts of low representational resolution. Several other parallels with findings from human studies of myside bias are also detailed in the discussion.
Repeated climate-driven dispersal and speciation in peripheral populations of Pleistocene mastodons
Authors: Karpinski Emil , Baleka Sina , Boehm Andrew R. , Fedak Tim , Widga Chris , Poinar Hendrik N. 
Published: December 2024

AbstractRecent ancient DNA work has shed some light on the responses of mastodons to Pleistocene glacial/interglacial cycling but focused primarily on their expansion into Beringia. However, genetics has complicated our understanding of the relationships withinMammut, specifically between Pacific and American mastodon phylogeography and questioned whether these are in fact two separate species or regionally localized morphotypes. Here we expand on both avenues by sequencing and contextualizing the mitochondrial genome of a Pacific mastodon, as well as from several North American eastern specimens throughout the last 800 thousand years. We show that Pacific mastodons fall within a previously established, and deeply divergent mitochondrial clade, extending the range of this species into western Canada and potentially Mexico. We also present evidence for at least three discrete expansion events into northeastern coastal regions (i.e. Nova Scotia and the eastern continental shelf), and identify two new mastodon clades, which contain temporally distinct, but geographically co-occurrent specimens. This work sheds further light on mastodon taxonomy and phylogeography across North America throughout the Pleistocene, highlighting interglacial range expansion into northeastern America mirroring the effects on the western side of the continent (Beringia).
Functional Genomics Validation of PPAR gamma Signalling in PASMCs: Therapeutic Implications for Pulmonary Arterial Hypertension
Authors: Su Renzhi , Pritazahra Armalya , Saverimuttu Shirin C.C. , Clapp Lucie H , Lovering Ruth C , Patel Jigisha A 
Published: December 2024

AbstractGene Ontology (GO) is a tool which provides gene functional annotations, an essential resource for knowledge discovery and the analysis of biological datasets. Although considerable research has quantified the functional similarity between gene products and physiological processes, there is a need to identify which of these may contribute to pathophysiological states in humans. Previous studies have identified the role of PPARG in multiple signalling pathways, particularly those of TGFB1 and BMP2, in pulmonary artery smooth muscle cells and their relation to pulmonary arterial hypertension (PAH). To enhance the description of PPARG in the GO resource we systematically curated the proteins it interacts with and its physiological role in PASMCs. In addition, we curated the microRNAs that play a role in PAH through their regulation of PPARG expression and their downstream impact on cellular processes. This project curated experimental evidence describing 101 human miRNAs that regulate the expression of 17 PPARG signalling pathway-relevant proteins. Of these, 91 of our curated miRNAs were previously unannotated in terms of directly regulating the expression of these priority proteins. By submitting these annotations to the GO Consortium database, we have significantly expanded the breadth and depth of the GO description of PPARG-associated signalling pathways.
ANKRD5: a key component of the axoneme required for sperm motility and male fertility
Authors: Yu Shuntai , Yin Guoliang , Jin Peng , Zhang Weilin , Tian Yingchao , Xu Xiaotong , Shao Tianyu , Li Yushan , Sun Fei , Zhu Yun , Wang Fengchao 
Published: December 2024

AbstractSperm motility is crucial for male reproduction and relies on the structural integrity of the sperm axoneme, which has a “9+2” microtubule configuration. This structure includes nine outer microtubule doublets that house various macromolecular complexes. The nexin-dynein regulatory complex (N-DRC) forms a crossbridge between the outer microtubule doublets, stabilizing them and facilitates sperm tail bending. Our investigation of ANKRD5, which is highly expressed in the sperm axoneme, reveals its interaction with TCTE1 and DRC4/GAS8, both key components of the N-DRC. The components of the N-DRC are often vital for sperm motility. ANKRD5-/-mice exhibited reduced sperm motility and male infertility; however transmission electron microscopy and cryoelectron tomography showed no significant alterations in microtubule doublets. Moreover, ANKRD5 deficiency did not affect ATP levels, and its interactions with TCTE1 and DRC4/GAS8 were found to be independent of calcium regulation. These findings establish that ANKRD5 is critical for maintaining axoneme stability, which is important for sperm motility.Significance StatementMale infertility affects 8%-12% of men globally, with defects in sperm motility accounting for 40%-50% of these cases. The axoneme, serving as the sperm’s motor apparatus, features a 9+2 microtubule arrangement, with the nexin-dynein regulatory complex (N-DRC) providing essential structural support between outer microtubule doublets. Understanding the synergistic relationship between the N-DRC’s structure and its protein composition is crucial for advancing male reproductive biology. In this study, we identify the protein ANKRD5 as a component of the axoneme that can interact with N-DRC components, which is crucial for sperm motility. This discovery enhances our understanding of sperm motility mechanisms and suggests potential targets for male contraceptive development.
Fusions of catalytically inactive RusA to FokI nuclease coupled with PNA enable programable site-specific double-stranded DNA breaks
Authors: Saleh Ahmed , Sivakrishna Rao Gundra , Wang Qiaochu , Mahfouz Magdy 
Published: December 2024

