Pflugers Archiv : European journal of physiology最新文献

{"title":"A role for plasma membrane Ca²⁺ ATPases in regulation of cellular Ca²⁺ homeostasis by sphingosine kinase-1.","authors":"Luisa Michelle Volk, Jan-Erik Bruun, Sandra Trautmann, Dominique Thomas, Stephanie Schwalm, Josef Pfeilschifter, Dagmar Meyer Zu Heringdorf","doi":"10.1007/s00424-024-03027-7","DOIUrl":"10.1007/s00424-024-03027-7","url":null,"abstract":"<p><p>Sphingosine-1-phosphate (S1P) is a ubiquitous lipid mediator, acting via specific G-protein-coupled receptors (GPCR) and intracellularly. Previous work has shown that deletion of S1P lyase caused a chronic elevation of cytosolic [Ca²⁺]_i and enhanced Ca²⁺ storage in mouse embryonic fibroblasts. Here, we studied the role of sphingosine kinase (SphK)-1 in Ca²⁺ signaling, using two independently generated EA.hy926 cell lines with stable knockdown of SphK1 (SphK1-KD1/2). Resting [Ca²⁺]_i and thapsigargin-induced [Ca²⁺]_i increases were reduced in both SphK1-KD1 and -KD2 cells. Agonist-induced [Ca²⁺]_i increases, measured in SphK1-KD1, were blunted. In the absence of extracellular Ca²⁺, thapsigargin-induced [Ca²⁺]_i increases declined rapidly, indicating enhanced removal of Ca²⁺ from the cytosol. In agreement, plasma membrane Ca²⁺ ATPase (PMCA)-1 and -4 and their auxiliary subunit, basigin, were strongly upregulated. Activation of S1P-GPCR by specific agonists or extracellular S1P did not rescue the effects of SphK1 knockdown, indicating that S1P-GPCR were not involved. Lipid measurements indicated that not only S1P but also dihydro-sphingosine, ceramides, and lactosylceramides were markedly depleted in SphK1-KD2 cells. SphK2 and S1P lyase were upregulated, suggesting enhanced flux via the sphingolipid degradation pathway. Finally, histone acetylation was enhanced in SphK1-KD2 cells, and the histone deacetylase inhibitor, vorinostat, induced upregulation of PMCA1 and basigin on mRNA and protein levels in EA.hy926 cells. These data show for the first time a transcriptional regulation of PMCA1 and basigin by S1P metabolism. It is concluded that SphK1 knockdown in EA.hy926 cells caused long-term alterations in cellular Ca²⁺ homeostasis by upregulating PMCA via increased histone acetylation.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"1895-1911"},"PeriodicalIF":2.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11582158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The contribution of the sphingosine 1-phosphate signaling pathway to chronic kidney diseases: recent findings and new perspectives.","authors":"Stephanie Schwalm, Roxana Manaila, Anke Oftring, Liliana Schaefer, Stephan von Gunten, Josef Pfeilschifter","doi":"10.1007/s00424-024-03029-5","DOIUrl":"10.1007/s00424-024-03029-5","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) is a multifactorial condition with diverse etiologies, such as diabetes mellitus, hypertension, and genetic disorders, often culminating in end-stage renal disease (ESRD). A hallmark of CKD progression is kidney fibrosis, characterized by the excessive accumulation of extracellular matrix components, for which there is currently no effective anti-fibrotic therapy. Recent literature highlights the critical role of sphingosine 1-phosphate (S1P) signaling in CKD pathogenesis and renal fibrosis. This review provides an in-depth analysis of the latest findings on S1P metabolism and signaling in renal fibrosis and in specific CKDs, including diabetic nephropathy (DN), lupus nephritis (LN), focal segmental glomerulosclerosis (FSGS), Fabry disease (FD), and IgA nephropathy (IgAN). Emerging studies underscore the therapeutic potential of modulating S1P signaling with receptor modulators and inhibitors, such as fingolimod (FTY720) and more selective agents like ozanimod and cenerimod. Additionally, the current knowledge about the effects of established kidney protective therapies such as glucocorticoids and SGLT2 and ACE inhibitors on S1P signaling will be summarized. Furthermore, the review highlights the potential role of S1P as a biomarker for disease progression in CKD models, particularly in Fabry disease and diabetic nephropathy. Advanced technologies, including spatial transcriptomics, are further refining our understanding of S1P's role within specific kidney compartments. Collectively, these insights emphasize the need for continued research into S1P signaling pathways as promising targets for CKD treatment strategies.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"1845-1861"},"PeriodicalIF":2.