bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aperiodic neural activity distinguishes between phasic and tonic REM sleep
Authors: Rosenblum Yevgenia , Bogdány Tamás , Nádasy Lili Benedikta , Kovács Ilona , Gombos Ferenc , Ujma Péter , Bódizs Róbert , Adelhöfer Nico , Simor Péter , Dresler Martin 
Published: August 2024

AbstractIntroductionTraditionally categorized as a uniform sleep phase, rapid eye movement (REM) sleep exhibits substantial heterogeneity with its phasic and tonic constituents showing marked differences regarding neuronal network activity, environmental alertness and information processing. Here, we investigate how tonic and phasic states differ with respect to aperiodic neural activity, a marker of arousal levels, sleep stages, depth of sleep and sleep intensity. We also attempt to challenge the binary categorisation of REM sleep states by introducing graduality into their definition. Specifically, we quantify the intensity of phasic oculomotor events and investigate their temporal relationships with aperiodic activity.MethodWe analyzed 57 polysomnographic recordings from three open-access datasets of healthy young volunteers aged 21.7±1.4 years. REM sleep heterogeneity was assessed using either binary phasic-tonic categorization or quantification of eye movement (EM) amplitudes detected by electrooculography with the YASA algorithm. Slopes of the aperiodic power component measured by electroencephalography in the low (2–30Hz) and high (30–48Hz) frequency bands were calculated using the Irregularly Resampled Auto-Spectral Analysis. For statistical analyses, we used ANOVA, Spearman correlations and cross-correlations.ResultsThe binary approach revealed that the phasic state is characterized by steeper low-band aperiodic slopes compared to the tonic state with the strongest effect observed over the frontal area. The phasic state also showed flatter high-band slopes with the strongest effect over central and parietal areas. The gradual approach confirmed this result further showing that higher EM amplitudes are linked to steeper low-band and flatter high-band aperiodic slopes. The temporal analysis within REM episodes revealed that aperiodic activity preceding or following EM events did not cross-correlate with EM amplitudes.ConclusionThis study demonstrates that aperiodic slopes can serve as a reliable objective marker able to differentiate between phasic and tonic constituents of REM sleep and reflect the intensity of phasic oculomotor events for instantaneous measurements. However, EM events could not be predicted by preceding aperiodic activity and vice versa, at least not with scalp electroencephalography.
Deletion of endocannabinoid synthesizing enzyme DAGLα from cerebellar Purkinje cells decreases social preference and elevates anxiety
Authors: Smith Gabriella , McCoy Kathleen , Di Prisco Gonzalo Viana , Kuklish Alexander , Grant Emma , Bhat Mayil , Patel Sachin , Mackie Ken , Atwood Brady , Kalinovsky Anna 
Published: August 2024

ABSTRACTThe endocannabinoid (eCB) signaling system is robustly expressed in the cerebellum starting from the embryonic developmental stages to adulthood. There it plays a key role in regulating cerebellar synaptic plasticity and excitability, suggesting that impaired eCB signaling will lead to deficits in cerebellar adjustments of ongoing behaviors and cerebellar learning. Indeed, human mutations inDAGLαare associated with neurodevelopmental disorders. In this study, we show that selective deletion of the eCB synthesizing enzyme diacylglycerol lipase alpha (Daglα) from mouse cerebellar Purkinje cells (PCs) alters motor and social behaviors, disrupts short-term synaptic plasticity in both excitatory and inhibitory synapses, and reduces Purkinje cell activity during social exploration. Our results provide the first evidence for cerebellar-specific eCB regulation of social behaviors and implicate eCB regulation of synaptic plasticity and PC activity as the neural substrates contributing to these deficits.Abstract FigureGraphical abstract.Cerebellar anatomy, morphology of Purkinje cells, localization, density, and spontaneous activity of excitatory and inhibitory synapses are normal in cerebellar-Purkinje-cell-specific Daglα KOs. However, endocannabinoid-dependent short-term synaptic plasticity (DSE and DSI) and activity of Purkinje cells in lobe VI during social exploration are dramatically reduced, and the KO mice exhibit alterations in sensorimotor coordination, deceased social preference, and increased anxiety.
A site selection decision framework for effective kelp restoration
Authors: Giraldo-Ospina Anita , Bell Tom , Carr Mark H. , Caselle Jennifer E. 
Published: August 2024

