bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multimodal investigation of the neurocognitive deficits underlying dyslexia in adulthood
Authors: Cristina Cara , Giulia Zantonello , Marta Ghio , Marco Tettamanti 
Published: November 2024

AbstractDyslexia is a neurobiological disorder characterised by reading difficulties, yet its underlying causes remain unclear. Neuroimaging and behavioural studies found anomalous responses in tasks requiring phonological processing, motion perception, and implicit learning, and showed gray and white matter abnormalities in several brain regions of dyslexics compared to controls, indicating that dyslexia is a heterogeneous condition and promoting a multifactorial approach. In order to evaluate whether the combination of behavioural and multimodal MRI can have greater sensitivity in identifying neurocognitive traits of dyslexia compared to monocomponential approaches, in 19 dyslexic and 19 control subjects we acquired behavioural cognitive assessments, multiple (phonological, visual motion, rhythmic) mismatch-response functional MRI tasks, structural diffusion-weighted and T1-weighted images. To examine between-group differences in the multimodal neurocognitive measures, we applied univariate and multivariate approaches. Results showed that dyslexics performed worse than controls in behavioural phonological tasks. Neuroimaging analyses revealed that individuals with dyslexia present reduced cerebellar responses to mismatching rhythmic stimuli, as well as structural disorganization in several white matter tracts and cortical regions previously implicated in dyslexia. Most importantly, in line with the view of dyslexia as a multifactorial phenomenon, a machine learning model trained with features from all three MRI modalities (functional, diffusion, and T1-weighted) discriminated between dyslexics and controls with greater accuracy than models including just one modality. The individual classification scores in the multimodal machine learning model correlated with behavioural reading accuracy. These results confirm that dyslexia should be approached as a composite condition characterised by multiple distinctive cognitive and brain features.
Transferrin receptor-mediated transport at the blood-brain barrier is elevated during early development but maintained across adult aging
Authors: Torres Vanessa O. , Pizzo Michelle E. , Chan Darren , Dugas Jason C. , Huynh David , Joy David , Liang Eric K. , Sarrafha Lily , Becerra Isabel , Chau Roni , Chew Kylie S. , Chow Johann , Earr Timothy K. , Khoury Nathalie , Lechtenberg Kendra J. , Leung Amy W. , Nguyen Hoang N. , Ojo Emmanuel S. , Roche Elysia , Solanoy Hilda , Tong Mabel , Tong Raymond K. , Henne Kirk , Lewcock Joseph W. , Watts Ryan J. , Calvert Meredith E. , Thorne Robert G. , Zuchero Y. Joy Yu 
Published: November 2024

AbstractTransferrin receptor (TfR)-mediated transcytosis across the blood-brain barrier (BBB) is a promising strategy to improve delivery of biologics to the central nervous system (CNS). However, it remains unclear whether age and aging-related diseases impact TfR expression and/or BBB transport capacity. Here, we used the TfR-targeted antibody transport vehicle (ATVTfR) to enhance CNS delivery in healthy mice and in the 5xFAD mouse model of Alzheimer’s disease (AD). Healthy neonates exhibited the highest vascular TfR expression and ATVTfRbrain exposure, whereas BBB transport capacity remained stable across adulthood. Additionally, neither TfR expression nor ATVTfRbrain uptake changed significantly in 5xFAD mice. Further, vascular TfR expression in AD patient brains was similar to age-matched controls, suggesting that TfR transport may be conserved for AD in humans. The elevated TfR-mediated brain delivery observed in early mouse development suggests the potential of added efficacy in utilizing TfR platforms for the treatment of early childhood diseases. Preservation of ATVTfRtransport in adult mice across healthy aging and in an AD model supports continued application of TfR platforms in age-related diseases.
The Glutamatergic Projection from the Substantia Nigra Pars Reticulata to the Dorsal Raphe Nucleus Facilitates Social Hierarchy in Mice
Authors: Fan Yanzhu , Ge Shaoxiang , Lu Lidi , Niu Wenjun , Wang Zhiyue , Jiao Xiaoguo , Fang Guangzhan 
Published: November 2024

