bluuebunny/crossref_metadata_2025_split huggingface dataset:
Calneuron 1 reveals the pivotal roles in schizophrenia via perturbing human forebrain development and causing hallucination-like behavior in mice
Authors: Li Hui-Juan , Yu Xiao , Liu Xi , Xu Jinhong , Chen Jinlong , Cheng Tianlin , Chung Sangmi , Shu Yousheng , Shao Zhicheng 
Published: April 2024

AbstractSchizophrenia is a highly heritable neurodevelopmental disorder with unknown genetic pathogenic mechanisms. Here, we selected 11 schizophrenia risk genes and generated single-gene-knockout-precise-dorsal/ventral-forebrain-organoids (SKOPOS) via CRISPR-Cas9 system. 90 bulk and 249,430 single-cell RNA-sequencing of SKOPOS revealed that knockout of 11 risk genes lead to different levels of deficits in dorsal/ventral forebrain organoids. Among them, calneuron 1 (CALN1) acts as a pivotal pathogenic gene of schizophrenia via severe disruption of gene expression network, interaction with about 32% (34/106) known schizophrenia risk genes, delayed maturation and impaired spontaneous neural circuit in human developing forebrain. Furtherly, including the spontaneous abrupt burst spiking in cortical neurons and the defects of spatial memory, cognition and social ability,Caln1KO mice surprisingly displayed spontaneous startle behavior and head-twitch response correlated with hallucination-like behavior, which could be inhibited by antipsychotic drug SEP-363856. In summary,CALN1is identified as a pivotal pathogenic gene of schizophrenia in forebrain development.
Electrophysiological Brain Network Estimation with Simultaneous Scalp EEG and Intracranial EEG: Inference Algorithm and Applications
Authors: Yang Shihao , Liu Feng 
Published: April 2024

AbstractActivity in the human brain is composed of complex firing patterns and interactions among neurons and neuronal circuits. The neuroimaging field underwent a paradigm shift over the past decades from mapping tasked evoked brain regions of activations towards identifying and characterizing the dynamic brain networks of coordinating brain regions. Electrophysiological signals are the direct manifestation of brain activities, thus characterizing the whole brain electrophysiological networks (WBEN) can serve as a fundamental tool for neuroscience studies and clinical applications. The electrophysiological network inferred from electroencephalogram (EEG) source imaging suffers from low accuracy limited by the Restricted Isometry Property (RIP), while the invasive EEG-derived electrophysiological networks can only characterize partial brain regions where invasive electrodes reside. In this work, we introduce the first framework for the integration of scalp EEG and intracranial EEG (iEEG) for WBEN estimation with a principled estimation framework based on state-space models, where an Expectation-Maximization (EM) algorithm is designed to infer the state variables and brain connectivity simultaneously. We validated the proposed method on synthetic data, and the results revealed improved performance compared to traditional two-step methods using scalp EEG only, which demonstrates the importance of the inclusion of iEEG signal for WBEN estimation. For real data with simultaneous EEG and iEEG, we applied the developed framework to understand the information flows of the encoding and maintenance phases during the working memory task. The information flows between the subcortical and cortical regions are delineated, which highlights more significant information flows from cortical to subcortical regions compared to maintenance phases. The results are consistent with previous research findings, however with the view of the whole brain scope, which underscores the unique utility of the proposed framework.
Endothelial c-Src mediates neovascular tuft formation in Oxygen-Induced Retinopathy
Authors: Frampton Emmanuelle , Som Priyanka , Hill Brittany , Yu Alexander , Noordstra Ivar , Gordon Emma , Schimmel Lilian 
Published: April 2024

AbstractIntroductionVascular retinopathy, characterised by abnormal blood vessel growth in the retina, frequently results in vision impairment or loss. Neovascular tufts, a distinctive pathological feature of this condition, are highly leaky blood vessel structures, exacerbating secondary complications. Despite their clinical significance, the mechanisms underlying tuft development are not fully elucidated, posing challenges for effective management and treatment of vascular retinopathy. In this study, we investigate the role of c-Src in neovascular tuft formation. Although c-Src has been acknowledged as a pivotal regulator in developmental angiogenesis within the retinal vasculature, its specific role in governing pathological retinal angiogenesis remains to be fully understood.MethodsWe utilised the Oxygen-Induced Retinopathy (OIR) model to induce the formation of neovascular tufts in both Cre-mediated vascular specific c-Src knockout mice and their wildtype littermates. Subsequently, we conducted high-resolution imaging and analysis of isolated retinas, to elucidate the precise role of c-Src in the formation of vascular tufts.Resultsc-Src depletion demonstrated a significant reduction in the formation of neovascular tufts within the OIR model, underscoring the pivotal role of c-Src in pathological retinal angiogenesis. Notably, this decrease in tuft formation was observed independently of any alterations in cell death, cell proliferation or cell adhesion and the absence of c-Src did not impact tuft pericyte coverage and junctional morphology.ConclusionThese findings underscore the critical role of c-Src in the pathogenesis of neovascular tufts in vascular retinopathy. Understanding the molecular mechanisms involving c-Src may offer valuable insights for the development of targeted therapies aimed at mitigating vision-threatening complications associated with retinopathy.
InstructPLM: Aligning Protein Language Models to Follow Protein Structure Instructions
Authors: Qiu Jiezhong , Xu Junde , Hu Jie , Cao Hanqun , Hou Liya , Gao Zijun , Zhou Xinyi , Li Anni , Li Xiujuan , Cui Bin , Yang Fei , Peng Shuang , Sun Ning , Wang Fangyu , Pan Aimin , Tang Jie , Ye Jieping , Lin Junyang , Tang Jin , Huang Xingxu , Heng Pheng Ann , Chen Guangyong 
Published: April 2024

AbstractLarge language models are renowned for their efficacy in capturing intricate patterns, including co-evolutionary relationships, and underlying protein languages. However, current methodologies often fall short in illustrating the emergence of genomic insertions, duplications, and insertion/deletions (indels), which account for approximately 14% of human pathogenic mutations. Given that structure dictates function, mutated proteins with similar structures are more likely to persist throughout biological evolution. Motivated by this, we leverage crossmodality alignment and instruct fine-tuning techniques inspired by large language models to align a generative protein language model with protein structure instructions. Specifically, we present a method for generating variable-length and diverse proteins to explore and simulate the complex evolution of life, thereby expanding the repertoire of options for protein engineering. Our proposed protein LM-based approach, InstructPLM, demonstrates significant performance enhancements both in silico and in vitro. On native protein backbones, it achieves a perplexity of 2.68 and a sequence recovery rate of 57.51, surpassing Protein-MPNN by 39.2% and 25.1%, respectively. Furthermore, we validate the efficacy of our model by redesigning PETase and L-MDH. For PETase, all fifteen designed variable-length PETase exhibit depolymerization activity, with eleven surpassing the activity levels of the wild type. Regarding L-MDH, an enzyme lacking an experimentally determined structure, InstructPLM is able to design functional enzymes with an AF2-predicted structure. Code and model weights of InstructPLM are publicly available*.
A Libra in the Brain: Neural Correlates of Error Awareness Predict Moral Wrongness and Guilt Proneness
Authors: Chen Chenyi , Kao Scott S.-C. , Fan Yang-Teng , Chen Yu-Chun , Cheng Yawei 
Published: April 2024

AbstractError awareness is a fundamental mechanism in humans. Through traditional psychological tasks, certain neural activities that represent errors in objective manners have been identified. However, there is limited knowledge on how humans subjectively determine right from wrong in moral contexts. In this study, participants (N=39) mentally simulated themselves as the agents of moral and immoral behaviors, while viewing a series of actions with EEG recording and MRI scanning, respectively. A significant difference in error-related negativity (ERN) was observed among morally wrong scenarios, accompanied by higher wrongfulness ratings. Additionally, individual differences in guilt-proneness could predict the subjects’ ERN amplitude. The ERN amplitude was correlated with the BOLD activity in the anterior mid-cingulate cortex and anterior insula to immoral scenarios, reflecting error awareness toward moral wrongfulness. The late potential component displayed greater negativity to immoral scenarios and was correlated with BOLD activities in the amygdala, ventromedial prefrontal cortex, and temporoparietal junction, indicating cognitive and affective evaluation in moral judgment. In line with the moral dynamic framework, our results demonstrated individual variability in moral judgments, as indicated by dispersed and overlapping cognitive neural networks. This suggests that subjective evaluations of wrongfulness are underpinned by neural mechanisms, associated with those involved in objective error awareness.
Connectomes, simultaneous EEG-fMRI resting-state data and brain simulation results from 50 healthy subjects
Authors: Meier Jil , Triebkorn Paul , Schirner Michael , Ritter Petra 
Published: April 2024

ABSTRACTWe present raw and processed multimodal empirical data as well as simulation results from a study with The Virtual Brain (TVB).Simultaneous electroencephalography (EEG) - functional magnetic resonance imaging (fMRI) resting-state data, diffusion-weighted MRI, and structural MRI were acquired for 50 healthy adult subjects (18 - 80 years of age) at the Charité University Medicine, Berlin, Germany.We constructed personalized models from this multimodal data with TVB by optimizing parameters on an individual basis that predict multiple empirical features in fMRI and EEG, e.g. dynamic functional connectivity and bimodality in the alpha band power.We annotated this large comprehensive empirical and simulated data set according to the openMINDS meta data schema and structured it following Brain Imaging Data Structure (BIDS) standards for EEG and MRI as well as the BIDS Extension Proposal for computational modeling data.This dataset provides ready-to-use data for future research at various levels of processing including the thereof inferred brain simulation results for a large data set of healthy subjects with a wide age range.
Advancing Tolerogenic Immunotherapy: A Multi-Epitope Vaccine Design Targeting the CYP2D6 Autoantigen in Autoimmune Hepatitis Through Immuno-Informatics
Authors: Kolla Harish Babu , Kumar Anuj , Nanjunadappa Roopa Hebbandi , Hillyard Briley , Dutt Mansi , Chauhan Deepak , Marshal Jean , Kelvin David , Umeshappa Channakeshava Sokke 
Published: April 2024

AbstractJuvenile autoimmune hepatitis (JAIH) is a rare autoimmune disorder affecting children, characterized by the immune system’s misguided attack on liver cells, primarily targeting the CYP2D6 autoantigen. This repeated attack leads to hepatic inflammation, fibrosis, and eventual liver failure. Current therapeutic strategies predominantly rely on immunosuppressive agents or whole B cell depletion antibodies, which render patients susceptible to infections and cancers. Hence, there is an urgent need for antigen-specific therapies to mitigate the severity of autoimmune hepatitis. Tolerogenic antigens represent a promising avenue in immunotherapy, capable of dampening autoimmunity. Here, we present a novel computationally designed multi-epitope tolerogenic vaccine tailored to target CYP2D6, aimed at inducing tolerogenic dendritic cells (DCs) and halting autoimmune progression in JAIH patients. To validate our approach, we have developed a similar vaccine for testing in mouse models of JAIH. The selected tolerogenic epitopes exhibit antigenicity without allergenicity or toxicity, and specifically induce IL-10 production (restricted to CD4+ T cell epitopes). In our vaccine design, tolerogenic poly-epitopes are linked with Toll-like receptor (TLR)-4-agonist, the 50S ribosomal unit, and IL-10, effectively programming DCs towards a tolerogenic state. Molecular docking and dynamic simulations have confirmed strong binding affinities and stable complexes between the vaccine structures, TLR4 and IL-10 receptor alpha (IL-10RA), indicating their potential forin vivoDC interaction and programming. Consequently, this innovative vaccine approach demands further exploration through wet lab experiments to assess its tolerogenicity, safety, and efficacy, thereby laying the groundwork for potential application in clinical settings.
A Membrane Lipid Signature Unravels the Dynamic Landscape of Group 1 ILCs
Authors: Frey Halle C. , Sun Xin , Oudeif Fatima , Corona Darleny L. , He Zijun , Won Taejoon , Schultz Tracy L. , Carruthers Vern B. , Laouar Amale , Laouar Yasmina 
Published: April 2024

ABSTRACTIn an era where the established lines between cell identities are blurred by intra-lineage plasticity, distinguishing between stable and transitional states becomes imperative. This challenge is particularly pronounced within the Group 1 ILC lineage, where the similarity and plasticity between NK cells and ILC1s obscure their classification and the assignment of their unique contributions to immune regulation. This study exploits the unique property of Asialo-GM1 (AsGM1)—a membrane lipid associated with cytotoxic attributes absent in ILC1s—as a definitive criterion to distinguish between these cells. By prioritizing cytotoxic potential as the cardinal differentiator, our strategic use of the AsGM1 signature achieved precise delineation of NK cells and ILC1s across tissues, validated by RNA-seq analysis. This capability extends beyond steady-state classifications, adeptly capturing the binary classification of NK cells and ILC1s during acute liver injury. By leveraging two established models of NK-to-ILC1 plasticity driven by TGFβ andToxoplasma gondii, we demonstrate the stability of the AsGM1 signature, which sharply contrasts with the loss of Eomes. This signature identified a spectrum of known and novel NK cell derivatives—ILC1-like entities that bridge traditional binary classifications in aging and infection. The early detection of the AsGM1 signature at the immature NK (iNK) stage, preceding Eomes, and its stability, unaffected by transcriptional reprogramming that typically alters Eomes, position AsGM1 as a unique, site-agnostic marker for fate mapping NK-to-ILC1 plasticity. This provides a powerful tool to explore the expanding heterogeneity within the Group 1 ILC landscape, effectively transcending the ambiguity inherent to the NK-to-ILC1 continuum.
Cleaner gobies can solve a biological market task when the correct cue is larger
Authors: Ranucci Maddalena , Court Mélanie , Pereira Beatriz P. , Romeo Daniele , Paula José Ricardo 
Published: April 2024

AbstractAnimal cognition is deeply influenced by interactions with the environment. A notable example of sophisticated cognition in the animal kingdom is described by the mutualistic relationship between cleaner fish and clients, where decision-making processes play a pivotal role in partner choice and fish survival. In this context, while extensive research has explored the cognition of the cleaner wrasseLabroides dimidiatus, its Caribbean counterparts,Elacatinus spp., have been comparatively inadequately evaluated. In this study, we used plexiglass plates as surrogates for clients and assessed the ability of cleaner gobies,Elacatinus oceanops, to solve a biological market task where prioritising an ephemeral food plate over a permanent one would double the food reward. We varied cue-based decision-making using both ecologically relevant cues (plate size and colour) and non-relevant ones (presentation side). Additionally, we tested their capacity for reversal learning, an indicator of complex cognitive abilities. Notably, cleaner gobies were able to solve the biological markets task when the distinguishing cue was a larger plate size. Given that these gobies tend to prioritise larger predatory clients in nature, our results align with their natural inclination. Furthermore, considering these gobies were bred in captivity and never experienced cleaning interactions in their lifetime, our data might suggest that their intrinsic cognitive abilities are shaped by evolutionary pressures rooted in their ecological roles. In essence, even in the absence of direct ecological interactions, innate cognitive abilities in cleaner gobies seem to be deeply influenced by evolutionary forces tied to their natural ecological functions. However, their inability to solve the same task involving other cues, may be influenced by factors such as captivity-reared fish or limitations in the experimental design. Further research, including wild individuals, is essential to elucidate the cognitive abilities of the studied species and its implications in the ecological context and evolutionary history.
VPS41 deletion triggers progressive loss of insulin stores and downregulation of beta-cell identity
Authors: Yau Belinda , An Yousun , Germanos Mark , Schwarzkopf Patricia , van der Kraan A Gabrielle , Larance Mark , Webster Hayley , Burns Christian , Asensio Cedric S , Kebede Melkam A 
Published: April 2024

SummaryVacuolar protein sorting-associated protein 41 (VPS41) has been established as a requirement for normal insulin secretory function in pancreatic beta-cells. Genetic deletion of VPS41 in mouse pancreatic beta-cells results in diabetes, though the mechanisms are not understood. Presently, we show that VPS41 deletion results in rapid mature insulin degradation and downregulation of beta-cell identity. This phenotype is observedin vivo,with VPS41KO mice displaying progressive loss of insulin content and beta-cell function with age. In acute VPS41 depletionin vitro, the loss of insulin is associated with increased degradative pathway activity, increased Adapter Protein 3 complex colocalisation with lysosomes, increased nuclear localisation of transcription factor E3, and downregulation of PDX1 and INS mRNA expression. Inhibition of lysosomal degradation rescues the rapidly depleted insulin content. These data evidence a VPS41-dependent mechanism for both insulin content degradation and loss of beta-cell identity in beta-cells.
3D bioprinting of Liver Microenvironment Model Using Photocrosslinkable Decellularized Extracellular Matrix based Hydrogel
Authors: Tabatabaei Rezaei Nima , Kumar Hitendra , Liu Hongqun , Rajeev Ashna , Natale Giovanniantonio , Lee Samuel S. , Park Simon S. , Kim Keekyoung 
Published: April 2024

AbstractThe liver, as one of the vital organs in the body, plays a crucial role in various bodily functions. Numerous factors can cause liver damage, that the sole remedy for severe liver conditions is the transplantation of healthy liver tissue. In response to the transplantation challenges, innovative approaches involving hydrogel-based technologies have emerged, leading to the creation of highly functionalized tissues. The development of three-dimensional printing and patterning of cell-laden biomaterial matrices offers promising advances for creating tissue-specific structures in tissue engineering and bioprinting. However, the matrix materials currently employed in bioprinting liver microtissue often fail to capture the complexity of the natural extracellular matrix (ECM), hindering their ability to restore innate cellular shapes and functions. Liver ECM-based hydrogels are increasingly recognized for their potential as biomimetic 3D cell culture systems that facilitate the exploration of liver disease, metabolism, and toxicity mechanisms. Yet, the conventional production of these hydrogels relies on slow thermal gelation processes, which restrict the manipulation of their mechanical characteristics. In this research, we introduce a novel approach with a functionalized photocrosslinkable liver decellularized extracellular matrix (dECM). By combining liver dECM methacrylate (LdECMMA) with gelatin methacrylate (GelMA), we achieved accelerated crosslinking under visible light irradiation and the ability to tune the mechanical, rheological, and physiological properties of the material. We encapsulated human hepatocellular carcinoma cells within an optimal concentration of the GelMA-LdECMMA hybrid hydrogel and examined cell proliferation and function over an extended period. The findings revealed that the GelMA-LdECMMA hybrid hydrogel enhances liver cell proliferation and function, holding significant promise for applications in drug screening and liver cancer metastasis research.
Pinging the Hidden Attentional Priority Map: Suppression Needs Attention
Authors: Huang Changrun , van Moorselaar Dirk , Foster Joshua J. , Donk Mieke , Theeuwes Jan 
Published: April 2024

AbstractAttentional capture by an irrelevant salient distractor is attenuated when the distractor is presented more frequently in one location compared to other locations, suggesting that people learn to suppress an irrelevant salient location. However, to date it is unclear whether this suppression is proactive, applied before attention has been directed to the distractor location, or reactive, occurring after attention has been directed to that specific location. The aim of the present study is to investigate how suppression is accomplished by using the pinging technique, which allows one to probe how attention is distributed across the visual field prior to the presentation of the search display. In an EEG experiment, participants performed a visual search task wherein they were tasked with identifying a shape singleton in the presence of an irrelevant color singleton. Compared to all other locations, this color singleton appeared more frequently at a specific location, which was termed the high-probability location. Prior to the search task, we introduced a continuous recall spatial memory task to reveal the hidden attentional priority map. Participants had to memorize the location of a memory cue continuously and report this location after the visual search task. Critically, after the presentation of the memory cue but before the onset of the search display, a neutral placeholder display was presented to probe how the hidden priority map is reconfigured by the learned distractor suppression. Behaviorally, there was clear evidence that the high-probability location was suppressed, as search was more efficient when the distractor appeared at this location. To examine the priority map prior to search, we adopted an inverted encoding approach to reconstruct the tuning profile of the memorized position in the spatial memory task. Inverted modeling resulted in reliable tuning profiles during memory maintenance that gradually decayed and that were revived again by the onset of a neutral placeholder display preceding search. After the onset of the placeholders, the tuning profile observed was characterized by a spatial gradient centered over the high-probability location, with tuning being most pronounced at the-to-be suppressed location. This finding suggests that while learned suppression is initiated prior to search display onset, it is preceded by an initial phase of spatial selection, which is in line with a reactive suppression account. Together these results further our understanding of the mechanism of spatial distractor suppression.