AbstractHighlightsSite selection is one of the most important factors for ecosystem restoration successA spatial prioritization framework for application to kelp restoration in CaliforniaThe framework merges kelp metrics derived fromin-situsurveys and satellite imagerySite prioritization classification for every kelp forest site in CaliforniaThis framework can be applied to other species and regions with similar datasetsWe present a decision support framework in the form of a spatially explicit site classification scheme to prioritize locations for conducting kelp restoration. The framework was created for the entire coast of California, where kelp has been lost and restoration projects are increasingly proposed, but the framework is broadly applicable to other coastal habitats or species that are being considered for restoration. We first created spatial distribution models using almost two decades ofin situkelp forest monitoring data and a comprehensive suite of environmental and biological variables, and used the outputs to evaluate the historical stability of kelp forests prior to a marine heatwave (MHW). We then used kelp canopy abundance data derived from satellite imagery to measure the impact of the MHW (i.e. extent of forest loss) and the recent state of kelp forests, including the trend of increase or decrease following the MHW. Finally, we integrated these site-specific kelp metrics to construct a classification tree for prioritizing restoration sites. Outputs of site prioritization are mapped across the study region, readily usable for managers and restoration practitioners with site-specific recommendations for restoration approaches. The framework can be updated due to knowledge of the important predictors of kelp and with new satellite imagery. Further, the framework can be adapted to other species and regions with similar data sets. This regional site selection framework is intended to be used in addition to socio-ecological, socio-economic, and administrative considerations.
Coralline companions: Exploring microbes in coral ecosystems
Authors: Bharti Daizy , Ghosh Arnab , Kumar Santosh 
Published: August 2024

ABSTRACTCoral reefs exhibit remarkable resilience to natural disturbances but face challenges due to global changes and emerging diseases. In the present study, we recorded a total of 51 ciliates and over 400 bacteria associated with healthy and diseased corals from the Ramsar site Gulf of Mannar Marine National Park, India, based on morphology, silver staining, and Next Generation Sequencing. Our study contributes to the growing understanding of ciliate diversity and provides insights into the dynamics of ciliate-associated coral diseases, towards developing effective biocontrol agents for coral bleaching and conservation strategies to safeguard coral reef ecosystems.
Overcoming cryo-EM map anisotropy reveals ALK-cytokine assemblies with distinct stoichiometries
Authors: Felix Jan , De Munck Steven , Bazan J. Fernando , Savvides Savvas N. 
Published: August 2024

AbstractActivation of Anaplastic lymphoma kinase (ALK) and leukocyte tyrosine kinase (LTK) by their cognate cytokines ALKAL2 and ALKAL1 play important roles in development, metabolism, and cancer. Recent structural studies revealed ALK/LTK-cytokine assemblies with distinct stoichiometries. Structures of ALK-ALKAL2 and LTK-ALKAL1 complexes with 2:1 stoichiometry determined by X-ray crystallography (De Muncket al.Nature, 2021) contrasted the 2:2 ALK-ALKAL2 complexes determined by cryo-EM (Reshetnyaket al.,Nature, 2021) and X-ray crystallography (Liet al., Nature, 2021). Here, we show based on reanalysis of the cryo-EM data deposited in EMPIAR- 10930 that over half of the ALK-ALKAL2 particles in the dataset are classified into 2D classes obeying a 2:1 stoichiometry besides the originally reported structure displaying 2:2 stoichiometry. Unlike particles representing the 2:2 ALK-ALKAL2 complex, particles for the 2:1 ALK-ALKAL2 complex suffer severely from preferred orientations that resulted in cryo-EM maps displaying strong anisotropy. Here, we show that extensive particle orientation rebalancing in cryoSPARC followed by 3D refinement with Blush regularization in RELION constitutes an effective strategy for avoiding map artefacts relating to preferred particle orientations and report a 3D reconstruction of the 2:1 ALK-ALKAL2 complex to 3.2 Å resolution from EMPIAR-10930. This new cryo-EM structure together with the crystal structures of ALK-ALKAL2 and LTK-ALKAL1 complexes with 2:1 stoichiometry reconciles a common receptor dimerization mode for ALK and LTK and provides direct evidence for the presence of an ALK-ALKAL2 complex with 2:1 stoichiometry next to the reported 2:2 stoichiometric assembly in the EMPIAR-10930 dataset. Finally, our analysis emphasizes the importance of public deposition of raw cryo-EM data to allow reanalysis and interpretation.
A variant centric analysis of allele sharing in dogs and wolves
Authors: Funk Matthew W. , Kidd Jeffrey M. 
Published: August 2024

