bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alzheimer’s Disease Knowledge Graph Enhances Knowledge Discovery and Disease Prediction
Authors: Yang Yue , Yu Kaixian , Gao Shan , Yu Sheng , Xiong Di , Qin Chuanyang , Chen Huiyuan , Tang Jiarui , Tang Niansheng , Zhu Hongtu 
Published: July 2024

AbstractBackgroundAlzheimer’s disease (AD), a progressive neurodegenerative disorder, continues to increase in prevalence without any effective treatments to date. In this context, knowledge graphs (KGs) have emerged as a pivotal tool in biomedical research, offering new perspectives on drug repurposing and biomarker discovery by analyzing intricate network structures. Our study seeks to build an AD-specific knowledge graph, highlighting interactions among AD, genes, variants, chemicals, drugs, and other diseases. The goal is to shed light on existing treatments, potential targets, and diagnostic methods for AD, thereby aiding in drug repurposing and the identification of biomarkers.ResultsWe annotated 800 PubMed abstracts and leveraged GPT-4 for text augmentation to enrich our training data for named entity recognition (NER) and relation classification. A comprehensive data mining model, integrating NER and relationship classification, was trained on the annotated corpus. This model was subsequently applied to extract relation triplets from unannotated abstracts. To enhance entity linking, we utilized a suite of reference biomedical databases and refine the linking accuracy through abbreviation resolution. As a result, we successfully identified 3,199,276 entity mentions and 633,733 triplets, elucidating connections between 5,000 unique entities. These connections were pivotal in constructing a comprehensive Alzheimer’s Disease Knowledge Graph (ADKG). We also integrated the ADKG constructed after entity linking with other biomedical databases. The ADKG served as a training ground for Knowledge Graph Embedding models with the high-ranking predicted triplets supported by evidence, underscoring the utility of ADKG in generating testable scientific hypotheses. Further application of ADKG in predictive modeling using the UK Biobank data revealed models based on ADKG outperforming others, as evidenced by higher values in the areas under the receiver operating characteristic (ROC) curves.ConclusionThe ADKG is a valuable resource for generating hypotheses and enhancing predictive models, highlighting its potential to advance AD’s disease research and treatment strategies.
ZIP13 regulates lipid metabolism by changing intracellular iron and zinc balance
Authors: Fukunaka Ayako , Tanaka Gen , Kimura Toru , Hengphasatporn Kowit , Saito Daisuke , Shigeta Mayo , Shibata Hiroshi , Ichinose Takayuki , Abe Ichitaro , Shimura Mari , Sato Takashi , Nakagawa Yuko , Horii Takuro , Hatada Izuho , Kajimura Shingo , Kiyonari Hiroshi , Sakurai Hiroyuki , Shigeta Yasuteru , Watada Hirotaka , Fukada Toshiyuki , Fujitani Yoshio 
Published: July 2024

AbstractMetabolic diseases are caused by a prolonged energy imbalance, and adipose tissue is known to be the main contributor. We previously reported that ZIP13, an Slc39a transporter whose deficiency causes Ehlers-Danlos syndrome spondylocheirodysplastic type 3 associated with lipoatrophy, inhibits the adipocyte browning pathway by modulating intracellular zinc status. The precise mechanisms of how ZIP13 regulates the homeostasis of adipose tissue remain unclear and therefore, we investigated the role of ZIP13 in mature adipocytes using adipocyte-specificZip13-deficient mice. We herein demonstrate that these mice show accelerated lipolysis and reduced respiratory exchange ratio. In addition, abundance of iron and zinc balance were altered during differentiation in normal adipocytes, whereas iron distribution was substantially affected inZip13-deficient adipocytes, which downregulated PDE activity and enhanced β-adrenergic receptor signaling pathways. Importantly, we confirmed that ZIP13 could transport both zinc and iron, using theXenopusoocyte transport system andin silicostructural dynamics simulations, and that the defect in iron distribution perturbs proper lipolysis. Together, these results illustrate that ZIP13 acts as a key regulator for lipolysis in adipocytes via the proper use of metals, and that the ZIP13-iron axis plays an important role in regulation of lipid metabolism.
The SmARTR pipeline: a modular workflow for the cinematic rendering of 3D scientific imaging data
Authors: Macrì Simone , Di-Poï Nicolas 
Published: July 2024