ABSTRACTProgrammable site-specific nucleases have revolutionized the genome editing. However, these systems still face challenges such as guide dependency, delivery issues, and off-target effects. Harnessing the natural functions of structure-guided nucleases offer promising alternatives for generating site-specific double-strand DNA breaks. Yet, structure-guided nucleases require precise reaction conditions and validation forin-vivoapplicability. To address these limitations, we developed thePNA-CoupledFokI-(d)RusA(PC-FIRA) system. PC-FIRA combines the sequence-specific binding ability of peptide nucleic acids (PNAs) with the catalytic efficiency of FokI nuclease fused to a structurally-guided inactive RusA resolvase (FokI-(d)RusA). This system allows for precise double-strand DNA breaks without the constraints of existing site-specific nuclease and structure-guided nucleases. Throughin vitrooptimizations, we achieved high target specificity and cleavage efficiency. This included adjusting incubation temperature, buffer composition, ion concentration, and cleavage timing. Diverse DNA structures, such as Holliday Junctions, linear, and circular DNA, were tested demonstrating the potential activity on different target forms. Further investigation has revealed the PC-FIRA system capacity for facilitating the precise deletion of large DNA fragments. This can be useful in cloning, large-fragment DNA assembly, and genome engineering, with promising applications in biotechnology, medicine, agriculture, and synthetic biology.
Purifying circular RNA by ultrafiltration
Authors: Guillen-Cuevas Karen , Lu Xiaoming , Birtwistle Marc R. , Husson Scott M. 
Published: December 2024

AbstractDeveloping messenger RNA (mRNA) vaccines for COVID-19 renewed and intensified the interest in using mRNA for disease prevention and treatment. Despite their efficacy, linear mRNA molecules are short-lived in the human body, primarily due to enzymatic degradation at the free ends. In contrast, circular RNA (circRNA) exhibits enhanced stability and resistance to exonuclease degradation. However, this stability depends highly on purity. Unfortunately, thein vitrotranscription/self-splicing reaction products contain a mixture of circular and linear RNAs. Yet, practical methods for purifying circRNA from solutions containing linear RNA contaminants are lacking. In this study, we explored the feasibility of using ultrafiltration to purify protein-encoding circRNA produced by the self-splicing of a precursor RNA (preRNA) duringin vitrotranscription (IVT). We measured the sieving coefficients, a separation metric, of circRNA, linear precursor RNA, and nicked RNA conformers using polyethersulfone membranes with molecular weight cutoffs from 30 to 300 kDa, analyzing performance as a function of permeate flux. We also estimated the RNA critical fluxes and determined suitable operating conditions for purification. We achieved a purity of 86% with a yield above 50%. By comparison, the purity achieved by size-exclusion high-performance liquid chromatography (SE-HPLC), the leading alterative separation technology, was 41% with a yield of 45%. These findings highlight ultrafiltration as a superior method for purifying circRNA at the research scale. Its scalability suggests that it could play a critical role in enabling the large-scale manufacturing of circRNA-based therapeutics.
A Reference Tissue Implementation of Simultaneous Multifactor Bayesian Analysis (SiMBA) of PET Time Activity Curve Data
Authors: Matheson Granville J. , Lundberg Johan , Gärde Martin , Veldman Emma R. , Tateno Amane , Okubo Yoshiro , Tiger Mikael , Ogden R. Todd 
Published: December 2024

ABSTRACTPET analysis is conventionally performed as a two-stage process of quantification followed by analysis. We recently introduced SiMBA (Simultaneous Multifactor Bayesian Analysis), a hierarchical model that performs quantification and analysis for all brain regions of all individuals at once, and in so doing improves both the accuracy of parameter estimation as well as inferential efficiency. However until now, SiMBA has only been implemented for the two-tissue compartment model. We have now extended this general approach to also allow a non-invasive reference tissue implementation that includes both the full reference tissue model and the simplified reference tissue model. In simulated data, SiMBA improves quantitative parameter estimation accuracy, reducing error by, on average, 57% for binding potential (BPND). In considerations of statistical power, our simulation studies indicate that the efficiency of SiMBA modeling approximately corresponds to improvements that would require doubling the sample size if using conventional methods, with no increase in the false positive rate. We applied the model to PET data measured with [11C]AZ10419369, which binds selectively to the serotonin 1B receptor, in datasets collected at three different PET centres (n=139, n=44 and n=39). We show that SiMBA yields replicable inferences by comparing associations between PET parameters and age in the different datasets. Moreover, we show that time activity curve data from different centres can be combined in a single SiMBA model using covariates to control between-centre parameter differences, in order to harmonise data between centres. In summary, we present a novel approach for noninvasive quantification and analysis of PET time activity curve data which improves quantification and inferences, enables effective between-centre data harmonisation, and also yields replicable outcomes. This method has the potential to significantly expand the range of research questions which can be meaningfully tested using conventional sample sizes with PET imaging.
Two distinct structural variants involvingEDN3cause hyperpigmentation in chicken
Authors: Ma Cheng , Huang Xun-He , Wang Feng-Juan , Zhang Shu-Run , Shi Xian , Weng Zhuo-Xian , Du Bingwang , Zhang Ya-Ping , Andersson Leif , Peng Min-Sheng 
Published: December 2024