AbstractSocial hierarchy constitutes a fundamental organizational characteristic among various social species, significantly influencing individual survival, health, and reproductive success within these societies. Neurons in the substantia nigra pars reticulata (SNr) exhibit extensive connectivity with the dorsal raphe nucleus (DRN), a critical structure implicated in social interaction, reward processing, and the establishment of social rank. However, the specific neuronal types within the SNr, as well as the associated neural circuits that regulate social dominance, remain inadequately characterized. This study aims to elucidate the crucial role of SNr glutamatergic neurons in the establishment and maintenance of social hierarchy in mice. Employing fiber photometry, we observed that the activation of SNr glutamatergic neurons increased during the initiation of effortful behaviors in the tube test. Further investigations revealed that optogenetic activation or chemogenetic inhibition of the glutamatergic neural circuit connecting the SNr to the DRN induced upward or downward shifts in social ranks, respectively. Additionally, our findings indicate that the activation of SNr glutamatergic terminals in the DRN reduces anxiety levels in mice. Collectively, these results underscore the critical role of the glutamatergic pathway from the SNr to the DRN in regulating social hierarchy. This work enhances our understanding of the functions of SNr glutamatergic neurons in both physiological contexts and neurological disorders.
Risk factors for invasive Group A Streptococcal infection in children aged 6 months to 5 years, a case-control study, the Netherlands, February-May 2023
Authors: Hazelhorst Elizabeth I , van Ewijk Catharina E , Wielders Cornelia CH , te Wierik Margreet JM , Hahné Susan JM , de Melker Hester E , Knol Mirjam J , de Gier Brechje 
Published: November 2024

SummaryIn 2022, an increase in invasive Group A Streptococcal infections (iGAS) was observed in the Netherlands. A particular increase was seen among children, therefore we aimed to assess risk factors for iGAS in children aged 6 months to 5 years. A prospective case-control study was conducted between February and May 2023. We approached parents of notified iGAS cases to complete a questionnaire on exposures during 4 weeks prior to disease onset. Controls were recruited via social media and matched to cases (10:1) on sex and birthyear. Conditional logistic regression was performed to estimate odds ratios (OR) of exposures. For the analysis we included 18 cases and 103 controls. Varicella prior to onset of iGAS disease was reported in 2 (11%) cases and 1 (1%) control (OR: 12.0, 95% CI: 1.1-139.0). Exposure to GAS-like illnesses impetigo, pharyngitis and scarlet fever was reported in 8 (44%) cases and 15 (15%) controls (OR: 7.1, 95% CI: 1.8-29.0). Our findings are in line with previous studies by identifying varicella as a risk factor for iGAS among young children and highlight the association with non-invasive GAS infections in the community as a possible source of transmission.
Reducing phytate, an antinutritional factor, in sorghum dough using phytase-expressingSaccharomyces cerevisiae
Authors: Kale Tanaya , Kamble Rutuja , Pawar Aditi , Dawankar Sahil , Reshamwala Shamlan M. S. 
Published: November 2024

AbstractPhytate, a major antinutritional factor present in millets and legumes, chelates minerals like calcium, iron and zinc leading to their poor bioavailability. Phytase fromAspergillus japonicuswas expressed extracellularly inSaccharomyces cerevisiaeand its ability to reduce phytate in sorghum flour was determined. When theA. japonicusphytase-expressing strain was used to ferment sorghum dough, phytate reduction increased by 43% as compared to control strain. This approach of simultaneous proofing and phytate reduction can be used to increase micronutrient availability of non-wheat food products.
Interactions established by isoform-specific TrkB-T1 sequences govern inflammatory response and neurotoxicity in stroke
Authors: Ugalde-Triviño Lola , Tejeda Gonzalo S. , Esteban-Ortega Gema M. , Díaz-Guerra Margarita 
Published: November 2024

