bioRxiv : the preprint server for biology最新文献

{"title":"Coordinated spinal locomotor network dynamics emerge from cell-type-specific connectivity patterns.","authors":"F David Wandler, Benjamin K Lemberger, David L McLean, James M Murray","doi":"10.1101/2024.12.20.629829","DOIUrl":"10.1101/2024.12.20.629829","url":null,"abstract":"<p><p>Even without detailed instruction from the brain, spinal locomotor circuitry generates coordinated behavior characterized by left-right alternation, segment-to-segment propagation, and variable-speed control. While existing models have emphasized the contributions of cellular- and network-level properties, the core mechanisms underlying rhythmogenesis remain incompletely understood. Further, neither family of models has fully accounted for recent experimental results in zebrafish and other organisms pointing to the importance of cell-type-specific intersegmental connectivity patterns and recruitment of speed-selective subpopulations of interneurons. Informed by these experimental findings and others, we developed a hierarchy of increasingly detailed models of the locomotor network. We find that coordinated locomotion emerges in an inhibition-dominated network in which connectivity is determined by intersegmental phase relationships among interneurons and variable-speed control is implemented by recruitment of speed-selective subpopulations. Further, while structured excitatory connections are not necessary for rhythmogenesis, they are useful for increasing peak locomotion frequency, albeit at the cost of smooth transitions at intermediate frequencies, suggesting a basic computational trade-off between speed and control. Together, this family of models shows that network-level interactions are sufficient to generate coordinated, variable-speed locomotion, providing new interpretations of intersegmental excitatory and inhibitory connectivity, as well as the basic, recruitment-based mechanism of speed control.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel environment exposure drives temporally defined and region-specific chromatin accessibility and gene expression changes in the hippocampus.","authors":"Lisa Traunmüller, Erin E Duffy, Hanqing Liu, Stella Sanalidou, Elena G Assad, Senmiao Sun, Naeem S Pajarillo, Nancy Niu, Eric C Griffith, Michael E Greenberg","doi":"10.1101/2024.10.31.621351","DOIUrl":"10.1101/2024.10.31.621351","url":null,"abstract":"<p><p>The interaction of mammals with a novel environment (NE) results in structural and functional changes in multiple brain areas, including the hippocampus. This experience-dependent circuit reorganization is driven in part by changes in gene expression however, the dynamic sensory experience-driven chromatin states and the diverse cell type specific gene expression programs that are regulated by novel experiences are not well described. We employed single- nucleus multiomics (snRNA- and ATAC-seq) and bulk RNA-seq of the hippocampal DG, CA3, and CA1 regions to characterize the temporal evolution of cell-type-specific chromatin accessibility and gene expression changes that occur in 14 different cell types of the hippocampus upon exposure of mice to a novel environment. We observe strong hippocampal regional specificity in excitatory neuron chromatin accessibility and gene expression as well as great diversity in the inhibitory neuron and non-neuronal transcriptional responses. The novel environment-regulated genes in each cell type were enriched for genes that encode secreted factors, and cell-type-specific expression of their cognate receptors identified promising candidates for the modulation of learning and memory processes. Our characterization of the effect of novel experience on chromatin revealed thousands of cell-type-specific changes in chromatin accessibility. Coordinated analysis of chromatin accessibility and gene expression changes within individual cell types identified Fos/AP-1 as a key driver of novel experience-induced changes in chromatin accessibility and cell-type-specific gene expression. Together, these data provide a rich resource of hippocampal chromatin accessibility and gene expression profiles across diverse cell types in response to novel experience, a physiological stimulus that affects learning and memory.