bluuebunny/crossref_metadata_2025_split huggingface dataset:
Super-silencer perturbation by EZH2 and REST inhibition leads to large loss of chromatin interactions and reduction in cancer growth
Authors: Zhang Ying , Chen Kaijing , Tang Seng Chuan , Cai Yichao , Nambu Akiko , See Yi Xiang , Fu Chaoyu , Raju Anandhkumar , Lebeau Benjamin , Ling Zixun , Mutwil Marek , Lakshmanan Manikandan , Osato Motomi , Tergaonkar Vinay , Fullwood Melissa Jane 
Published: August 2023

AbstractHuman silencers have been shown to exist and regulate developmental gene expression. However, the functional importance of human silencers needs to be elucidated, such as whether they can form “super-silencers” and whether they are linked to cancer progression. Here, through interrogating two putative silencer components ofFGF18gene, we found that two nearby silencers can cooperate via compensatory chromatin interactions to form a “super-silencer”. Furthermore, double knockout of two silencers exhibited synergistic upregulation ofFGF18expression and changes of cell identity. To perturb the “super-silencers”, we applied combinational treatment of an EZH2 inhibitor GSK343, and a REST inhibitor, X5050 (“GR”). We found that GR led to severe loss of TADs and loops, while the use of one inhibitor by itself only showed mild changes. Such changes in TADs and loops were associated with reduced CTCF and TOP2A mRNA levels. Moreover, GSK343 and X5050 synergistically upregulated super-silencer-controlled genes related to cell cycle, apoptosis and DNA damage, leading to anticancer effects bothin vitroandin vivo. Overall, our data demonstrated the first example of a “super-silencer” and showed that combinational usage of GSK343 and X5050 to disrupt “super-silencers” could potentially lead to cancer ablation.
Modelling Osteoarthritis pathogenesis through Mechanical Loading in an Osteochondral Unit-on-Chip
Authors: Mainardi Andrea , Börsch Anastasiya , Occhetta Paola , Ivanek Robert , Ehrbar Martin , Krattiger Lisa , Oertle Philipp , Loparic Marko , Martin Ivan , Rasponi Marco , Barbero Andrea 
Published: August 2023

AbstractA cure for osteoarthritis (OA), the most prevalent musculoskeletal disease, remains an unmet need. Investigating the molecular and cellular processes leading to OA is challenged by the absence of human models that capture the complex interplay among different tissues in the joint under pathophysiological mechanical loading.In this study, we have engineered an OsteoChondral Unit (OCU)-on-chip system where composite hyaline cartilage - mineralized osseous microtissue analogues are exposed to controlled, tissue-specific compression regimes akin to those of the OCUin vivo. Through single-cell transcriptomic analysis, we demonstrate the critical relevance of the mineralized layer in inducing chondrocyte subpopulations implicated in the progression of OA.Upon exposure to hyperphysiological loading, the OCU-on-chip captures early phenotypic traits of OA pathogenesis, comprising alterations of subchondral mineral content and acquisition of previously described OA genetic signatures.This system enabled to identify novel upstream drivers of OA metabolic changes, including mechanically induced ribosomal alterations, as well as associated molecular targets towards the development of disease-modifying OA therapies.
The Diversity of NLRs inBrassica rapaPan-genome
Authors: Liu Shuhao , Zhu Yimeng , Ke Boyang , Wang Jun , Peng Xianjia , Zhang Shaoke , Zhao Ruoxuan , Wang Haizheng , Lou Jing , Li Jiaruo , Zheng Yunhong , Huang Tao , Wang Siyao , Lang Zebin , Wang Leye , Sun Xizhe , Wang Chunyang 
Published: August 2023

