bluuebunny/crossref_metadata_2025_split huggingface dataset:
The cGAS-STING Pathway Is Essential in Acute Ischemia-Induced Neutropoiesis and Neutrophil Priming in the Bone Marrow
Authors: Zhu Jiankun , Ruan Xinjia , Mangione MariaSanta C , Parra Pablo , Su Xiaoping , Luo Xiang , Cao Dian J 
Published: July 2024

AbstractAcute myocardial ischemia triggers a rapid mobilization of neutrophils from the bone marrow to peripheral blood, facilitating their infiltration into the infarcted myocardium. These cells are critical for inducing inflammation and contributing to myocardial repair. While neutrophils in infarcted tissue are better characterized, our understanding of whether and how ischemia regulates neutrophil production, differentiation, and functionality in the bone marrow remains limited. This study investigates these processes and the influence of the cGAS-STING pathway in the context of myocardial infarction. The cGAS-STING pathway detects aberrant DNA within cells, activates STING, and initiates downstream signaling cascades involving NFKB and IRF3. We analyzed neutrophils from bone marrow, peripheral blood, and infarct tissues using MI models generated from wild-type,Cgas-/-, andSting-/-mice. These models are essential for studying neutropoiesis (neutrophil production and differentiation), as it involves multiple cell types. RNA sequencing analysis revealed that ischemia not only increased neutrophil production but also promoted cytokine signaling, phagocytosis, chemotaxis, and degranulation in the bone marrow before their release into the peripheral blood. Inhibition of the cGAS-STING pathway decreased neutrophil production after MI and down-regulated the same pathways activated by ischemia. Neutrophils lacking cGAS or STING were less mature, exhibited reduced activation, and decreased degranulation. Deletion of cGAS and STING decreased the expression of a large group of IFN-stimulated genes and IFIT1+ neutrophils from peripheral blood and the infarct tissue, suggesting that cGAS-STING plays an essential role in neutrophils with the IFN-stimulated gene signature. Importantly, transcriptomic analysis ofCgas-/-andSting-/-neutrophils from bone marrow and MI tissues showed downregulation of similar pathways, indicating that the functionality developed in the bone marrow was maintained despite infarct-induced stimulation. These findings highlight the importance of neutropoiesis in dictating neutrophil function in target tissues, underscoring the critical role of the cGAS-STING pathway in neutrophil-mediated myocardial repair post-ischemia.
Lipid droplet surface promotes three-dimensional morphological evolution of non-rhomboidal cholesterol crystals
Authors: Lee Hyun-Ro , Kang Seunghan , Choi Siyoung Q. 
Published: July 2024

AbstractCholesterol crystals, which cause inflammation and various diseases, predominantly grow in a platy, rhomboid structure on the plasma membranes but exhibit an uneven three-dimensional architecture intracellularly. Here, we demonstrate how cholesterol crystallizes in a non-rhomboidal shape on the surface of lipid droplets and develops into three-dimensional sheet-like agglomerates using anin vitrolipid droplet reconstitution system with stereoscopic fluorescence imaging. Our findings reveal that interfacial cholesterol transport on the lipid droplet surface and unique lipid droplet components significantly influence the nucleation-and-growth dynamics of cholesterol crystals, leading to crystal growth in various polygonal shapes. Furthermore, cholesterol crystals readily agglomerate to form large, curved sheet structures on the confined, spherical surfaces of lipid droplets. This discovery enhances our understanding of the volumetric morphological growth of intracellular cholesterol crystals.
Phase transition of WTAP regulates m6A modification of interferon-stimulated genes
Authors: Cai Sihui , Zhou Jie , Luo Xiaotong , Zhang Chenqiu , Jin Shouheng , Ren Jian , Cui Jun 
Published: July 2024