AbstractPhenotypic diversity and its genetic basis are central questions in biology, with domesticated animals offering valuable insights due to their rapid evolution the last 10,000 years. In chickens, fibromelanosis (FM) is a striking pigmentation phenotype characterized by hyperpigmentation. A previous study identified a complex structural variant causing upregulated expression of theEndothelin 3(EDN3) gene. However, the detailed structural arrangement and functional consequences of the variant remained unclear. In this study, we conducted a comprehensive genomic survey of 692 FM chickens representing 55 breeds and uncovered two distinct structural variants causing the FM phenotype:FM*A,the previously reported complex rearrangement involving theEDN3locus1, andFM*B, a tandem duplication of a 16 kb region upstream ofEDN3. We demonstrate that both structural variants (SVs) significantly upregulateEDN3expression, withFM*Bassociated with even higher expression thanFM*A. A luciferase reporter assays showed that the 16 kb region inFM*Bcontains powerful enhancers and the copy number expansion of this element is a likely explanation forEDN3upregulation and hyperpigmentation. Furthermore, our analysis of linkage disequilibrium patterns allowed us to resolve the complex arrangement of duplications and inversion on theFM*Ahaplotype.
Spermidine alleviates depression via control of the stress response
Authors: Mackert Sarah , Niemeyer Christine , Mecdad Yara , Ebert Tim , Bajaj Thomas , Durand Sylvère , Hofer Sebastian J. , Zellner Andreas , Besteher Bianca , Engelmann Jan , Gisabella Barbara , Kempf Valerie , Heckmann Lily A. , Laakmann Marcel , Newman Emily L. , Sokn Clara , Heinz Daniel E. , Junglas Ellen , Uribe-Marino Andrés , Magnes Christoph , Klengel Claudia , Müller Anna , Opriessnig Lydia , Meinitzer Andreas , Lennarz Martina , Martin Katja M. Wirtz , Albatarni Rawan , Brockherde Marieke , Lieb Klaus , Rohner Henrik , Stoffel-Wagner Birgit , Philipsen Alexandra , Kuster Bernhard , Kölle Markus , Ressler Kerry J. , Opel Nils , Schmidt Mathias V. , Pantazopoulos Harry , Müller Marianne B. , Kroemer Guido , Eisenberg Tobias , Hartmann Jakob , Madeo Frank , Gassen Nils C. 
Published: December 2024

AbstractDepression is a stress-associated disorder, and it represents a major global health issue. Its pathophysiology is complex and remains insufficiently understood, with current medications often showing limited efficacy and undesirable side effects. Here, we identify imbalanced polyamine levels and dysregulated autophagy as key components of the acute stress response in humans, and as hallmarks of chronic stress and depressive disorders. Moreover, conventional antidepressant pharmacotherapy increases endogenous plasma concentrations of the polyamine spermidine exclusively in patients who respond to the treatment, suggesting a link between spermidine and successful outcomes. In a clinical trial, involving drug-naive depressed individuals, three weeks of spermidine supplementation increased autophagy and alleviated symptoms of depression. Behavioral and mechanistic findings of spermidine supplementation were validated in various mouse stress and depression models. In summary, spermidine supplementation mitigates polyamine dysregulation and stimulates autophagy under pathological stress conditions, offering a novel and well-tolerated treatment approach for stress-related depressive disorders.
Frizzled1 and Frizzled2 are not redundant for competitive survival under low-Wingless levels in the developingDrosophilawing epithelium
Authors: Hingole Swapnil , Verma Kritika , Chaudhary Varun 
Published: December 2024