AbstractThe speciesBrassica rapais mainly cultivated as a vegetable crop with high economic value. But infectious diseases, such as soft rot disease and clubroot disease can cause severe yield losses. Introducing resistance genes through breeding is an efficient and sustainable way to reduce the susceptibility and improve the yield of crops. Nucleotide-Binding Leucine-Rich Repeat (NLR) genes are the main types of resistance genes. They can recognize pathogen effectors and initiate downstream immune response. However, the intraspecific diversity ofNLRgenes inBrassica rapahas remained unknown. Based on domain similarity search and machine learning pipeline, we identified 2188 NLRs in 17 accessions ofBrassica rapagenomes, which constitute the species-wide pan-NLRome inBrassica rapa. The diversity of the four types ofNLRgenes are significantly different in the aspects of chromosome location, number stability, integrated domains (IDs), evolutionary trajectory, and positive selection sites. Phylogenetic analyses show TNL-type NLRs whose N terminus contain Toll/interleukin-1 receptor (TIR) domain experienced accession-specific expansion. Moreover, the expanded TNL-type NLRs carry more positively selected amino acid residues which are mainly located on the protein surface based on their 3D structures. These evidences might imply their important biological function in perceiving pathogen effectors. Taken together, our study provides better insights into the diversity and variation ofNLRgenes inBrassica rapapangemone, which can facilitate the biofunction assigning, cloning, and subsequent application in breeding programs.
Liquid Crystalline Layering and Divalent Cations Cooperatively Enhance DNA Condensation
Authors: Kodikara Sineth G. , Gyawali Prabesh , Gleeson James T. , Jakli Antal , Sprunt Samuel , Balci Hamza 
Published: August 2023

AbstractThe layered liquid crystalline (LC) phases formed by DNA molecules which include rigid and flexible segments (‘gapped DNA’) enable the study of both end-to-end stacking and side-to-side lateral interactions that drive the condensation of DNA molecules. The resulting layer structure exhibits long-range inter-layer and intra-layer positional correlations. Using synchrotron small-angle x-ray scattering (SAXS) measurements, we investigate the impact of divalent Mg2+cations on the stability of the inter- and intra-layer DNA ordering as a function of temperature between 5-65 °C and for different terminal base pairings at the blunt ends of the gapped DNA constructs, which mediate the strength of the attractive end-to-end interaction. We demonstrate that the stabilities at a fixed DNA concentration of both inter-layer and intra-layer order are significantly enhanced even at a few mM Mg2+concentration. The stability continues to increase up to ∼30 mM Mg2+concentration, but at higher (∼100 mM) Mg2+content repulsion between positive ions counteracts and reverses the increase. On the other hand, sufficiently strong base-stacking interactions promote intra-layer order even in the absence of multivalent cations, which demonstrates the impact of liquid crystal layering on the DNA condensation process. We discuss the implications of these results in terms cation-mediated DNA-DNA attraction.
Task success in trained spiking neuronal network models coincides with emergence of cross-stimulus-modulated inhibition
Authors: Zhu Yuqing , Smith Chadbourne M.B. , Tang Mufeng , Scherr Franz , MacLean Jason N. 
Published: August 2023

AbstractThe neocortex is composed of spiking neuronal units interconnected in a sparse, recurrent network. Neuronal networks exhibit spiking activity that transforms sensory inputs into appropriate behavioral outputs. In this study, we train biologically realistic spiking neural network (SNN) models to identify the architectural changes which enable task-appropriate computations. Specifically, we employ a binary state change detection task, where each state is defined by motion entropy. This task mirrors behavioral paradigms that mice perform in the lab. SNNs are composed of excitatory and inhibitory units randomly interconnected with connection likelihoods and strengths matched to observations from mouse neocortex. Following training, we discover that SNNs selectively adjust firing rates depending on state, and that excitatory and inhibitory connectivity between input and recurrent layers change in accordance with this rate modulation. Input channels that exhibit bias to one specific motion entropy input develop stronger connections to recurrent excitatory units during training, while channels that exhibit bias to the other input develop stronger connections to inhibitory units. Furthermore, recurrent inhibitory units which positively modulated firing rates to one input strengthened their connections to recurrent units of the opposite modulation. This specific pattern of cross-modulation inhibition emerged as the optimal solution when imposing Dale’s law throughout training of the SNNs. Removing this constraint led to the absence of the emergence of this architectural solution. This work highlights the critical role of interneurons and the specific architectural patterns of inhibition in shaping dynamics and information processing within neocortical circuits.
Regulating temperature and humidity inhibits the disease severity of tomato
Authors: Li Tianzhu , Li Jianming 
Published: August 2023