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11582123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain region specific regulation of anandamide (down) and sphingosine-1-phosphate (up) in association with anxiety (AEA) and resilience (S1P) in a mouse model of chronic unpredictable mild stress.","authors":"Caroline Fischer, Dominique Thomas, Robert Gurke, Irmgard Tegeder","doi":"10.1007/s00424-024-03012-0","DOIUrl":"10.1007/s00424-024-03012-0","url":null,"abstract":"<p><p>Chronic unpredictable and unavoidable stress is associated with mental health problems such as depression and anxiety, whereas cycles of stress and stress relief strengthen resilience. It has been suggested that increased breakdown of brain endocannabinoids (eCB) promotes a feeling of adversity. To assess the impact of stress on bioactive lipid homeostasis, we analyzed eCB, sphingolipids, and ceramides in seven brain regions and plasma in a mouse model of chronic unpredictable mild stress. Chronic unpredictable mild stress (CUMS) was associated with low levels of anandamide in hippocampus and prefrontal cortex in association with indicators of anxiety (elevated plus maze). Oppositely, CUMS caused elevated levels of sphingosine-1-phosphate (S1P d18:1) and sphinganine-1-phosphate (S1P d18:0) in the midbrain and thalamus, which was associated with readouts of increased stress resilience, i.e., marble burying and struggling in the tail suspension tests. In the periphery, elevated plasma levels of ceramides revealed similarities with human major depression and suggested unfavorable effects of stress on metabolism, but plasma lipids were not associated with body weight, sucrose consumption, or behavioral features of depression or anxiety. The observed brain site-specific lipid changes suggest that the forebrain succumbs to adverse stress effects while the midbrain takes up defensive adjustments.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"1863-1880"},"PeriodicalIF":2.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11582197/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142036618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phosphatidic acid is involved in regulation of autophagy in neurons in vitro and in vivo.","authors":"Maximilian Schiller, Gregory C Wilson, Simone Keitsch, Matthias Soddemann, Barbara Wilker, Michael J Edwards, Norbert Scherbaum, Erich Gulbins","doi":"10.1007/s00424-024-03026-8","DOIUrl":"10.1007/s00424-024-03026-8","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is a common and severe psychiatric disease, which does not only lead to variety of neuropsychiatric symptoms, but unfortunately in a relatively large proportion of cases also to suicide. The pathogenesis of MDD still requires definition. We have previously shown that ceramide is increased in the blood plasma of patients with MDD. In mouse models of MDD, which are induced by treatment with corticosterone or application of chronic unpredictable stress, increased blood plasma ceramide also increased and caused an inhibition of phospholipase D in endothelial cells of the hippocampus and reduced phosphatidic acid levels in the hippocampus. Here, we demonstrated that corticosterone treatment of PC12 cells resulted in reduced cellular autophagy, which is corrected by treatment with phosphatidic acid. In vivo, treatment of mice with corticosterone or chronic unpredictable stress also reduced autophagy in hippocampus neurons. Autophagy was normalized upon i.v. injection of phosphatidic acid in these mouse models of MDD. In an attempt to identify targets of phosphatidic acid in neurons, we demonstrated that corticosterone reduced levels of the ganglioside GM1 in PC-12 cells and the hippocampus of mice, which were normalized by treatment of cells or i.v. injection of mice with phosphatidic acid. GM1 application also normalized autophagy in cultured neurons. Phosphatidic acid and GM1 corrected stress-induced alterations in behavior, i.e., mainly anxiety and anhedonia, in experimental MDD in mice. Our data suggest that phosphatidic acid may regulate via GM1 autophagy in neurons.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"1881-1894"},"PeriodicalIF":2.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11582205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unlocking the potential: unveiling tyrphostins with Michael-reactive cyanoacrylate motif as promising inhibitors of human 5-lipoxygenase.","authors":"Maximilian Molitor, Amelie Menge, Sebastian Mandel, Sven George, Susanne Müller, Stefan Knapp, Bettina Hofmann, Dieter Steinhilber, Ann-Kathrin Häfner","doi":"10.1007/s00424-024-03019-7","DOIUrl":"10.1007/s00424-024-03019-7","url":null,"abstract":"<p><p>Human 5-lipoxygenase (5-LO) is the key enzyme in the biosynthesis of leukotrienes, mediators of the innate immune system that also play an important role in inflammatory diseases and cancer. In this study, we present compounds, containing a Michael-reactive cyanoacrylate moiety as potent inhibitors of 5-LO. Representatives of the tyrosine kinase inhibitor family called tyrphostins, structurally related to known 5-LO inhibitors, were screened for their 5-LO inhibitory properties using recombinant human 5-LO, intact human PMNL (polymorphonuclear leukocytes), and PMNL homogenates. