bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inferring community architectures of multisensory pathways inDrosophilavia unsupervised network embedding
Authors: Sun Xiyang , Komaki Fumiyasu 
Published: December 2024

AbstractUnderstanding the complex architecture and functions of neural circuits is central to unraveling the mechanisms of multisensory integration. In this study, we analyzed the structural properties of theDrosophilaadult brain to infer community structures within multisensory pathways. We adopt a network embedding method developed by ourselves, the Bidirectional Heterogeneous Graph Neural Network with Random Teleport (BHGNN-RT), designed to generate vector representations of neurons in a directed, heterogeneous brain connectome. This approach takes advantage of both structural connectivity and network heterogeneity features, enabling effective clustering of neurons and revealing hierarchical community architectures in olfactory and broader multisensory systems. We applied BHGNN-RT to the fly brain connectome to examine connectivity-based community organization in major neuronal classes along multisensory pathways, revealing distinct neural groups with unique connectivity patterns in the antennal lobe, lateral horn, mushroom body, and other brain regions. Further analysis showed how different neural groups contribute to the integration of sensory information in olfactory and multisensory systems. We also investigated the bilateral symmetry of the olfactory pathway, shedding light on how sensory signals are processed with ipsilateral and contralateral connections to ensure robust perception. Our findings demonstrate the utility of graph representation learning in analyzing the structural connectivity of complex neural systems. The insights gained from BHGNN-RT provide a deeper understanding of the community architecture in theDrosophilabrain and contribute to a broader comprehension of the mechanisms underlying multisensory integration.
Kabasura Kudineer Choornam, a medicinal polyherbal formulation, modulates human macrophage polarization and phagocytic function
Authors: Korkmaz Asli , Unuvar Duygu , Gunalp Sinem , Helvaci Derya Goksu , Sag Duygu 
Published: December 2024

AbstractBackgroundKabasura kudineer choornam(KKC) is a polyherbal formulation with 15 ingredients. It has been shown to have anti-inflammatory and anti-microbial properties and demonstrate efficacy in managing the symptoms of H1N1 swine flu and COVID-19. However, its mechanism of action is not fully comprehended.PurposeHerein, we examined the effect of theKKCon the polarization and function of primary human macrophages.MethodsHuman monocyte-derived macrophages (M0 macrophages) pre-treated withKKCextract were polarized into M1, M2a, or M2c subtypes. The expression of the M1/M2 polarization markers was analyzed by qPCR, flow cytometry, and ELISA, and the phagocytosis capacity of macrophages was analyzed by flow cytometry.ResultsOur data show that theKKCtreatment increased the expression of the M1 markers IDO1, IL-1β, IL-12a(p35), and TNF in both polarized and unpolarized macrophages at mRNA level. However, it decreased the secretion of IL-12 (p70) in M1 macrophages and increased the secretion of TNF in M0, M2a, and M2c macrophages. IL-10 secretion was increased in M0 and M2a macrophages, while it was decreased in M1 macrophages after theKKCtreatment. Interestingly, allKKC-treated macrophage phenotypes displayed a downregulation in the expression of the M1/M2 surface markers CD64, CD206, CD209, and CD163, which also play a role in phagocytosis. In accordance with this result, the phagocytic capacity of both polarized and unpolarized macrophages was decreased after theKKCtreatment.ConclusionIn conclusion,KKCextract modulates macrophage inflammatory response and could be a potential supplement for the treatment of infectious and inflammatory diseases.
The angiosperm seed life cycle follows a developmental reverse hourglass
Authors: Sami Asif Ahmed , Bentsink Leónie , Artur Mariana A. S. 
Published: December 2024

AbstractThe seed life cycle is one of the most crucial stages in determining the ecological success of angiosperms. It broadly comprises three developmental phases - embryogenesis, maturation, and germination. Among these phases, seed maturation is particularly critical, serving as a bridge between embryo development and germination. During this phase, seeds accumulate nutrient reserves and acquire essential physiological traits, such as desiccation tolerance, vital for seed survival in diverse environments. Phylotranscriptomics inArabidopsis thalianahas shown that embryogenesis and germination follow an hourglass-like development, with high expression of older and conserved genes at the mid-developmental stages. However, unlike embryogenesis and germination, a phylotranscriptomic study of seed maturation has not yet been performed and a comprehensive overview of the phylotranscriptomic landscape throughout the entire seed life cycle is still lacking. Here, we combined existing RNA-seq data covering all three phases of theArabidopsisseed life cycle to construct a complete picture of the phylotranscriptomic pattern of the seed life cycle by generating transcriptome age index (TAI) and transcriptome divergence index (TDI) profiles. We found that the seed life cycle resembles a reverse hourglass-like pattern, with seed maturation exhibiting increased expression of younger genes with divergent expression patterns compared to embryogenesis and germination. Notably, this pattern of increased expression of younger genes during seed maturation is also conserved across both dicot and monocot species. Tissue-specific phylotranscriptomic analyses revealed that, in monocots, the increased expression of younger genes during maturation is largely driven by genes expressed in the endosperm. Overall, our findings highlight the major shifts in phylotranscriptomic patterns during the seed life cycle and establish seed maturation as a pivotal developmental phase enabling the expression of young and rapidly evolving genes critical for seeds’ adaptive capacity in their surrounding environment.
Nuclear metabolism oscillation during the cell cycle reveals a link between the phosphatidylinositol pathway and histone methylation
Authors: Gañez-Zapater Antoni , Kourtis Savvas , Espinar Lorena , García-López Laura , Wiegand Laura , Guirola Maria , Fontaine Frédéric , Müller André C , Sdelci Sara 
Published: December 2024

AbstractThe progression of the cell cycle is regulated by the expression of specific genes and fluctuations in cellular metabolic states. Previous research has employed cell cycle-based transcriptomics, proteomics, and metabolomics analyses to identify cell cycle-dependent changes at the gene expression, protein, and metabolic levels. However, the role of protein compartmentalization in regulating protein function, coupled with evidence that metabolic enzymes can localize to the nucleus and influence chromatin states, suggests that fluctuations in nuclear metabolism may play a role in regulating cell cycle progression. In this study, we developed an approach to resolve chromatin and nuclear changes during the cell cycle in an unbiased and systematic manner. This was achieved by integrating cell cycle fluorescent reporters with chromatin mass spectrometry and cellular imaging. Our investigation focused on metabolic enzymes and revealed that phosphatidylinositol metabolism localizes to the nucleus in a cell cycle-dependent manner. Moreover, disruption of phosphatidylinositol metabolism affects the nuclear distribution of phosphatidylinositol 4,5-bisphosphate, alters the number and morphology of nucleoli, and influences the maintenance of distinct heterochromatin states throughout the cell cycle. Finally, given the established link between phosphatidylinositol metabolism and methionine synthesis, as well as the differential impact observed on distinct histone marks when phosphatidylinositol metabolism is perturbed, we proposed that distinct pools of methionine may be involved in the maintenance of histone marks that decorate heterochromatin in a cell cycle-dependent manner.
Task and Behavior-Related Variables Are Encoded by the Postrhinal and Medial Entorhinal Cortex During Non-Spatial Associative Learning
Authors: Nystuen Ingeborg Nymoen , Rogge Frederik Sebastian , Aasen Anna Hjertvik , Grødem Sverre , Malthe-Sørenssen Anders , Lepperød Mikkel Elle , Hafting Torkel , Fyhn Marianne , Lensjø Kristian Kinden 
Published: December 2024

AbstractThe medial entorhinal cortex (MEC) is pivotal in spatial computations and episodic memory. In particular, an animal’s position can be decoded from the activity of entorhinal grid cells. However, it remains elusive whether MEC could play a more general role in different types of associative learning and how the representations develop during the learning process. It has been shown that the postrhinal cortex (POR), which is directly connected to MEC, integrates visual stimuli with salient outcomes. Here, we use a non-spatial visual association task to investigate whether MEC neurons represent low-level visual cues during learning. Using a Go/NoGo visual association task, we recorded neural activity in MEC and POR throughout the learning phase as mice associated drifting gratings with rewarded, aversive, or neutral outcomes.Our findings reveal that the neural tuning curves in both the POR and MEC change with the learning of the task. From the start of training, the POR neurons exhibited response tuning to the visual cues, and the tuning was stable to cue orientations during learning. In contrast, MEC neurons did not initially respond very strongly to visual cues but developed a robust tuning toward the rewarded trials. While the MEC’s representation of visual information was limited, it encoded other task elements. A large fraction of the neurons formed distinct functional clusters that were either activated or suppressed by reward-related behavior. Remarkably, these clusters segregated anatomically in MEC and maintained strong within-cluster correlations before and after training. Notably, although the same functional clusters were apparent in the POR, they did not show any anatomical structure as in the MEC. Task reversal induced significant changes in network responses across both regions, with a decrease in overall task-responsive neurons but a slight increase in stimulus representation. Strikingly, information about the choice to lick emerged with learning in both brain areas, and most significantly within the functional cell clusters representing reward consumption and plus-cue stimulus. Our results demonstrate that although neurons in MEC and POR develop behavior-modulated tuning during learning of a non-spatial visual association task, the MEC exhibits stronger within-cluster correlations and anatomical organization. Conversely, the POR population exhibits less structural organization and more specific stimulus-tuning, which is reflective of being a higher visual association area. Our findings reveal that the MEC can encode task– and behavior-related variables beyond spatial information.
Kcnb1-Kcng4 axis regulates Scospondin secretion and Reissner fiber development
Authors: Amini Rasieh , Jain Ruchi P. , Korzh Vladimir 
Published: December 2024

AbstractThe voltage-gated potassium channel Kv2.1 plays a role in the development of the ventricular system and the subcommissural organ in zebrafish. Here, a role for Kv2.1 in the secretion of the major component of Reissner’s fiber, Scospondin, was demonstrated. The results showed that Kv2.1 acts as a negative regulator of Scospondin secretion and Reissner fiber assembly. Kv2.1 regulates formation of Scospondin microfilaments and their assembly in Reissner fiber. Cholesterol playing a key role in Scospondin secretion. After the Reissner fiber is formed, it is detached from the hindbrain floor plate, where Scospondin produced initially. The tension of the fiber depends on its attachment to the subcommissural and flexural organs. In turn fiber tension affects the morphogenesis of these organs. This process of Reissner fiber formation depends on the input provided by the Hedgehog and Wnt/β-catenin signaling pathways on the anterior roof and floor plates.
Regulation of co-translational mRNA decay by PAP and DXO1 in Arabidopsis
Authors: Carpentier Marie-Christine , Receveur Anne-Elodie , Cadoudal Adrien , Merret Rémy 
Published: December 2024

ABSTRACTBackgroundmRNA decay is central in the regulation of mRNA homeostasis in the cell. The recent discovery of a co-translational mRNA decay pathway (also called CTRD) has changed our understanding of the mRNA decay process. This pathway has emerged as an evolutionarily conversed mechanism essential for specific physiological processes in eukaryotes, especially in plants. In Arabidopsis, this pathway is targeted mainly by the exoribonuclease XRN4. However, the details of the molecular regulation of this pathway are still unclear.ResultsIn this study, we first tested the role of the 3ʹ-phosphoadenosine 5ʹ-phosphate (PAP), an inhibitor of exoribonucleases in the regulation of CTRD. Using 5’Pseq approach, we discovered that FRY1 inactivation impaired XRN4-CTRD activity. Based on this finding, we demonstrated that exogenous PAP treatment stabilizes CTRD mRNA targets. Furthermore, we also tested the implication of the exoribonuclease DXO1 in CTRD regulation. We found that DXO1, another exoribonuclease sensitive to PAP, is also involved in the CTRD pathway, especially by targeting NAD+-capped mRNAs. DXO1 specifically targets mRNAs linked to stress response.ConclusionsOur study provides further insights into the regulation of CTRD in Arabidopsis and demonstrates that other exoribonucleases can be implicated in this pathway.
Intensive Chemotherapy Induces Cardiotoxicity via Reverse Electron Transport
Authors: Pinto Carla , Liu Youzhong , Benaouadi Sabrina , Sainte-Marie Yannis , Laaouamir Lotfi , Marsal Dimitri , Gastel Nick Van , Savagner Frédérique , Farge Thomas 
Published: December 2024

AbstractChemotherapy-induced cardiotoxicity has emerged as an important focus in oncology, driven by the growing number of cancer survivors. Intensive chemotherapies (iCT) used in the treatment of acute myeloid leukemia (AML) often lead to significant adverse cardiac events, which can reduce therapeutic benefits, limit treatment options, or even necessitate discontinuation—particularly for patients with pre-existing cardiac conditions, resulting in a loss of therapeutic opportunity. This study shows that the iCT triggers severe mitochondrial dysfunction in cardiac tissue, mirroring effects seen in ischemia-reperfusion models. Specifically, iCT results in succinate accumulation and elevated reactive oxygen species production, consistent with reverse electron transport phenomenon. Importantly, these effects were entirely prevented with RET inhibitors such as malonate or S1QEL1.1.In vivo, we demonstrate that malonate administration successfully prevents iCT-induced cardiotoxicity, maintaining left ventricular ejection fraction and fibrosis levels comparable to controls. Additionally, in an MLL-AF9-driven AML model, malonate sensitized leukemic cells to iCT. These findings support the dual potential of malonate: as an OXPHOS metabolism inhibitor to overcome chemoresistance in AML, while also reducing cardiotoxic risk for already vulnerable patients.One Sentence Summary:This study demonstrates that malonate prevents chemotherapy-induced cardiotoxicity by inhibiting mitochondrial reverse electron transport (RET), preserving cardiac function, and simultaneously sensitizing AML cells to intensive chemotherapy.
Fraxinus excelsiorupdated long-read genome reveals the importance of MADS-box genes in tolerance mechanisms against ash dieback
Authors: Franco Ortega Sara , Bedford James A. , James Sally R. , Newling Katherine , Ashton Peter D. , Boshier David H. , Clark Jo , Hartley Susan E. , Harper Andrea L. 
Published: December 2024

AbstractAsh dieback caused by the fungusHymenoscyphus fraxineushas devastated the European ash tree population since it arrived in Europe in 1992. Great effort has been put into breeding programmes to increase the genetic diversity of ash trees and find heritable genetic markers associated with resistance, or tolerance mechanisms, to ash dieback. To facilitate identification of molecular markers, we used Oxford Nanopore Technologies combined with Illumina sequencing to obtain an accurate and contiguous ash genome. We used this genome to reanalyse transcriptome data from a Danish ash panel of 182 tree accessions. Using associative transcriptomics, we identified 175 gene expression markers (GEMs), including 11 genes annotated as dormancy MADS-box transcription factors which are associated with ash bud dormancy, flowering and senescence. We hypothesize that tolerant trees both break dormancy earlier in the year by increasing the expression of flowering-related SOC1 MADS-box and reducing the expression of SVP-like MADS-box, whilst also accelerating senescence by increasing the expression of JOINTLESS MADS-box genes. DNA methylation differences in the promoters of MADS-box genes between one tolerant and one susceptible tree indicate potential epigenetic regulation of these traits.Article SummaryAsh dieback has devastated European ash tree populations. To aid in breeding programmes focused on finding solutions against this pathogen, we have assembled a new ash genome. This new genome helped us to identify genes related to tree biological life cycles, expressed differently in tolerant and susceptible trees. For the first time, we have also discovered that susceptible and tolerant trees showed different DNA methylation frequencies in those genes, suggesting epigenetic regulation. DNA methylation can turn on/off gene expression without changing the DNA sequence. These genes, and their regulatory elements, are ideal targets during breeding programmes combating this pathogen.
Coenzyme M: An Archaeal Antioxidant as an Agricultural Biostimulant
Authors: Brown Jeremy H. , Vijayan Jithesh , de Queiroz Aline Rodrigues , Ramos Natalia Figueroa , Bickford Nate , Wuellner Melissa , Buan Nicole R. , Stone Julie M. , Glowacka Katarzyna , Roston Rebecca L. 
Published: December 2024

AbstractRising global food demand necessitates improved crop yields. Biostimulants offer a potential solution to meet these demands. Among them, antioxidants have shown potential to improve yield, nutritional quality and resilience to climate change. However, large-scale production of many antioxidants is challenging. Here, we investigate Coenzyme M (CoM), a small, achiral antioxidant from archaea, as a potential biostimulant, investigating its effects on growth and physiology. CoM significantly increased biomass of the model plantArabidopsis thalianain a concentration-dependent manner consistent with it being metabolized. In tobacco, CoM increased photosynthetic light capture capacity, consistent with observed growth improvements. Interestingly, this effect was independent of carbon capture rates. Furthermore, CoM promoted early-stage shoot growth in various crops species, including tobacco, basil, cannabis, and soybean. Our results suggest CoM is a promising, scalable biostimulant with potential to modify photosynthesis and enhance crop productivity.Key PointsAntioxidant application improves plant growth but is typically too expensive to use widely.Coenzyme M is a small, easily made antioxidant of Archaeal origin.Applied exogenously, Coenzyme M conditionally increases plant biomass.Coenzyme M represents an antioxidant with potential to be a widely used biostimulant.
Chemogenetic Activation of Medial Prefrontal Cortex Projections to the Nucleus Accumbens Shell Suppresses Cocaine-Primed Reinstatement in EcoHIV Infected Mice
Authors: Xie Qiaowei , Namba Mark D. , Dasari Rohan , Buck Lauren A. , Side Christine M. , Goldberg Samuel L. , Park Kyewon , Jackson Joshua G. , Barker Jacqueline M. 
Published: December 2024

AbstractHIV is highly comorbid with cocaine use disorder (CUD). Relapse is a major challenge in the treatment of CUD, and people living with HIV (PLWH) exhibit shorter time to relapse. One driver of relapse may be re-exposure to cocaine, which can be modeled in rodents using cocaine-primed reinstatement. This process involves neuroadaptations within the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) shell, regions that mediate cocaine reward learning and relapse-related behavior. HIV infection interacts with cocaine to alter corticostriatal circuits, which may further dysregulate cocaine seeking. To investigate the impact of HIV infection on cocaine reward learning and reinstatement and the role of mPFC-NAc circuits, we utilized the EcoHIV mouse model, a chimeric form of HIV-1 which can infect wild-type mice. Our findings demonstrate that EcoHIV infection enhances cocaine-primed reinstatement. We also observed increased cocaine-induced expression of the cellular activation marker cFos in the NAshell in EcoHIV-infected mice. Given the role of the mPFC-NAshell circuit in cocaine-seeking behaviors, we further demonstrated that chemogenetic activation of this circuit could reverse the behavioral deficits induced by EcoHIV. We propose that HIV infection contributes to neuroadaptations in the mPFC-NAshell circuit, and enhancing its activity may inhibit relapse-related behavior. These findings indicate that key neuronal circuits underlying cocaine reinstatement are similarly implicated in HIV infection and suggest potential strategies for managing relapse in PLWH.
Rule-Based Deconstruction and Reconstruction of Diterpene Libraries: Categorizing Patterns & Unravelling the Structural Landscape
Authors: Mathieu Davis T. , Schlecht Nicholas , van Aalst Marvin , Shebek Kevin M. , Busta Lucas , Babineau Nicole , Ebenhöh Oliver , Hamberger Björn 
Published: December 2024

AbstractTerpenoids make up the largest class of specialized metabolites with over 180,000 reported compounds currently across all kingdoms of life. Their synthesis accentuates one of natures most choreographed enzymatic and non-reversible chemistries, leading to an extensive range of structural functionality and diversity. Current terpenoid repositories provide a seemingly endless landscape to systematically survey for information regarding structure, sourcing, and synthesis. Efforts here investigate entries for the 20-carbon diterpenoid variants and deconstruct the complex patterns into simple, categorical groups. This deconstruction approach reduces over 60,000 unique diterpenoid structures to less than 1,000 categorical structures. Furthermore, the majority of diterpene entries (over 75%) can be represented by less than 25 core skeletons. Natural diterpenoid abundance was mapped throughout the tree of life and structural diversity was correlated at an atom-and-bond resolution. Additionally, all identified core structures provide guidelines for predicting how diterpene diversity originates via the mechanisms catalyzed by diterpene synthases. Over 95% of diterpenoid structures rely on cyclization. Here a reconstructive approach is reapplied based on known biochemical rules to model the birth of compound diversity. Reconstruction enabled prediction of highly probable synthesis mechanisms for bioactive taxane-relatives, which were discovered over three decades ago. This computational synthesis validates previously identified reaction products and pathways, as well as enables predicting trajectories for synthesizing real and theoretical compounds. This deconstructive and reconstructive approach applied to the diterpene landscape provides modular, flexible, and an easy-to-use toolset for categorically simplifying otherwise complex or hidden patterns.Significance StatementWe take a deconstructive and reconstructive approach to explore the origins of the diterpene landscape. Introduction of a navigational toolset enables users to survey compound libraries in ways formerly uncharted. Their utility demonstrated here, maps out diterpene cyclization routes, critical intermediate waypoints, and guidance for how to arrive at compounds previously off-the-map. Information acquired from these tools may imply the diterpene landscape is vastly unexplored, with the plateau for discovery potentially still out of sight.