AbstractThe environment significantly impacts the interactions between plants and pathogens, thus remarkably affecting crop disease occurrence. Regulating the environmental conditions in greenhouses to inhibit plant diseases is conducive to the development of green ecological agriculture. However, how to specific regulate the temperature and humidity to reduce plant diseases remain unclear. In this study, different methods of temperature and humidity regulation were performed. Histological observation and dual RNA–seq analysis showed that increasing temperature and decreasing humidity at 24 h post inoculation (hpi) for 12 h could effectively inhibit disease severity of tomatoes. The regulation induced the expression of heat shock proteins (HSPs) and defense–related genes of tomatoes in response toB. cinerea. Bcl–2–associated athanogenes (BAGs) may be involved in tomato resistance toB. cinereamediated by temperature and humidity regulation. In addition, the infection process and the expression of toxin–related genes ofB. cinereasuch as sesquiterpene botrydial (BOT) and polyketide botcinic acid (BOA) was inhibited. Overall, we obtained the optimal regulation method of temperature and humidity to alleviate tomato gray mold, and preliminarily explored its mechanisms of inhibiting the disease.
Disruption of the PAR3/INSC/LGN complex causes microtubule instability and peripheral neuropathy
Authors: Yeh Jui-Yu , Chao Hua-Chuan , Hung Yu-Chien , Tzou Fei-Yang , Hsiao Cheng-Tsung , Chou Cheng-Ta , Tsai Yu-Shuen , Liao Yi-Chu , Huang Shu-Yi , Kennerson Marina , Lee Yi-Chung , Chan Chih-Chiang 
Published: August 2023

AbstractPAR3/INSC/LGN form an evolutionarily conserved complex required for asymmetric cell division in the developing brain, but its post-developmental function and disease relevance in the peripheral nervous system (PNS) remains unknown. We mapped a new locus for axonal Charcot-Marie-Tooth disease (CMT2) and identified a missense mutation c.209T>G (p.Met70Arg) in the INSC (INSC) gene. Modelling theINSCM70Rvariant inDrosophila, we showed that it caused proprioceptive defects in adult flies, leading to gait defects resembling those in CMT2 patients. Cellularly, PAR3/INSC/LGN dysfunction caused tubulin aggregation and necrotic neurodegeneration, with microtubule-stabilizing agents rescuing both morphological and functional defects of theINSCM70Rmutation in the PNS. Our findings underscore the critical role of the PAR3/INSC/LGN machinery in the adult PNS and highlights a potential therapeutic target for INSC-associated CMT2.One-Sentence SummaryPAR3/INSC/LGN dysfunction causes peripheral neuropathy and is potentially treatable by stabilizing the microtubule network.
Transcriptional dysregulation and impaired neuronal activity inFMR1knock-out and Fragile X patients’ iPSC-derived models
Authors: Maussion Gilles , Rocha Cecilia , Abdian Narges , Yang Dimitri , Turk Julien , Valenzuela Dulce Carrillo , Pimentel Luisa , You Zhipeng , Morquette Barbara , Nicouleau Michael , Deneault Eric , Higgins Samuel , Chen Carol X.-Q. , Reintsch Wolfgang , Stanley Ho , Soubannier Vincent , Lépine Sarah , Modrusan Zora , Lund Jessica , Stephenson William , Schubert Rajib , Durcan Thomas M. 
Published: August 2023

AbstractThe lack of fragile X mental retardation protein (FMRP) protein, due to a repression of theFMR1gene, causes Fragile X syndrome (FXS), one of the most prevalent forms of syndromic autisms. TheFMR1gene codes for an RNA binding protein involved in the regulation of gene expression through RNA processing, control of local translation, and protein-protein interactions; processes that are crucial for proper brain development.Taking advantage of induced pluripotent stem cells (iPSCs) and CRISPR-Cas9 genome editing technologies, we generated iPSC-derived cortical neural progenitors and cortical neurons from anFMR1knock-out and patient cell line with the aim of identifying common phenotypes between the two cellular models. Using RNA sequencing, quantitative PCR and multielectrode array approaches, we assessed how the absence of the functionalFMR1gene affects the transcriptional profiles and the activities of iPSC-derived cortical neuronal progenitor cells (NPCs) and neurons with both models.We observed thatFMR1KO and FXS patient cells have a decrease in their mean firing rate; a cellular activity that can also be blocked by tetrodotoxin (TTX) application in wild-type active neurons. Relative to wild-type neurons, inFMR1KO neurons, increased expression of presynaptic mRNA and transcription factors involved in the forebrain specification and decreased levels of mRNA coding AMPA and NMDA subunits were observed. Intriguingly, 40% of the differentially expressed genes were commonly deregulated between NPCs and differentiating neurons with significant enrichments in FMRP targets and Autism Related Genes found amongst downregulated genes. This implies that an absence of functional FMRP affects transcriptional profiles at the NPC stage, resulting in impaired activity and differentiation of the progenitors into mature neurons over time.These findings from theFMR1KO lines were also shared with FXS patients’ iPSC-derived cells that also present with an impairment in activity and neuronal differentiation, illustrating the critical role of FMRP protein in neuronal development.
E-cigarette vapour induces cellular senescence in primary lung fibroblasts and may contribute to lung pathology
Authors: Bozier Jack , Wang Baoming , de Vries Maaike , Brandsma Corry-Anke , van den Berge Maarten , Timens Wim , Heijink Irene H. , Oliver Brian G.G. , Woldhuis Roy R. 
Published: August 2023

ABSTRACTCellular senescence has been recognized to play a role in COPD pathophysiology. Non-aerosolized E-liquid treatment of a lung fibroblast foetal cell line resulted in cellular senescence induction, but this has not been assessed using E-vapour exposure and using primary lung fibroblasts. Therefore, we investigated whether E-vapour exposure induces cellular senescence in primary human lung fibroblasts and whether this affects their tissue repair function.Primary human lung fibroblasts were stimulated with E-cigarette vapour extracts, and cigarette smoke extract (CSE) and Paraquat (PQ) as positive controls. IL-8 secretion was measured to confirm a stimulatory response. Multiple senescence markers (p16, p21, SA-β-gal, and proliferation) were assessed and the tissue repair function was assessed using a scratch assay. Finally, we tried to validate our findings in an E-cigarette-exposed mouse model.Upon stimulation with CSE, PQ, and E-vapour extracts, cellular senescence was induced, which seemed dose-dependent and nicotine-independent. E-vapour-induced senescence resulted in an impaired tissue repair function. No significant difference was observed in the E-cigarette-exposed mouse model.In this study, we identify E-cigarette vapours’ potential to induce cellular senescence in primary human lung fibroblasts and that this affects their tissue repair function, which further adds to the identified risks of E-cigarette use.
Modulation of riboflavin biosynthesis and utilization in mycobacteria
Authors: Chengalroyen Melissa D. , Mehaffy Carolina , Lucas Megan , Bauer Niel , Raphela Mabule L. , Oketade Nurudeen , Warner Digby F. , Lewinsohn Deborah A. , Lewinsohn David M. , Dobos Karen M. , Mizrahi Valerie 
Published: August 2023