SummaryUgalde-Triviño et al. develop cell-penetrating peptides derived from neurotrophin receptor TrkB-T1 to identify isoform-specific protein interactions and demonstrate protective effects on neuroinflammation and neurotoxicity reducing brain damage in a mice model of ischemic stroke, of relevance to human therapy.AbstractGlia reactivity, neuroinflammation and excitotoxic neuronal death are central processes to ischemic stroke and neurodegenerative diseases, altogether a leading cause of death, disability, and dementia. Due to the high incidence of these pathologies and the lack of efficient treatments, it is a priority developing brain protective therapies impacting both neurons and glial cells. Truncated neurotrophin receptor TrkB-T1, a protein produced by all these cells, plays relevant roles in excitotoxicity and ischemia. We have hypothesized that interactions established by isoform-specific TrkB-T1 sequences might be relevant to neurotoxicity and/or reactive gliosis and, therefore, constitute a therapeutic target. We identify here the TrkB-T1-specific interactome, poorly described to date, and demonstrate that interference of these protein-protein interactions using brain-accessible TrkB-T1-derived peptides can prevent reactive gliosis and decrease excitotoxicity-induced damage in cellular and mouse models of stroke. The pivotal role played by TrkB-T1 on microglia and astrocyte reactivity suggests that isoform-derived peptides could become important in development of therapies for human stroke and other excitotoxicity-associated pathologies.
Conservation ofcis-regulatory codes over half a billion years of evolution
Authors: Ogawa Yohey , Liu Yu , Myers Connie A. , Morshedian Ala , Fain Gordon L. , Sampath Alapakkam P. , Corbo Joseph C. 
Published: November 2024

ABSTRACTThe identification of homologous cell types across species represents a crucial step in understanding cell type evolution. The retina is particularly amenable to comparative analysis because the basic morphology, connectivity, and function of its six major cell classes have remained largely invariant since the earliest stages of vertebrate evolution. Here, we show that the retina’s highly conserved cellular architecture is mirrored by deep conservation of the underlyingcis-regulatory codes that control gene expression. We use comparative single-cell chromatin accessibility analysis of lamprey, fish, bird, and mammalian retinas— representing over half a billion years of evolutionary divergence—to demonstrate cross-species conservation ofcis-regulatory codes in all six retinal cell classes. This conservation persists despite extensive turnover ofcis-regulatory regions between distant species. Conservation manifests as the clustering of multiple distinct high-affinity transcription factor (TF) binding sites toward the center of cell-class-specific open chromatin regions with little cross-species preservation of higher-order syntax. Hierarchical clustering of machine-learning models of retinalcis-regulatory codes from diverse species recovers six clusters corresponding to the six retinal cell classes. Thus, the retina’s cellularBauplanis controlled bycis-regulatory codes which predate the divergence of extant vertebrates and persist despite nearly complete enhancer turnover.
Smc5/6 association with microtubules controls dynamic pericentromeric chromatin folding
Authors: Carré-Simon Ànnia , Batrin Renaud , Isler Sarah , Dahl Pinholt Henrik , Földes Timothy , Laflamme Guillaume , Barbi Maria , Mirny Leonid , D’Amours Damien , Fabre Emmanuelle 
Published: November 2024

AbstractCentromeres and pericentromeres are specialized chromatin regions whose organization is critical for proper chromosome segregation through dynamic microtubule attachment. Smc5/6, highly enriched in pericentromeres, associates with microtubules. However, whether Smc5/6 contributes to chromatin folding and dynamics in these regions remains unclear. Here, we dissect Smc5/6 function at budding yeast centromeres by constructingsmc5-2KE,a separation-of-function mutant that reduces microtubule binding by replacing two lysines (K624 and K631) at the Smc5 hinge with glutamic acid. After demonstrating reduced microtubule binding bysmc5-2KE in vitro, we use high temporal resolution imaging in living cells and polymer modeling to show that Smc5/6 and microtubule binding restricts chromatin dynamics along chromosome arms, thus contributing to pericentromeric chromatin folding. Thesmc5-2KEmutant shows a strong pericentromere-specific reduction in homologous recombination repair, as well as defects in mitotic spindle length, centromere clustering and cytokinesis. Overall, our results reveal that Smc5/6-microtubule association ensures robust pericentromeric chromatin folding, contributing to genome integrity in the face of mitotic forces.
Upstream open reading frames buffer translational variability duringDrosophilaevolution and development
Authors: Sun Yuanqiang , Duan Yuange , Gao Peixiang , Liu Chenlu , Jin Kaichun , Dou Shengqian , Tang Wenxiong , Zhang Hong , Lu Jian 
Published: November 2024