AbstractCanines are an important model system for genetics and evolution. Recent advances in sequencing technologies have enabled the creation of large databases of genetic variation in canines, but analysis of allele sharing among canine groups has been limited. We applied GeoVar, an approach originally developed to study the sharing of single nucleotide polymorphisms across human populations, to assess the sharing of genetic variation among groups of wolves, village dogs, and breed dogs. Our analysis shows that wolves differ from each other at an average of approximately 2.3 million sites while dogs from the same breed differ at nearly 1 million sites. We find that 22% of variants are common across wolves, village dogs, and breed dogs, that ∼16% of variable sites are common across breed dogs, and that nearly half of the differences between two dogs of different breeds are due to sites that are common in all clades. These analyses represent a succinct summary of allele sharing across canines and illustrate the effects of canine history on the apportionment of genetic variation.
Emergence of temporal noise hierarchy in co-regulated genes of multi-output feed-forward loop
Authors: Nandi Mintu 
Published: August 2024

AbstractNatural variations in gene expression, called noise, are fundamental to biological systems. The expression noise can be beneficial or detrimental to cellular functions. While the impact of noise on individual genes is well-established, our understanding of how noise behaves when multiple genes are co-expressed by shared regulatory elements within transcription networks remains elusive. This lack of understanding extends to how the architecture and regulatory features of these networks influence noise. To address this gap, we study the multi-output feed-forward loop motif. The motif is prevalent in bacteria and yeast and influences co-expression of multiple genes by shared transcription factors. Focusing on a two-output variant of the motif, the present study explores the interplay between its architecture, co-expression patterns of the two genes (including symmetric and asymmetric expressions), and the associated noise dynamics. We employ a stochastic modeling approach to investigate how the binding affinities of the transcription factors influence symmetric and asymmetric expression patterns and the resulting noise dynamics in the co-expressed genes. This knowledge could guide the development of strategies for manipulating gene expression patterns through targeted modulation of transcription factor binding affinities.
Reassessing the Neural Correlates of Social Exclusion: A Replication Study of the Cyberball Paradigm Using Arterial Spin Labelling
Authors: Labek Karin , Viviani Roberto 
Published: August 2024

AbstractBackground/ObjectivesThe cyberball paradigm has been used in numerous neuroimaging studies to elicit activation in neural substrates of social exclusion, which have been interpreted in terms of activity associated with “social pain”. The objectives of the study were to assess not only the replicability but also the specificity of the areas activated by this paradigm.MethodsFunctional imaging with arterial spin labelling, an approach to image longer mental states.Resultswe replicated findings of previous meta-analyses of this paradigm in the inferior frontal gyrus and ventral cingular cortex. However, these areas were also active in a watch condition (in which participants were not excluded), although less so.ConclusionsThese findings relativize a simple and specific interpretation of these areas as the neural substrates of social exclusion and social pain, as in previous studies. In a broader experimental context, similar activations have been reported by neuroimaging studies when semantic disambiguation and evaluation of action goals are required, an interpretation that may apply also to the effects elicited by this paradigm.
Clostridioides difficileToxins Unhinged: Allosterically Switchable Network Orientsβ-flap
Authors: Finn Lauren M. , Cummer Rebecca , Castagner Bastien , Keller Bettina G. 
Published: August 2024