AbstractIn theDrosophilawing epithelium, canonical Wnt signaling is activated by the gradient of secreted Wingless protein (Wnt1 homolog), which interacts redundantly with the Frizzled1 and Frizzled2 receptors. While sharing overlapping functions, these receptors also have distinct non-canonical roles and exhibit differential expression patterns along the Wingless gradient. Moreover, Frizzled2, unlike Frizzled1, is thought to be essential for sustaining low-level Wingless signaling and promoting cell survival in the absence of the ligand. This raises the possibility of the two receptors acting differently along the Wingless gradient. In this study, we investigated the role of these receptors in cell survival across varying Wingless levels. We find that the loss of Frizzled2 in cells at a distance from the Wingless-producing cells—where Wingless levels are low— leads to competitive elimination of cells. In contrast, Frizzled1 is dispensable for cell survival, regardless of distance from the Wingless source. Our findings show that Frizzled2 is essential for competitive cell survival under low-Wingless conditions and the two receptors are not equally redundant across the Wingless concentration gradient, providing insight into a mechanism for spatial and temporal precision in developmental signaling.
From womb to crib: How fetal activity patternsin uteroreveal postnatal sleep behavior
Authors: Markovic Andjela , Mühlematter Christophe , Blume Christine , Zimmermann Petra , Kurth Salome 
Published: December 2024

AbstractImportanceThe human circadian system, a critical biological mechanism governing the sleep-wake cycle, begins to oscillate before birth. Distinct fetal behavioral states have been described using short-duration ultrasound recordings, but the alignment of fetal activity with day and night cycles (i.e., diurnal rhythms) remains poorly understood due to the lack of long-term monitoring. Accordingly, a substantial knowledge gap exists concerning the evolution of fetal diurnal rhythms into infant sleep-wake cycles.ObjectiveTo investigate the development of fetal diurnal rhythms and their evolution into postnatal infant sleep, as well as the role of maternal factors and melatonin in shaping early circadian entrainment.MethodsIn this cohort study, conducted in 2022 and 2023, we collected over 20 000 hours of wearable acceleration and temperature data from 32 fetuses and their mothers during continuous 5-day monitoring in the third trimester of pregnancy. The cohort was subsequently followed longitudinally from the prenatal period through 6 months postpartum, with infant sleep outcomes assessed at three key time points (first postnatal weeks, 3 months, and 6 months) using sleep diaries and questionnaires. The first postnatal assessment additionally included breast milk and infant stool sample collection.ResultsMulti-level modelling revealed early diurnal rhythms in fetuses that align with maternal activity and circadian rhythms. Random Forest analyses identified fetal day/night sleep duration ratio – a simplified proxy for fetal circadian entrainment – as the strongest predictor of postnatal infant sleep, with fetuses preferring nighttime sleep maintaining this preference postnatally. Maternal sleep regularity (i.e., consistent sleep patterns characterized by low day-to-day variability in sleep timing) during pregnancy also predicted infant sleep, associating with a stronger preference for nighttime sleep in infants.Conclusions and relevanceThese findings highlight the potential influence of intrauterine and maternal factors on the evolution of circadian entrainment. Our study contributes to a broader understanding of the earliest emergence of circadian rhythms, supporting future research on their long-term health impacts. Maternal sleep regularity stands out as the earliest modifiable target for interventions, offering an actionable pathway to promote infant circadian entrainment, with potential long-term benefits for family dynamics and well-being.
Exploring the Aβ Plaque Microenvironment in Alzheimer’s Disease Mice by Multimodal Lipid-Protein-Histology Imaging on a Benchtop Mass Spectrometer
Authors: Müller Elisabeth , Enzlein Thomas , Niemeyer Dagmar , von Ammon Livia , Stumpo Katherine , Biber Knut , Klein Corinna , Hopf Carsten 
Published: December 2024

AbstractAmyloid-β (Aβ) plaque deposits in the brain are a hallmark of Alzheimer’s disease (AD) neuropathology. Plaques consist of complex mixtures of peptides like Aβ1-42, characteristic lipids such as gangliosides, and they are targeted by reactive microglia and astrocytes. In pharmaceutical research and development it is therefore a formidable challenge to contextualize different biomolecular classes and cell types of the Aβ plaque microenvironment in a coherent experimental workflow on a single tissue section and on a benchtop imaging reader. Here, we developed such a workflow that combines lipid MALDI mass spectrometry imaging using a vacuum-stable matrix with histopathology stains and with MALDI HiPLEX-immunohistochemistry of plaques and multiple protein markers on a bench-top imaging mass spectrometer. The three data layers consisting of lipid, protein markers, and histology can be co-registered and evaluated together. Multimodal data analysis suggests extensive co-localization of Aβ plaques with the peptide precursor protein, with a defined subset of lipids and with reactive glia cells on a single brain section of APP/PS1 AD model mice. Plaque-associated lipids like ganglioside GM2 and phosphatidylinositol PI38:4 isoforms were readily identified using the tandem MS-capabilities of the mass spectrometer. Taken together, our data suggests that complex pathology involving multiple lipids, proteins and cell types can be interrogated by this spatial multiomics workflow on an easy-to-use benchtop mass spectrometer.