SUMMARYAdvancements in non-invasive surface and internal imaging techniques, along with computational methods, have revolutionized 3D visualization of organismal morphology. These breakthroughs not only enhance research and medical anatomical analysis, but also facilitate the preservation and digital archiving of scientific specimens. We introduce the SmARTR pipeline (Small Animal Realistic Three-dimensional Rendering), a comprehensive workflow integrating wet lab procedures, 3D data acquisition, and processing to produce photorealistic 3D scientific data through cinematic rendering. This versatile pipeline supports multi-scale visualizations, from tissue-level to whole-organism details across diverse living organisms and is adaptable to various imaging sources and platforms. Its modular design and customizable rendering scenarios, provided by detailed SmARTR networks in a free software environment, make it a powerful tool for 3D data analysis. Accessible to a broad audience, SmARTR serves as a valuable resource not only for multiple fields of research in life sciences but also for education, diagnosis, outreach, and artistic endeavors.
TLR9 signaling requires ligand-induced phosphorylation of two specific tyrosine residues by EGFR and Syk
Authors: Veleeparambil Manoj , Wang Chenyao , Kessler Patricia M , Willard Belinda , Sen Ganes C , Chattopadhyay Saurabh 
Published: July 2024

AbstractToll-like receptors (TLRs) are transmembrane proteins required for recognizing microbial components or cellular danger signals to activate intracellular signaling pathways leading to induction of anti-microbial and inflammatory genes. Inactive TLRs require ligand-induced activation to recruit adaptor proteins, e.g., MyD88, to trigger the synthesis of cytokines and interferons. TLR9 is an endosomal membrane-bound protein, which binds to CpG-containing microbial DNA or endogenous signals from dead cells or tissue damage. We showed that TLR9 activation requires EGFR, a tyrosine (Tyr) kinase, which interacts with and phosphorylates the cytoplasmic domain of TLR9. Blocking EGFR activity pharmacologically, or knocking out EGFR gene in myeloid cells, suppressed lethal TLR9-induced hepatotoxicity. Here, we reveal that TLR9 required two Src family of kinases, Syk and Lyn, which, together with EGFR, led to phosphorylation and activation of TLR9. Lack of either of these kinases inhibited TLR9-MyD88 interaction, thereby inhibiting TLR9-mediated gene induction. Unlike EGFR, which constitutively binds TLR9, activated Syk interacted with TLR9 in a CpG-dependent manner. Activated Syk interacted with TLR9 and was critical for activating TLR9-bound EGFR. Quantitative mass spectrometric analyses revealed TLR9 was phosphorylated, sequentially, on Tyr870and Tyr980by Syk and EGFR, respectively. Mutation of either of these tyrosines led to complete loss of TLR9-induced cytokine production. For activation, Syk was phosphorylated by Lyn, which was activated by CpG-mediated scavenger-receptor A, and surprisingly, independent of TLR9. In summary, our results uncovered the molecular details of TLR9 activation by its Tyr-phosphorylation, which is critical for TLR9-mediated intracellular signaling.
Simultaneous dual-color calcium imaging in freely-behaving mice
Authors: Dong Zhe , Feng Yu , Diego Keziah , Baggetta Austin M. , Sweis Brian M. , Pennington Zachary T. , Lamsifer Sophia I. , Zaki Yosif , Sangiuliano Federico , Philipsberg Paul A. , Morales-Rodriguez Denisse , Kircher Daniel , Slesinger Paul , Shuman Tristan , Aharoni Daniel , Cai Denise J. 
Published: July 2024

AbstractMiniaturized fluorescence microscopes (miniscopes) enable imaging of calcium events from a large population of neurons in freely behaving animals. Traditionally, miniscopes have only been able to record from a single fluorescence wavelength. Here, we present a new open-source dual-channel Miniscope that simultaneously records two wavelengths in freely behaving animals. To enable simultaneous acquisition of two fluorescent wavelengths, we incorporated two CMOS sensors into a single Miniscope. To validate our dual-channel Miniscope, we imaged hippocampal CA1 region that co-expressed a dynamic calcium indicator (GCaMP) and a static nuclear signal (tdTomato) while mice ran on a linear track. Our results suggest that, even when neurons were registered across days using tdTomato signals, hippocampal spatial coding changes over time. In conclusion, our novel dual-channel Miniscope enables imaging of two fluorescence wavelengths with minimal crosstalk between the two channels, opening the doors to a multitude of new experimental possibilities.TeaserNovel open-source dual-channel Miniscope that simultaneously records two wavelengths with minimal crosstalk in freely behaving animals.
Restoration of locus coeruleus noradrenergic transmission during sleep
Authors: Sima Jiao , Zhang Yuchen , Farriday Declan , Ahn Andy Young-Eon , Lopez Eduardo Ramirez , Jin Chennan , Harrell Jade , Darmohray Dana , Silverman Daniel , Dan Yang 
Published: July 2024