AbstractN6-methyladenosine (m6A) is the most prevalent modification of mRNA which controls diverse physiological processes. Although m6A modification is reported to regulate type I interferon (IFN) responses by targeting the mRNA of IFN-β and the interferon stimulated genes (ISGs), the detailed mechanism of how m6A methyltransferase complex (MTC) responses quickly to conduct the modification on nascent mRNA co-transcriptionally during IFN-β stimulation remains largely unclear. Here, we demonstrate that WTAP, the adaptor protein of m6A MTC, goes through dephosphorylation regulated phase transition from aggregates to liquid droplets under IFN-β stimulation. Phase transition of WTAP mediates the m6A modification of a subset of ISGs mRNA to restrict their expression. In mechanism, we found that formation of aggregates prevents WTAP from binding on the promoter region of ISGs or conducting m6A modification on mRNA in untreated cells. while IFN-β induced WTAP droplets interacts with nucleus-translocated transcriptional factor STAT1 and recruits MTC on the promoter region of ISGs, directing the co-transcriptional m6A modification on ISGs mRNA. Collectively, our findings reveal a novel regulatory role of WTAP phase transition under viral infection to orchestrate dynamic m6A modification with the cooperation of transcriptional factors and MTC, and precisely manipulate signaling pathway.
Positive and negative selective assortment in pairwise interactions
Authors: Izquierdo Segismundo S. , Izquierdo Luis R. , Hauert Christoph 
Published: July 2024

AbstractIn populations subject to evolutionary processes, the assortment of players with different genes or strategies can have a large impact on players’ payoffs and on the expected evolution of each strategy in the population. Here we consider assortment generated by a process of partner choice known asselective assortment. Under selective assortment, players looking for a mate can observe the strategies of a sample of potential mates or co-players, and select one of them to interact with. This selection mechanism can generate positive assortment (if there is a preference for players using the same strategy), or negative assortment. We study the impact of selective assortment in the evolution and in the equilibria of a population, providing results for different games under different evolutionary dynamics (including the replicator dynamics).
Circulating Myeloid-Derived Suppressor Cell load and disease severity are associated to an enhanced oligodendroglial production in a murine model of multiple sclerosis
Authors: Serrano-Regal Mari Paz , Camacho-Toledano Celia , Alonso-García Inmaculada , Ortega María Cristina , Machín-Díaz Isabel , Lebrón-Galán Rafael , García-Arocha Jennifer , Calahorra Leticia , Clemente Diego 
Published: July 2024

ABSTRACTBackgroundMultiple sclerosis (MS) is a chronic, inflammatory and demyelinating disease of the central nervous system (CNS) that is highly heterogeneous in terms of disease severity and tissue damage extent. Improving myelin restoration is essential to prevent neurodegeneration and the associated disability in MS patients. However, remyelinating therapies are failing in clinical trials, in part, due to the absence of classifying biomarkers of different endogenous regenerative capacities amongst enrolled patients. We previously reported that circulating monocytic myeloid-derived suppressor cells (M-MDSCs) at the onset of the murine model of MS experimental autoimmune encephalomyelitis (EAE) are associated with milder disease courses and less degree of demyelination and axonal damage in spinal cord lesions, while at peak are indicative of a better symptom recovery. Moreover, M-MDSCs are able to promotein vitrooligodendrocyte precursor cell (OPC) proliferation and differentiation towards mature oligodendrocytes (OLs) through the release of the soluble factor osteopontin.ResultsHere, we show a relationship between disease severity and a gradient of OPCs between the rim and the core in mixed active-inactive lesions of MS patients, along with a positive correlation between M-MDSC density and OPC abundance in the same lesions. We also show that EAE disease severity negatively influences the density of total and newly generated OPCs found associated to the demyelinated lesions of the spinal cord at the peak of the disease. In addition, disease severity also impacts the abundance of newly generated OLs originated either during the effector phase or during the early recovery phase. We also demonstrate the positive association between infiltrated M-MDSCs and the abundance of OPCs in the periplaque of demyelinating lesions at the peak of EAE. Interestingly, circulating M-MDSCs at EAE onset and peak of the disease are directly associated to a higher density of newly generated OLs in the plaque and periplaque, respectively.ConclusionDisease severity clearly impacts oligodendrocyte generation during a neuroinflammatory insult like EAE. Our results set the basis for further studies on M-MDSCs as a promising new biomarker that identify a CNS prone to the generation of new OLs that may contribute to restore myelin.
CB-1 receptor agonist drastically changes oscillatory activity, defining active sleep
Authors: Topchiy Irina , Kocsis Bernat 
Published: July 2024