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pediatric cerebrospinal fluid immune profiling distinguishes pediatric-onset multiple sclerosis from other pediatric-onset acute neurological disorders.","authors":"Diego A Espinoza, Tobias Zrzavy, Gautier Breville, Simon Thebault, Amaar Marefi, Ina Mexhitaj, Mengyuan Kan, Micky Bacchus, Jessica Legaspi, Samantha Fernandez, Anna Melamed, Mallory Stubblebine, Yeseul Kim, Zachary Martinez, Caroline Diorio, Andreas Schulte-Mecklenbeck, Heinz Wiendl, Ayman Rezk, Rui Li, Sona Narula, Amy T Waldman, Sarah E Hopkins, Brenda Banwell, Amit Bar-Or","doi":"10.1101/2025.02.27.637541","DOIUrl":"10.1101/2025.02.27.637541","url":null,"abstract":"<p><p>The cerebrospinal fluid (CSF) provides a unique glimpse into the central nervous system (CNS) compartment and offers insights into immune processes associated with both healthy immune surveillance as well as inflammatory disorders of the CNS. The latter include demyelinating disorders, such as multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), that warrant different therapeutic approaches yet are not always straightforward to distinguish on clinical and imaging grounds alone. Here, we establish a comprehensive phenotypic landscape of the pediatric CSF immune compartment across a range of non-inflammatory and inflammatory neurological disorders, with a focus on better elucidating CNS-associated immune mechanisms potentially involved in, and discriminating between, pediatric-onset MS (MS) and other pediatric-onset suspected neuroimmune disorders, including MOGAD. We find that CSF from pediatric patients with non-inflammatory neurological disorders is primarily composed of non-activated CD4+ T cells, with few if any B cells present. CSF from pediatric patients with acquired inflammatory demyelinating disorders is characterized by increased numbers of B cells compared to CSF of both patients with other inflammatory or non-inflammatory conditions. Certain features, including particular increased frequencies of antibody-secreting cells (ASCs) and decreased frequencies of CD14+ myeloid cells, distinguish MS from MOGAD and other acquired inflammatory demyelinating disorders.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plug-and-play assembly of biodegradable ionizable lipids for potent mRNA delivery and gene editing <i>in vivo</i>.","authors":"Xuexiang Han, Ying Xu, Adele Ricciardi, Junchao Xu, Rohan Palanki, Vivek Chowdhary, Lulu Xue, Ningqiang Gong, Mohamad-Gabriel Alameh, William H Peranteau, James M Wilson, Drew Weissman, Michael J Mitchell","doi":"10.1101/2025.02.25.640222","DOIUrl":"10.1101/2025.02.25.640222","url":null,"abstract":"<p><p>mRNA-based gene editing therapeutics offer the potential to permanently cure diseases but are hindered by suboptimal delivery platforms. Here, we devise a robust combinatorial chemistry for plug-and-play assembly of diverse biodegradable ionizable lipids and identify a lead candidate that produces superior lipid nanoparticles for various gene editing tools delivery <i>in vivo</i> . Our study highlights the utility of this synthetic approach and the generality of this platform for potent <i>in vivo</i> gene editing.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Parallel multiOMIC analysis reveals glutamine deprivation enhances directed differentiation of renal organoids.","authors":"Iman Sarami, Katherine E Hekman, Ashwani Kumar Gupta, Justin M Snider, David Ivancic, Manja Zec, Manoj Kandpal, Issam Ben-Sahra, Rajasree Menon, Edgar A Otto, Floyd H Chilton, Jason A Wertheim","doi":"10.1101/2025.02.27.640060","DOIUrl":"10.1101/2025.02.27.640060","url":null,"abstract":"<p><p>Metabolic pathways play a critical role in driving differentiation but remain poorly understood in the development of kidney organoids. In this study, parallel metabolite and transcriptome profiling of differentiating human pluripotent stem cells (hPSCs) to multicellular renal organoids revealed key metabolic drivers of the differentiation process. In the early stage, transitioning from hPSCs to nephron progenitor cells (NPCs), both the glutamine and the alanine-aspartate-glutamate pathways changed significantly, as detected by enrichment and pathway impact analyses. Intriguingly, hPSCs maintained their ability to generate NPCs, even when deprived of both glutamine and glutamate. Surprisingly, single cell RNA-Seq analysis detected enhanced maturation and enrichment for podocytes under glutamine-deprived conditions. Together, these findings illustrate a novel role of glutamine metabolism in regulating podocyte development.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct cAMP regulation in scleroderma lung and skin myofibroblasts governs their dedifferentiation via p38α inhibition.","authors":"Jared D Baas, John Varga, Carol Feghali-Bostwick, Marc Peters-Golden, Sean M Fortier","doi":"10.1101/2025.02.26.640163","DOIUrl":"10.1101/2025.02.26.640163","url":null,"abstract":"<p><p>Fibrosis in systemic sclerosis/scleroderma (SSc) is characterized by the progressive accumulation and persistence in multiple organs of pathologic fibroblasts whose contractile properties and exuberant secretion of collagens promote tissue stiffness and scarring. Identifying a tractable mechanism for inactivating and possibly clearing these ultimate effector cells of fibrosis, conventionally termed myofibroblasts (MFs), represents an appealing therapeutic strategy for patients with SSc. This can be accomplished by their phenotypic dedifferentiation, a process known to be promoted by generation of the intracellular second messenger cyclic AMP (cAMP). Notably, however, the abilities of SSc fibroblasts derived from different tissues to generate cAMP - and dedifferentiate in response to it - have never been directly characterized or compared. Here we compared these two processes in lung and skin MFs derived from patients with SSc. While directly increasing intracellular cAMP induced comparable dedifferentiation of lung and skin SSc MFs, dedifferentiation in response to the well-recognized cAMP stimulus prostaglandin E₂ (PGE₂) was diminished or absent in MFs from skin as compared to lung, in part due to differences in the expression of its target G protein-coupled receptors (GPCRs). Importantly, treatment with a phosphodiesterase 4 inhibitor rescued the dedifferentiating effects of PGE₂ in skin SSc MFs. Finally, both cAMP-mediated and direct pharmacologic inhibition of the MAPK p38α promoted dedifferentiation of lung and skin SSc MFs. We conclude that activation of the cAMP pathway and its subsequent inhibition of p38α dedifferentiates SSc MFs from both lung and skin, and may thus represent a therapeutic strategy to alleviate multi-organ fibrosis in SSc.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"APOE Genotype Influences on The Brain Metabolome of Aging Mice - Role for Mitochondrial Energetics in Mechanisms of Resilience in APOE2 Genotype.","authors":"Kamil Borkowski, Nuanyi Liang, Na Zhao, Matthias Arnold, Kevin Huynh, Naama Karu, Siamak Mahmoudiandehkordi, Alexandra Kueider-Paisley, Takahisa Kanekiyo, Guojun Bu, Rima Kaddurah-Daouk","doi":"10.1101/2025.02.25.640178","DOIUrl":"10.1101/2025.02.25.640178","url":null,"abstract":"<p><p>Alzheimer's disease (AD) risk and progression are significantly influenced by APOE genotype with APOE4 increasing and APOE2 decreasing susceptibility compared to APOE3. While the effect of those genotypes was extensively studied on blood metabolome, less is known about their impact in the brain. Here we investigated the impacts of APOE genotypes and aging on brain metabolic profiles across the lifespan, using human APOE-targeted replacement mice. Biocrates P180 targeted metabolomics platform was used to measure a broad range of metabolites probing various metabolic processes. In all genotypes investigated we report changes in acylcarnitines, biogenic amines, amino acids, phospholipids and sphingomyelins during aging. The decreased ratio of medium to long-chain acylcarnitine suggests a reduced level of fatty acid β-oxidation and thus the possibility of mitochondrial dysfunction as these animals age. Additionally, aging APOE2/2 mice had altered branch-chain amino acids (BCAA) profile and increased their downstream metabolite C5 acylcarnitine, indicating increased branched-chain amino acid utilization in TCA cycle and better energetic profile endowed by this protective genotype. We compared these results with human dorsolateral prefrontal cortex metabolomic data from the Religious Orders Study/Memory and Aging Project, and we found that the carriers of APOE2/3 genotype had lower markers of impaired BCAA katabolism, including tiglyl carnitine, methylmalonate and 3-methylglutaconate. In summary, these results suggest a potential involvement of the APOE2 genotype in BCAA utilization in the TCA cycle and nominate these humanized APOE mouse models for further study of APOE in AD, brain aging, and brain BCAA utilization for energy. We have previously shown lower plasma BCAA to be associated with incident dementia, and their higher levels in brain with AD pathology and cognitive impairment. Those findings together with our current results could potentially explain the AD-protective effect of APOE2 genotype by enabling higher utilization of BCAA for energy during the decline of fatty acid β-oxidation.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A conserved somatic sex determination cascade instructs trait-specific sexual dimorphism in horned dung beetles.","authors":"London C Mitchell, Armin P Moczek, Erica M Nadolski","doi":"10.1101/2024.10.10.617608","DOIUrl":"10.1101/2024.10.10.617608","url":null,"abstract":"<p><p>Sex-specific trait expression represents a striking dimension of morphological variation within and across species. The mechanisms instructing sex-specific organ development have been well studied in a small number of insect model systems, suggesting striking conservation in some parts of the somatic sex determination pathway while hinting at possible evolutionary lability in others. However, further resolution of this phenomenon necessitates additional taxon sampling, particularly in groups in which sexual dimorphisms have