AbstractSleep is indispensable for health and wellbeing, but its basic function remains elusive. The locus coeruleus (LC) powerfully promotes arousal by releasing noradrenaline. We found that noradrenaline transmission is reduced by prolonged wakefulness and restored during sleep. Fiber-photometry imaging of noradrenaline using its biosensor showed that its release evoked by optogenetic LC neuron activation was strongly attenuated by three hours of sleep deprivation and restored during subsequent sleep. This is accompanied by the reduction and recovery of the wake-promoting effect of the LC neurons. The reduction of both LC evoked noradrenaline release and wake-inducing potency is activity dependent, and the rate of noradrenaline transmission recovery depends on mammalian target of rapamycin (mTOR) signaling. The decline and recovery of noradrenaline transmission also occur in spontaneous sleep-wake cycles on a timescale of minutes. Together, these results reveal an essential role of sleep in restoring transmission of a key arousal-promoting neuromodulator.
A chromosome-level genome assembly ofDracaena cambodianaand comparative genomics analysis highlights the distinct biological features of two resource species of dragon’s blood
Authors: Xu Yanhong , Peng Junxiang , Li Sipeng , Liu Yang , Wen Dong , Jiang Jiemei , Rong Mei , Wei Wei , Wang Qiuling , Jin Yue , Yang Shuwen , Wang Siyu , Wei Jian-he 
Published: July 2024

AbstractThis study reports a chromosome-level genome forDracaena cambodiana, one of two typical dracaena species in China. This work will help to deepen the understanding of the dracaena species and the conservation and development of plant resources. The final assembly consisted of 54 scaffolds, spanning 1.08 Gb, with a scaffold N50 size of 52.29 Mb, encoded 36860 predicted protein-coding genes. A total of 1,064,810,157 bp of genome sequences were located on 20 chromosomes (2n = 40), accounting for 98.46%. We investigate the possible mechanisms of the longevity of dracaena, the longest-lived plant in the world, which involve DNA repair and post-translational modification. We also performed comparative genomic analysis of the previously assembled genome ofDracaena cochinchinesiswith this genome, and found that the two involved interaction of plant−pathogen interaction and ubiquitin mediated proteolysis, which may reveal why Dracaena has environmental adaptability and longevity characteristics.
Polyelectrolyte mannan from diatoms reshapes sunlit ocean microbiome
Authors: Krull J. , Crawford C.J. , Sidhu C. , Solanki V. , Bligh M. , Rößler L. , Singh R.K. , Huang G. , Robb C.S. , Teeling H. , Seeberger P.H. , Schweder T. , Hehemann J-H. 
Published: July 2024

AbstractAlgae catalyze half of the global solar powered reduction of carbon dioxide to organic molecules. While this organic synthesis shapes genomes of heterotrophic microbiota globally, many corresponding structures remain elusive. We show that diatoms release a mannan polyelectrolyte selecting for bacteria with a specifically adapted enzymatic cascade. NMR spectroscopy, chromatography, automated glycan assembly and enzymatic dissection resolved the structure of a C6 sulfated α-1,3-mannan with exceptional simplicity for a sulfated polysaccharide from algae. Biochemical, physiological and structural analyses demonstrated that some bacteria can hydrolyze this mannan with a cascade of just four enzymes. Circumnavigation metagenome data revealed corresponding genes in Atlantic, Pacific, Southern and Indian Ocean surface waters. We show that this sulfated mannan may exert substantial selection pressure on marine microbiota around the globe.
Mechanobiochemical finite element model to analyze impact-loading-induced cell damage, subsequent proteoglycan loss, and anti-oxidative treatment effects in articular cartilage
Authors: Kosonen Joonas P. , Eskelinen Atte S.A. , Orozco Gustavo A. , Coleman Mitchell C. , Goetz Jessica E. , Anderson Donald D. , Grodzinsky Alan J. , Tanska Petri , Korhonen Rami K. 
Published: July 2024

AbstractJoint trauma often leads to articular cartilage degeneration and post-traumatic osteoarthritis (PTOA). Pivotal determinants include trauma-induced excessive tissue strains that damage cartilage cells. As a downstream effect, these damaged cells can trigger cartilage degeneration via oxidative stress, cell death, and proteolytic tissue degeneration. N-acetylcysteine (NAC) has emerged as antioxidant capable of inhibiting oxidative stress, cell death, and cartilage degeneration post-impact. However, temporal effects of NAC are not fully understood and remain difficult to assess solely by physical experiments. Thus, we developed a computational framework to simulate a drop tower impact of cartilage with finite element analysis in ABAQUS, and model subsequent oxidative stress-related cell damage, and NAC treatment upon cartilage proteoglycan content in COMSOL Multiphysics, based on priorex vivoexperiments. Model results provide evidence that by inhibiting further cell damage by mechanically induced oxidative stress, immediate NAC treatment can reduce proteoglycan loss by mitigating cell death (loss of proteoglycan biosynthesis) and enzymatic proteoglycan depletion. Our simulations also indicated that delayed NAC treatment may not inhibit cartilage proteoglycan loss despite reduced cell death after impact. These results enhance understanding of temporal effects of impact-related cell damage and treatment that are critical for the development of effective treatments for PTOA. In the future, our modeling framework could increase understanding of time-dependent mechanisms of oxidative stress and downstream effects in injured cartilage and aid in developing better treatments to mitigate PTOA progression.Author summaryPost-traumatic osteoarthritis is a debilitating disease which is often initiated by trauma and characterized by cartilage degeneration. The degeneration is partly driven by trauma-induced damage, including oxidative stress, to cartilage cells. Multiple drugs have been studied to counteract the cell damage, but it remains difficult to inhibit the disease progression since temporal effects of such treatments are not fully understood. Here, we developed a computational framework to study effects of antioxidant treatment in mechanically impacted cartilage and compared our computational simulations with previously published experiments. Our results showed that the high strain induced cell damage occurring in the mechanically impacted region could be mitigated by N-acetylcysteine treatment. This mechanism could partly explain reduced cartilage proteoglycan loss compared to untreated samples. Our modeling framework could help enhance development of treatments to better inhibit osteoarthritis progression.
GelMetrics: An algorithm for analyzing the dynamics of gel-like phase separated condensates
Authors: Granik Naor , Amit Roee 
Published: July 2024

AbstractCellular compartments and organelles are essential for the spatial organization of biological matter. Recently, membraneless organelles like paraspeckles, stress granules, and Cajal bodies have garnered significant scientific interest due to their lack of membrane boundaries and crucial cellular functions. These organelles self-assemble through phase separation, a process in which a homogeneous solution separates into distinct phases. The phases most commonly encountered in cells are liquids and gels. Various microscopy techniques exist to study these phase-separated compartments. However, these are often inadequate for investigating the dynamics of gel-like condensates, where molecular motion occurs over tens of minutes rather than seconds. Here, we introduce a method to quantitatively measure the dynamics of gel-like phase-separated organelles by tracking their fluorescence signals over extended durations. We demonstrate that our algorithm can identify biological activity amidst measurement noise and estimate biophysical parameters which can provide insights into the dynamic behavior of the condensates. We validated our approach on synthetic RNA-protein granules, demonstrating its applicability both in vitro and in vivo.
Mitochondrial genomes of threeMelampusspecies (Ellobiidae; Gastropoda) and a proposed mitochondrial control region for Euthyneura
Authors: Inäbnit Thomas , Tiedemann Ralph , Dennis Alice B. 
Published: July 2024

AbstractMelampus bidentatuswas recently divided into three genetically divergent cryptic species:M. bidentatus, M. jaumeiandM. gundlachi. We have assembled and annotated a mitochondrial genome for each of these species. Comparisons with other taxa showed that these three species possess a gene order that is distinct from the conserved gene order found in the six (out of nine available) Ellobiid genera. Among the species with a derived gene order, mean nucleotide divergence over all genes was on average 1.57× higher than among mitogenomes with the conserved gene order. This suggests varying evolutionary rates of mitochondrial genes in this family. We also use comparisons among 130 mitochondrial genomes within Euthyneura to support the presence of a control region preceding the Isoleucin-tRNA, including in the novel genomes presented here.
Atypical chemokine receptor 3 regulates synaptic removal in disease astrocytes
Authors: Giusti V , Park J , Giusto E , Masatti L , Ramos-Gonzalez P , Iovino L , Sandre M , Emmi A , Kaur G , Coletto E , Calura E , Petrelli F , Porzionato A , De Caro R. , Cavaliere F , Chung WS , Civiero L 
Published: July 2024

AbstractAstrocytes participate in the clearance of obsolete or unwanted neuronal synapses. However, the molecular machinery recruited for the recognition of synapses is not fully clarified, especially in pathological conditions. Here, we investigated the phagocytic process through individual gene silencing using a druggable gene library. Our study demonstrates that astrocyte-mediated synapse engulfment is regulated by the Atypical chemokine receptor 3 (Ackr3). Mechanistically, we have shown that Ackr3 recognizes phosphatidylethanolamine (PE)-bound Cxcl12 at synaptic terminals both in vitro and in cell culture thus serving as a novel marker of synaptic dysfunction. Notably, both the receptor and its ligand are overexpressed in post-mortem AD human brains, and downregulation of the receptor in AD mouse models (5xFAD) significantly diminishes astrocyte-mediated synaptic elimination. Overall, this work unveils a novel, possibly targetable mechanism of astrocyte-mediated synaptic engulfment implicated in the most common neurodegenerative disease.
TheAPOEisoforms differentially shape the transcriptomic and epigenomic landscapes of human microglia in a xenotransplantation model of Alzheimer’s disease
Authors: Murphy Kitty B. , Hu Di , Wolfs Leen , Mancuso Renzo , De Strooper Bart , Marzi Sarah J. 
Published: July 2024

AbstractMicroglia play a key role in the response to amyloid beta in Alzheimer’s disease (AD). In this context, a major transcriptional response of microglia is the upregulation ofAPOE, the strongest late-onset AD risk gene. Of its three isoforms,APOE2is thought to be protective, whileAPOE4increases AD risk. We hypothesised that the isoforms functionally alter microglia by shaping their transcriptomic and chromatin landscapes. We used RNA- and ATAC-sequencing to profile gene expression and chromatin accessibility of human microglia isolated from a xenotransplantation model of AD. We identified widespread transcriptomic and epigenomic differences which are dependent onAPOEgenotype, and are corroborated across the profiling assays. Our results indicate that impaired microglial proliferation, migration and immune responses may contribute to the increased risk for late-onset AD inAPOE4carriers, while increased DNA-binding of the vitamin D receptor inAPOE2microglia may contribute to the isoform’s protective role.
Poor Self-Reported Sleep is Associated with Prolonged White Matter T2 Relaxation in Psychotic Disorders
Authors: Yesilkaya Haluk Umit , Chen Xi , Watford Lauren , McCoy Emma , Genc Ilgin , Du Fei , Ongur Dost , Yuksel Cagri 
Published: July 2024

BackgroundSchizophrenia (SZ) and bipolar disorder (BD) are characterized by white matter (WM) abnormalities, however, their relationship with illness presentation is not clear. Sleep disturbances are common in both disorders, and recent evidence suggests that sleep plays a critical role in WM physiology. Therefore, it is plausible that sleep disturbances are associated with impaired WM integrity in these disorders. To test this hypothesis, we examined the association of self-reported sleep disturbances with WM transverse (T2) relaxation times in patients with SZ spectrum disorders and BD with psychotic features.Methods28 patients with psychosis (17 BD-I, with psychotic features and 11 SZ spectrum disorders) were included. Metabolite and water T2 relaxation times were measured in the anterior corona radiata at 4T. Sleep was evaluated using the Pittsburgh Sleep Quality Index.ResultsPSQI total score showed a moderate to strong positive correlation with water T2 (r = 0.64, p<0.001). Linear regressions showed that this association was specific to sleep disturbance but was not a byproduct of exacerbation in depressive, manic, or psychotic symptoms. In our exploratory analysis, sleep disturbance was correlated with free water percentage, suggesting that increased extracellular water may be a mechanism underlying the association of disturbed sleep and prolonged water T2 relaxation.ConclusionOur results highlight the connection between poor sleep and WM abnormalities in psychotic disorders. Future research using objective sleep measures and neuroimaging techniques suitable to probe free water is needed to further our insight into this relationship.