ABSTRACTRiboflavin (vitamin B2) is the precursor of the flavin coenzymes, FAD and FMN, which play a central role in cellular redox metabolism. While humans must obtain riboflavin from dietary sources, certain microbes, includingMycobacterium tuberculosis(Mtb), can biosynthesize riboflavinde novo. Riboflavin precursors have also been implicated in the activation of mucosal-associated invariant T (MAIT) cells which recognize metabolites derived from the riboflavin biosynthesis pathway complexed to the MHC-I-like molecule, MR1. To investigate the biosynthesis and function of riboflavin and its pathway intermediates in mycobacterial metabolism, physiology and MAIT cell recognition, we constructed conditional knockdowns (hypomorphs) in riboflavin biosynthesis and utilization genes inMycobacterium smegmatis(Msm) and Mtb by inducible CRISPR interference. Using this comprehensive panel of hypomorphs, we analyzed the impact of gene silencing on viability, on the transcription of (other) riboflavin pathway genes, on the levels of the pathway proteins and on riboflavin itself. Our results revealed that (i) despite lacking a canonical transporter, both Msm and Mtb assimilate exogenous riboflavin when supplied at high concentration; (ii) there is functional redundancy in lumazine synthase activity in Msm; (iii) silencing ofribA2orribFis profoundly bactericidal in Mtb; and (iv) in Msm,ribA2silencing results in concomitant knockdown of other pathway genes coupled with RibA2 and riboflavin depletion and is also bactericidal. In addition to their use in genetic validation of potential drug targets for tuberculosis, this collection of hypomorphs provides a useful resource for investigating the role of pathway intermediates in MAIT cell recognition of mycobacteria.IMPORTANCEThe pathway for biosynthesis and utilization of riboflavin, precursor of the essential coenzymes, FMN and FAD, is of particular interest in the flavin-rich pathogen,Mycobacterium tuberculosis(Mtb), for two important reasons: (i) the pathway includes potential tuberculosis (TB) drug targets; and (ii) intermediates from the riboflavin biosynthesis pathway provide ligands for mucosal associated invariant T (MAIT) cells, which have been implicated in TB pathogenesis. However, the riboflavin pathway is poorly understood in mycobacteria, which lack canonical mechanisms to transport this vitamin and to regulate flavin coenzyme homeostasis. By conditionally disrupting each step of the pathway and assessing the impact on mycobacterial viability and on the levels of the pathway proteins as well as riboflavin, our work provides genetic validation of the riboflavin pathway as a target for TB drug discovery and offers a resource for further exploring the association between riboflavin biosynthesis, MAIT cell activation and TB infection and disease.
Extending ligand efficacy indices with compound pharmacokinetic characteristics towards holistic Compound Quality Scores
Authors: Tautermann Christofer S. , Borghardt Jens M. , Pfau Roland , Zentgraf Matthias , Weskamp Nils , Sauer Achim 
Published: August 2023

ABSTRACTThe suitability of a small molecule to become an oral drug is often assessed by simple physicochemical rules, the application of ligand efficacy scores (combining physicochemical properties with potency) or by multi-parameter composite scores based on physicochemical compound properties. These rules and scores are empirical and typically lack mechanistic background, such as information on pharmacokinetics (PK). We introduce a new type of Compound Quality Scores (specifically called dose-scores and cmax-scores), which explicitly include predicted or when available experimentally determined PK parameters, such as volume of distribution, clearance and plasma protein binding. Combined with on-target potency, these scores are surrogates for an estimated dose or the corresponding cmax. These Compound Quality Scores allow for prioritization of compounds in test cascades, and by integrating machine learning based potency and PK predictions, these scores allow prioritization for synthesis. We demonstrate the complementary and in most cases the superiority to existing efficiency metrics (such as ligand efficiency scores) by project examples.
Breakdown and repair of the aging brain metabolic system
Authors: Shichkova Polina , Coggan Jay S. , Kanari Lida , Boci Elvis , Favreau Cyrille , Antonel Stefano Maximiliano , Keller Daniel , Markram Henry 
Published: August 2023

AbstractThe study presented explores the complex relationship between the aging brain, energy metabolism, blood flow and neuronal activity by introducing a comprehensive, data-driven molecular model of the neuro-glial vascular system, including all key enzymes, transporters, metabolites, and blood flow vital for neuronal electrical activity with 16’800 interaction pathways. We find significant alterations in metabolite concentrations and differential effects on ATP supply in neurons and astrocytes and within subcellular compartments within aged brains, and identify reduced Na+/K+-ATPase as the leading cause of impaired neuronal action potentials. The model predicts that the metabolic pathways cluster more closely in the aged brain, suggesting a loss of robustness and adaptability. Additionally, the aged metabolic system displays reduced flexibility, undermining its capacity to efficiently respond to stimuli and recover from damage. Through transcription factor analysis, the estrogen-related receptor alpha (ESRRA) emerged as a central target connected to these aging-related changes. An unguided optimization search pinpointed potential interventions capable of restoring the brain’s metabolic flexibility and restoring action potential generation. These strategies include increasing the NADH cytosol-mitochondria shuttle, NAD+ pool, ketone β-hydroxybutyrate, lactate and Na+/K+-ATPase and reducing blood glucose levels. The model is open-sourced to help guide further research in brain metabolism.