AbstractBrain oscillations in different behavioral states are essential for cognition, and oscillopathies contribute to cognitive dysfunction in neuro-psychiatric diseases. Cannabis-1 receptor (CB1-R) activation was reported to suppress theta and fast gamma activities in rats during waking exploration, and here, we show that cannabis fundamentally alters network activity during sleep, as well. Prominent theta rhythm is present in rapid eye movement sleep (REMS), whereas fast oscillations appear as regular sequences of sleep spindles during intermediate sleep (IS) - both implicated in dreaming and memory consolidation. The CB1-R agonist disrupted these mechanisms, restructuring IS-REMS episodes; IS lengthened 6-fold and intruded REMS, where on-going theta was drastically reduced. The spindle architecture was also affected; its amplitude increased, and its peak frequency down-shifted into the theta range. Cannabis is known to induce psychotic-like conditions and cognitive deficits; thus, our results may help understanding the dual effect of cannabis on cognitive states and the role of network oscillations in psychiatric pathology.
LCSkPOA: Enabling banded semi-global partial order alignments via efficient and accurate backbone generation through extended LCSk++
Authors: Weerakoon Minindu , Saunders Christopher T , Heaton Haynes 
Published: July 2024

AbstractBackgroundMost multiple sequence alignment and string-graph alignment algorithms focus on global alignment, but many applications exist for semi-global and local string-graph alignment. Long reads require enormous amounts of memory and runtime to fill out large dynamic programming tables. Effective algorithms for finding the backbone and thus defining a band of an alignment such as the longest common subsequence with kmer matches (LCSk++) exist but do not work with graphs. This study introduces an adaptation of the Longest Common Subsequence with kmer matches (LCSk++) algorithm tailored for graph structures, particularly focusing on Partial Order Alignment (POA) graphs. POA graphs, which are directed acyclic graphs, represent multiple sequence alignments and effectively capture the relationships between sequences. Current state of the art methods like ABPOA and SPOA, while improving POA, primarily focus on global alignment and thus are limited in local and semi-global banding scenarios. Our approach addresses these limitations by extending the LCSk++ algorithm to accommodate the complexities of graph-based alignment.ResultsOur extended LCSk++ algorithm integrates dynamic programming and graph traversal techniques to detect conserved regions within POA graphs, termed the LCSk++ backbone. This backbone enables precise banding of the POA matrix for local and semi-global alignment, significantly enhancing the construction of consensus sequences. Compared to unbanded semi-global POA, our method demonstrates substantial memory savings (up to 98%) and significant run-time reductions (up to 37-fold), particularly for long sequences. The method maintains high alignment scores and proves effective across various string lengths and datasets, including synthetic and PacBio HiFi reads. Parallel processing further enhances runtime efficiency, achieving up to 150x speed improvements on conventional PCs.ConclusionThe extended LCSk++ algorithm for graph structures offers a substantial advancement in sequence alignment technology. It effectively reduces memory consumption and optimizes run times without compromising alignment quality, thus providing a robust solution for local and semi-global alignment in POA graphs. This method enhances the utility of POA in critical applications such as multiple sequence alignment for phylogeny construction and graph-based reference alignment.
Sex-Specific Changes in Cardiac Function and Electrophysiology During Progression of Adenine-Induced Chronic Kidney Disease in Mice
Authors: Dargam Valentina , Sanchez Anet , Kolengaden Aashiya , Perez Yency , Arias Rebekah , Cabrera Ana M Valentin , Chaparro Daniel , Tarafa Christopher , Coba Alexandra , Yapaolo Nathan , Todd Emily A. , Williams Monique M. , Shehadeh Lina A. , Hutcheson Joshua D. 
Published: July 2024

ABSTRACTBACKGROUNDChronic kidney disease (CKD) and cardiovascular disease (CVD) often co-exist and interact; however, notable sex-dependent differences are observed in how these conditions manifest and progress in parallel, despite men and women sharing similar risk factors. Identifying sex-specific diagnostic markers of cardiac structure and function throughout CKD progression could elucidate why the development and progression of these diseases differ by sex.METHODS AND RESULTSAdult, C57BL/6J male and female mice were subjected to a high-adenine (0.2%) diet throughout 12-weeks to induce CKD. Control mice were fed a normal chow diet. Every three weeks, electrocardiogram (ECG) and echocardiogram-based markers of cardiac physiology were evaluated. Adenine-induced CKD showed markers of left ventricular (LV) hypertrophy in male mice only. CKD males had markers indicative of LV systolic and diastolic dysfunction throughout regimen duration, worsening as disease progressed. Adenine males had a prolonged QTc and STc intervals when compared to Adenine females and Control males. Sex-dependent differences in the duration of the Speak-J marker, measured via ECG, was identified, with Adenine males showing increases in duration earlier than Adenine females compared to their Control counterparts.CONCLUSIONSIn this study, we identified sex-dependent differences in cardiac structure, function, and electrophysiology in a mouse model of CKD-induced CVD throughout disease progression. We found that male mice are more prone to developing LV hypertrophy, systolic dysfunction, and diastolic dysfunction, with significant increases in ECG markers indicative of ventricular dysfunction observed in adenine-treated males at late stages of the disease. Additionally, we identified a new ECG parameter, Speak-J duration, that highlights sex-specific cardiac electrophysiological changes, demonstrating the model’s utility in studying sex-dependent cardiac differences.
Systemic inflammation is a minor contributor to remnant cholesterol atherogenicity
Authors: Kraaijenhof Jordan M. , Kerkvliet Marije J. , Nurmohamed Nick S. , Grefhorst Aldo , Kroon Jeffrey , Wareham Nicholas J. , Hovingh G. Kees , Stroes Erik S.G. , Boekholdt S. Matthijs , Reeskamp Laurens F. 
Published: July 2024