AbstractAllosteric proteins exhibit a functional response upon substrate binding far from the active site.Clostridioides difficiletoxins use allosteric binding by an endogenous co-factor to orchestrate self-cleavage from within the target cell. This binding event induces a conformational shift, primarily effecting a lever-like “β-flap” region, with two known orientations. We uncovered a mechanism for this allosteric transition using extensive atomistic MD simulations and computational and experimental mutagenesis. The mechanism relies on a switchable interaction network. The most prominent interaction pair is K600–E743, with K600 interactions explaining ∼70 % of the allosteric effect. Rather than gradually morphing between two end states, the interaction network adopts two mutually exclusive configurations in the active and inactive state. Similar switchable networks may explain allostery more broadly. This mechanism in particular could aid in drug development targeting theClostridioides difficiletoxins autoproteolysis.
Spatial Transcriptomic Analysis Reveals HDAC Inhibition Modulates Microglial Dynamics to Protect Against Ischemic Stroke in Mice
Authors: Jayaraj Kevin , Kumar Ritesh , Shyamasundar Sukanya , Arumugam Thiruma V , Polepalli Jai S , Dheen S Thameem 
Published: August 2024

AbstractIschemic stroke significantly contributes to global morbidity and disability through a cascade of neurological responses. Microglia, the immune modulators within the brain, exhibit dual roles in exacerbating and ameliorating ischemic injury through neuroinflammatory and neuroprotective roles, respectively. Despite emerging insights into microglia’s role in neuronal support, the potential of epigenetic intervention to modulate microglial activity remains largely unexplored. We have previously shown that sodium butyrate, a histone deacetylase inhibitor (HDACi) epigenetically regulates inflammatory response of microglia after ischemic stroke and this study was aimed to characterize the transcriptomic profiles of microglia and their spatial distribution in the stroke brain followed by HDACi administration. We hypothesized that the administration of HDACi epigenetically modulates microglial activation and a region-specific microglial phenotype in the stroke brain, shifting their phenotype from neurotoxic to neuroprotective and facilitating neuronal repair and recovery in the ischemic penumbra. Utilizing a rodent model of middle cerebral artery occlusion (MCAo), spatial transcriptomics and 3D morphometric reconstruction techniques were employed to investigate microglial responses in critical penumbral regions, such as the hippocampus, thalamus, cortex and striatum following HDACi administration. We found that HDACi significantly altered the microglial transcriptomic landscape involving biological pathways of neuroinflammation, neuroprotection and phagocytosis as well as morphological phenotype, promoting a shift towards reparative, neurotrophic profiles within the ischemic penumbra. These changes were also associated with enhanced neuronal survival and reduced neuroinflammation in specific regions in the ischemic brain. By elucidating the mechanisms through which HDAC inhibition influences microglial function, our findings propose therapeutic avenues for neuroprotection and rehabilitation in ischemic stroke, and possibly other neurodegenerative conditions that involve microglia-mediated neuroinflammation.
Potent LILRB1 D1D2-containing antibodies inhibit RIFIN-mediated immune evasions
Authors: Wang Yizhuo , Tang Hengfang , Wang Wanxue , Li Ming , Zhu Chenchen , Dai Han , Zhao Hongxin , Wu Bo , Wang Junfeng 
Published: August 2024

AbstractThe spread of drug-resistant malaria parasites presents a major challenge to global efforts in malaria control, increasing the urgency for new treatments and vaccines. A promising approach involves developing antibodies that can counteract the parasite’s immune evasion mechanisms. In this study, we designed a receptor-containing antibody, targeting the D1D2 domain of the LILRB1 receptor, using a structure-based rational approach. We began with the MDB1 antibody as a scaffold and replaced the LILRB1-D3D4 insertion domain with D1D2.v, a high-affinity variant optimized through yeast surface display. The modified D1D2.v-IgG efficiently blocked the interaction between RIFIN#1 (from PF3D7_1254800) and LILRB1, thereby reversing the inhibition of NK cell activity caused by RIFIN#1. To further enhance this effect, we developed NK-biAb, a bispecific antibody based on D1D2.v-IgG that targets both RIFIN#1 and NKG2D receptors. NK-biAb exhibited superior biological performance compared to D1D2.v-IgG alone. These findings provide a clear framework for designing antibodies that target immune evasion in malaria, potentially guiding the development of more effective treatments and vaccines.
DNA methylation status classifies pleural mesothelioma cells according to their immune profile: implication for precision epigenetic therapy
Authors: Lofiego Maria Fortunata , Tufano Rossella , Bello Emma , Solmonese Laura , Marzani Francesco , Piazzini Francesca , Celesti Fabrizio , Caruso Francesca Pia , Rosaria Noviello Teresa Maria , Mortarini Roberta , Anichini Andrea , Ceccarelli Michele , Calabrò Luana , Maio Michele , Coral Sandra , Di Giacomo Anna Maria , Covre Alessia ,   the EPigenetic Immune-oncology Consortium Airc (EPICA) investigators
Published: August 2024