undergone significant elaboration and diversification. Here, we functionally investigate the somatic sex determination pathway in the gazelle dung beetle <i>Digitonthophagus gazella</i> , an emerging model system in the study of the development and evolution of sexual dimorphisms. We find that RNA interference (RNAi) targeting <i>transformer (tra)</i> caused chromosomal females to develop morphological traits largely indistinguishable from those normally only observed in males, and that <i>tra</i> ^RNAi is sufficient to induce splicing of the normally male-specific isoform of <i>doublesex</i> in chromosomal females, while leaving males unaffected. Further, <i>intersex</i> ^RNAi was found to phenocopy previously described RNAi phenotypes of <i>doublesex</i> in female but not male beetles. These findings match predictions derived from models of the sex determination cascade as developed largely through studies in <i>Drosophila melanogaster</i> . In contrast, <i>transformer2</i> ^RNAi resulted in larval mortality and was not sufficient to affect <i>doublesex</i> splicing, whereas RNAi targeting <i>Sex-lethal</i> and two putative orthologs of <i>hermaphrodite</i> yielded no obvious phenotypic modifications in either males or females, raising the possibility that the function of a subset of sex determination genes may be derived in select Diptera and thus non-representative of their roles in other holometabolous orders. Our results help illuminate how the differential evolutionary lability of the somatic sex determination pathway has contributed to the extraordinary morphological diversification of sex-specific trait expression found in nature.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142485481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor B cell infiltration in platinum-treated advanced urothelial carcinoma.","authors":"Konrad Stawiski, Júlia Perera-Bel, Alejo Rodriguez-Vida, Núria Juanpere Rodero, Jihyun Lee, Daniel E Michaud, Jennifer L Guerriero, Kent W Mouw, Aristotelis Bamias, Filipe Lf Carvalho, Joaquim Bellmunt","doi":"10.1101/2025.02.27.640395","DOIUrl":"10.1101/2025.02.27.640395","url":null,"abstract":"<p><p>Platinum-based chemotherapy combined with immunotherapy provides durable disease control in advanced urothelial cancer. However, cisplatin and carboplatin differently impact the tumor immune microenvironment, affecting chemo-immunotherapy response. Here, we evaluate immune cell populations and ecosystems associated with overall survival in patients treated with platinum-based chemotherapy. Our transcriptomic analysis of pretreatment tumor samples from three cohorts (189 patients) of advanced urothelial cancer showed that lymphoid cell infiltration was significantly associated with prolonged overall survival. In cisplatin-treated patients, high memory B cell infiltration provided a significant overall survival improvement, but no such association was found in carboplatin-treated patients. Additionally, gene expression signatures implicated in B cell memory lineage and associated cytokines were associated with better overall survival in independent cancer patient cohorts. Our findings highlight memory B cell infiltration as a potential prognostic biomarker in urothelial cancer and emphasize the role of the tumor immune microenvironment in chemotherapy response.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metagenomic selections reveal diverse antiphage defenses in human and environmental microbiomes.","authors":"Luis Rodriguez-Rodriguez, James Pfister, Liam Schuck, Arabella E Martin, Luis M Mercado-Santiago, Vincent S Tagliabracci, Kevin J Forsberg","doi":"10.1101/2025.02.28.640651","DOIUrl":"10.1101/2025.02.28.640651","url":null,"abstract":"<p><p>To prevent phage infection, bacteria have developed an arsenal of antiphage defense systems. Using functional metagenomic selections, we identified new examples of these systems from human fecal, human oral, and grassland soil microbiomes. Our antiphage selections in <i>Escherichia coli</i> revealed over 200 putative defenses from 14 diverse bacterial phyla, highlighting the broad phylogenetic interoperability of these systems. Many defense systems were unrecognizable based on sequence or predicted structure, so could only be identified via functional assays. In mechanistic studies, we show that some defense systems encode nucleases that only degrade covalently modified phage DNA, but which accommodate diverse chemical modifications. We also identify outer membrane proteins that prevent phage adsorption and a set of previously unknown defense systems with diverse antiphage profiles and modalities. Most defenses acted against at least two phages, indicating that broadly acting systems are widely distributed among non-model bacteria.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}