AbstractProtein abundance tends to be more evolutionarily conserved than mRNA levels both within and between species, yet the mechanisms underlying this phenomenon remain largely unknown. Upstream open reading frames (uORFs) are widespreadcis-regulatory elements in eukaryotic genomes that regulate translation, but it remains unclear whether and how uORFs contribute to stabilizing protein levels. In this study, we performed ribosome translation simulations on mRNA to quantitatively assess the extent to which uORF translation influences the translational variability of downstream coding sequences (CDS) across varying contexts. Our simulations revealed that uORF translation dampens CDS translational variability, with buffering capacity increasing in proportion to uORF efficiency, length, and number. We then compared the translatomes at different developmental stages of twoDrosophilaspecies, demonstrating that uORFs buffer mRNA translation fluctuations during both evolution and development. Experimentally, deleting a uORF in thebcdgene—a prominent example of translational buffering—resulted in extensive changes in gene expression and phenotypes inDrosophila melanogaster. Additionally, we observed uORF-mediated buffering between primates and within human populations. Together, our results reveal a novel regulatory mechanism by which uORFs stabilize gene translation during development and across evolutionary time.
ABA increases fatty acids levels in apple roots to boost colonization by arbuscular mycorrhizal fungi
Authors: Jing Shan , Li Mingjun , Zhu Lingcheng , Li Chunhui , Li Yuchao , Du Lijun , Wei Xiaoyu , Zhang Manrang , Ma Baiquan , Ruan Yongling , Ma Fengwang 
Published: November 2024

AbstractThe roots of most land plants are in symbiosis with arbuscular mycorrhizal (AM) fungi. The fungus promotes nutrient uptake from the soil while receiving plant photosynthate as lipids and sugars. Nutrient exchange must be regulated by both partners, but the mechanisms underlying the regulation of lipid supplement from the plant to the AM fungus remain elusive. Here, we conducted a molecular study on the role of increased abscisic acid (ABA) levels during AM fungus infection in the roots of apple (Malusspp.). AM fungus induced the expression of two ABA synthesis genes,MdNCED3.1and3.2, in apple roots and increased the ABA content, which promoted the growth of the AM fungus. The effect of ABA on symbiosis was confirmed in transgenic apple roots either overexpressing or silencingMdNCED3.1orMdNCED3.2. Transcriptome analysis and transgenic manipulation revealed that the transcription factor MdABF2 played a key role in the ABA-mediated formation of symbiosis during AM infection and that MdABF2 could regulate the expression levels of genes related to fatty acid (FA) synthesis (e.g.,MdKASIII) and translocation (such asMdSTR2) in apple roots. Activation of these genes boosted the levels of available fatty acids in the roots and increased the AM fungal colonization and arbuscule development in the roots. These results revealed a molecular pathway in which positive regulation of FA synthesis and transport by the ABA signaling pathway increases supplementation to AM fungi and promotes AM symbiosis.
Regulatory plasticity of the human genome
Authors: Srivastava Jaya , Ovcharenko Ivan 
Published: November 2024

AbstractEvolutionary turnover in non-coding regions has driven phenotypic divergence during past speciation events and continues to facilitate environmental adaptation through variants. We used a deep learning model to identify the substrates of regulatory turnover using genome wide mutations mimicking three evolutionary pathways: recent history (human-chimp substitutions), modern population (human population variation), and mutational susceptibility (random mutations). We observed enhancer turnover in approximately 6% of the whole genome, with more than 80% of the novel activity arising from repurposing of enhancers between cell-types. Frequency of turnover in a cell-type is remarkably similar across the three pathways, despite only ∼19% overlap in the source regions. The enhancers predisposed to turnover display reduced evolutionary constraints and are depleted in GWAS variants. Most of these occur within 100kb of a gene, with the highest turnover occurring near neurodevelopmental genes including CNTNAP2, NPAS3, and AUTS2. Flanking enhancers of these genes undergo high turnover irrespective of the mutational model pathway, suggesting a high plasticity in neurocognitive evolution. Based on susceptibility to random mutations, these enhancers were identified as vulnerable by nature and feature a higher abundance of cell type-specific transcription factor binding sites (TFBSs). Our findings suggest that enhancer repurposing within vulnerable loci drives regulatory innovation while keeping the core regulatory networks intact.
Older is Order: Entropy reduction in cortical spontaneous activity marks healthy aging
Authors: Chang Da , Wang Xiu , Chen Yaojing , Han Zhuo , Liu Bing , Zhang Zhanjun , Zuo Xi-Nian 
Published: November 2024

AbstractEntropy trajectories remain unclear for the aging process of human brain system due to the lacking of longitudinal neuroimaging resource. We used open data from an accelerated longitudinal cohort (PREVENT-AD) that included 24 healthy aging participants followed by 4 years with 5 visits per participant to establish cortical entropy aging curves and distinguish with the effects of age and cohort. This reveals that global cortical entropy decreased with aging, while a significant cohort effect was detectable that people who were born earlier showed higher cortical entropy. Such entropy reductions were also evident for large-scale cortical networks, although with different rates of reduction for different networks. Specifically, the primary and intermediate networks reduce their entropy faster than the higher-order association networks. We conclude two specific characteristics of the entropy of the human cortex with aging: the shift of the complexity hierarchy and the diversity of complexity strengthen.
Calcium signalling is required for anterior patterning in the mouse embryo
Authors: Stower Matthew J. , Tyser Richard C. V. , Thowfeequ Shifaan , Zhou Felix , Portela Marta , Miti Konstantinos , Sugnaseelan Jacintha , Lu Xin , Srinivas Shankar 
Published: November 2024

ABSTRACTAnterior-Posterior axis formation in the mouse embryo requires the active migration of the DVE cell population at E5.5. While intracellular Ca2+signalling has been shown to control cell migration in multiple cell contexts, it is unknown whether it is required for DVE migration. The pattern of Ca2+activity in the mouse embryo at early peri-implantation stages is also unknown. Using the GCaMP6f Ca2+reporter line we performed a detailed assessment of Ca2+dynamics between E0.5 – E5.5 using live imaging. We find that prior to implantation, Ca2+transients are rare, but at E5.5 widespread, periodic, Ca2+transients in extra-embryonic tissues can be observed, including in the VE and ExE. In contrast, cells of the E5.5 epiblast remain relatively quiescent but show sporadic large-scale multi-cellular waves. Inhibition of SERCA at E5.5 abolishes Ca2+transients and leads to DVE arrest, indicative that these transients are required for axial patterning. Together these results reveal the pattern of Ca2+handling in the early mouse embryo and a novel requirement in anterior-posterior axis formation.
AGAPE (computAtional G-quadruplex Affinitiy PrEdiction): The first AI In-silico workflow for G-quadruplex binding affinity prediction
Authors: D’anna Luisa , Perricone Ugo , De Simone Giada , Monari Antonio , Barone Giampaolo , Terenzi Alessio 
Published: November 2024

ABSTRACTAGAPE(computAtional G-quadruplex Affinitiy PrEdiction) is an innovative machine learning (ML)-based workflow developed to predict the potential stabilization of small molecules by G-quadruplex (G4) structures. G4s, especially prevalent in telomeres and oncogene promoters, represent promising therapeutic targets, yet designing selective binders remains challenging. This study, thus, addresses this gap by implementing an ML framework in KNIME, specifically designed for ease of use across the scientific community. TheAGAPEworkflow integrates 5666 classical and quantum chemical (QC) descriptors for G4 ligands, enabling a comprehensive representation of binding-relevant molecular features. Using data from G4LDB and in-house collections, we created a robust dataset of 1217 compounds categorized by Förster Resonance Energy Transfer (FRET) assays as ACTIVE or INACTIVE based on their G4 stabilization capacity. Feature selection algorithms and ML models, particularly XGBoost with Naïve Bayesian and Random Forest classifiers, were employed to achieve an optimized prediction model with an accuracy close to 90%. A consensus voting system among top-performing models further improved classification reliability.AGAPEefficiently predicts G4 stabilization, offers interpretability of key chemical interactions, and provides a scalable, accessible tool for G4-focused drug discovery. This workflow lays the foundation for targeted therapeutic development, enhancing ligand selectivity, and expanding the application of AI in chemoinformaticsGRAPHICAL ABSTRACT