AbstractBackgroundco-targeting of immune checkpoint inhibitors (ICI) CTLA-4 and PD-1 has recently become the new first-line standard of care therapy of pleural mesothelioma (PM) patients, with a significant improvement of overall survival over conventional chemotherapy. The analysis by tumor histotype demonstrated a greater efficacy of ICI therapy in non-epithelioid (non-E)vsepithelioid (E) PM; although some E PM patients also benefit from treatment. This evidence suggests that molecular tumor features, beyond histotype, could be relevant to improve the efficacy of ICI therapy in PM. Among these, tumor DNA methylation emerges as a promising factor to explore, due to its potential role in driving the immune phenotype of cancer cells. Thus, we utilized a panel of cultured PM cells of different histotype, to provide preclinical evidence supporting the role of the tumor methylation landscape and of its pharmacologic modulation, to prospectively improve the efficacy of ICI therapy of PM patients.Methodsthe methylome profile (EPIC array) of distinct E (#5) and non-E (#9) PM cell lines was analyzed, followed by integrated analysis with their associated transcriptomic profile (Clariom S array), before and afterin vitrotreatment with the DNA hypomethylating agent (DHA) guadecitabine. The most variable methylated probes were selected to calculate the methylation score (CIMP index) for each cell line at baseline. Genes that were differentially expressed and methylated were then selected for gene ontology analysis.Resultsthe CIMP index stratified PM cell lines in two distinct classes, CIMP (hyper-methylated; #7) and LOW (hypo-methylated; #7), regardless of their E or non-E histotype. Integrated analyses of methylome and transcriptome data revealed that CIMP PM cells had a substantial number of hyper-methylated, silenced genes, which negatively impacted their immune phenotype compared to LOW PM cells.Treatment with DHA reverted the methylation-driven immune-compromised profile of CIMP PM cells and enhanced the constitutive immune-favorable profile of LOW PM cells.Conclusionthe study highlighted the relevance of DNA methylation in shaping the constitutive immune classification of PM cells, that is independent from their histological subtypes. The identified role of DHA in shifting the phenotype of PM cells towards an immune-favorable state supports its role in clinical trials of precision epigenetic therapy combined with ICI.
A genome-wide association study identifies markers and candidate genes affecting tolerance to the wheat pathogenZymoseptoria tritici
Authors: Mikaberidze Alexey , McDonald Bruce A. , Kronenberg Lukas 
Published: August 2024

AbstractPlants defend themselves against pathogens using either resistance, measured as the host’s ability to limit pathogen multiplication, or tolerance, measured as the host’s ability to reduce the negative effects of infection. Tolerance is a promising trait for crop breeding, but its genetic basis has rarely been studied and remains poorly understood. Here, we reveal the genetic basis of leaf tolerance to the fungal pathogenZymoseptoria triticithat causes the globally important septoria tritici blotch disease on wheat. Leaf tolerance toZ. triticiis a quantitative trait that was recently discovered in wheat by using automated image analyses that quantified the symptomatic leaf area and counted the number of pycnidia found on the same leaf. A genome-wide association study including both tolerance and resistance to STB found a strong negative genetic correlation between these traits, indicative of a trade-off. We identified four chromosome intervals associated with tolerance and a separate chromosome interval associated with resistance. Within these intervals, we identified candidate genes, including wall-associated kinases similar toStb6, the first cloned STB resistance gene. A trade-off between tolerance and resistance would hinder breeding simultaneously for both traits, but our findings suggest a way forward using marker-assisted breeding. We expect that the methods described here can be used to characterize tolerance to other fungal diseases that produce visible fruiting bodies, such as speckled leaf blotch on barley, potentially unveiling conserved tolerance mechanisms shared among plant species.