AbstractBackgroundBoth plasma levels of remnant cholesterol and low-density lipoprotein cholesterol (LDL-C) levels are independent risk factors for atherosclerotic cardiovascular disease. However, only remnant cholesterol has consistently been associated with systemic inflammation. The extent to which inflammation mediates the effect of remnant cholesterol on major adverse cardiovascular events (MACE) remains unclear.Methods and ResultsThis study included 16,445 participants without prior atherosclerotic cardiovascular disease from the EPIC-Norfolk cohort, with a mean age of 58.8±9.1 years, of which 9,357 (56.9%) were women. Every 1 mmol/L higher remnant cholesterol was associated with 29.5% higher hsCRP levels (95% Confidence Interval (CI): 22.1, 37.4, p<0.001), whereas LDL-C was not significantly associated with hsCRP levels in the fully adjusted model. Additionally, each 1 mmol/L higher remnant cholesterol was associated with a hazard ratio (HR) of 1.31 (95% CI: 1.14, 1.50, p<0.001) for MACE, compared to a HR of 1.21 (95% CI: 1.13, 1.31, p<0.001) for LDL-C. Mediation analysis showed that hsCRP mediated 5.9% (95% CI: 1.2, 10.6%, p<0.001) of the effect of remnant cholesterol on MACE, whereas hsCRP did not mediate the effect of LDL-C.ConclusionsPlasma remnant cholesterol levels are independently associated with systemic inflammation and cardiovascular events. Inflammation, as measured with hsCRP, contributed minorly to the association between remnant cholesterol and MACE. This underscores the need to address both remnant cholesterol and systemic inflammation separately in the clinical management of cardiovascular disease.Graphical abstract:The study assessed the relationship between remnant cholesterol, systemic inflammation, and MACE risk in 16,445 participants free from atherosclerotic cardiovascular disease from the EPIC-Norfolk cohort. Every 1 mmol/L higher remnant cholesterol was associated with 29.5% higher hsCRP levels (95% CI: 22.1, 37.4, p<0.001), while LDL cholesterol was not significantly associated with hsCRP levels. Additionally, each 1 mmol/L higher remnant cholesterol was associated with a HR of 1.31 (95% CI: 1.14, 1.50, p<0.001) for MACE, compared to a HR of 1.21 (95% CI: 1.13, 1.31, p<0.001) for LDL-C. hsCRP mediated 5.9% (95% CI: 1.2, 10.6%, p<0.001) of the effect of remnant cholesterol on MACE, while it did not mediate the effect of LDL cholesterol. LDL: low-density lipoprotein cholesterol, HR: hazard ratio, CI: confidence interval, MACE: major adverse cardiovascular events.
The Origin of Cognitive Modules for Face Processing: A Computational Evolutionary Perspective
Authors: Liu Jirui , Wang Xuena , Liu Jia 
Published: July 2024

AbstractDespite extensive research, understanding how cognitive modules emerge remains elusive due to the complex interplay of genetic, developmental, and environmental factors. Computational modeling, however, provides a means of exploring their origins by directly manipulating these factors. Here we aimed to investigate the emergence of cognitive modules by developing the Dual-Task Meta-Learning Partitioned (DAMP) model, whose plastic architecture facilitates automatic structure optimization through a genetic algorithm that emulates natural selection by iteratively selecting for efficient learning fitness. We found that a specialized module for face identification robustly emerged in the DAMP model. Critically, the emergence of the face module was not influenced by the demands of cognitive tasks (identification versus categorization) or the type of stimuli (faces versus non-face objects). Instead, it was determined by the structural constraint of sparse connectivity within the network, suggesting that the face module may arise as an adaptation strategy to challenges posed by sparse connections in neural networks, rather than being an information processor required by certain stimuli or tasks. These findings provide a new evolutionary perspective on the formation of cognitive modules in the human brain, highlighting the pivotal role of the structural properties of neural networks in shaping their cognitive functionality.
Clinical Response to Azacitidine in Myelodysplastic Neoplasms is Associated with Distinct DNA Methylation Changes in Haematopoietic Stem and Progenitor cellsin vivo
Authors: Thoms Julie A.I. , Yan Feng , Hampton Henry R. , Davidson Sarah , Joshi Swapna , Saw Jesslyn , Sarowar Chowdhury H. , Lim Xin Ying , Nunez Andrea C. , Kakadia Purvi M. , Bhuyan Golam Sarower , Zou Xiaoheng , Nguyen Mary , Ghodousi Elaheh S. , Koch Forrest C. , Vafaee Fatemeh , Pickford Russell , Raftery Mark J. , Hough Sally , Buckland Griselda , Bailey Michelle , Ghodke Yuvaraj , Absar Noorul , Vaughan Lachlin , Pasalic Leonardo , Fong Chun Y. , Kenealy Melita , Hiwase Devendra K. , Stoddart Rohanna I. , Mohammed Soma , Lee Linda , Passam Freda H. , Larsen Stephen R. , Spring Kevin J. , Skarratt Kristen K. , Rebeiro Patricia , Presgrave Peter , Stevenson William S. , Ling Silvia , Tiley Campbell , Fuller Stephen J. , Roncolato Fernando , Enjeti Anoop K. , Hoenemann Dirk , Lemech Charlotte , Jolly Christopher J. , Bohlander Stefan K. , Curtis David J. , Wong Jason W H , Unnikrishnan Ashwin , Hertzberg Mark , Olivier Jake , Polizzotto Mark N. , Pimanda John E. 
Published: July 2024

AbstractHypomethylating agents are used as frontline therapy for myelodysplastic neoplasms (MDS), but clinical response is unpredictable. To determine whether response was associated within vivodynamics of DNA hypomethylation, we conducted a phase 2 trial for MDS using both injection and oral azacitidine (AZA). We established that global DNA methylation levels in peripheral blood and bone marrow mononuclear cells were comparable in AZA responders and non-responders during their course of treatment. However, there were distinct baseline and early drug induced differences in CpG methylation in haematopoietic stem and progenitor cells (HSPCs) in responders compared to non-responders that overlapped with regulatory regions of genes associated with tissue patterning, cell migration and myeloid differentiation. Following six cycles of therapy when clinical response typically manifests, differential hypomethylation in responder HSPCs pointed to marrow adaptation as a driver of enhanced haematopoiesis. Taken together, CpG methylation differences in HSPCs may explain variable response to AZA.
Correlated spontaneous activity sets up multi-sensory integration in the developing higher-order cortex
Authors: Dwulet JaeAnn M. , Zabouri Nawal , Kirchner Jan H. , Wosniack Marina E. , Raspanti Alessandra , Kong Deyue , Houwen Gerrit J. , Maldonado Paloma P. , Lohmann Christian , Gjorgjieva Julijana 
Published: July 2024

AbstractTo perceive and navigate complex sensory environments, animals combine sensory information from multiple modalities in specialized brain circuits. Known as multisensory integration, this process typically depends on the existence of co-aligned topographic connections from several sensory areas to downstream circuits exhibiting multimodal representations. How such topographically co-aligned connectivity necessary for multisensory integration gets set up in early stages of development is still unknown. Inspired by the role of spontaneous activity in refining topographic connectivity between early sensory circuits, here we investigated the potential of such spontaneous activity to also guide the co-alignment of multiple sensory modalities in RL, a higher-order associative cortical area rostro-lateral to V1. Analyzing spontaneous activity simultaneously recorded in primary visual and somatosensory cortex and area RL at different developmental ages before sensory experience, we identify candidate features of this activity to guide the emergence of co-aligned topographic multisensory projections with somatosensory leading the visual projection. We confirm this hypothesis using a computational model of activity-dependent circuit refinement, and show that the correlation of spontaneous activity between the visual and somatosensory primary cortex can establish an optimal fraction of multisensory neurons in RL for stimulus decoding. Our model provides an exciting new computational perspective of the role of spontaneous activity in the emergence of topographically co-aligned multimodal sensory representations in downstream circuits, specialized for the processing of rich sensory environments.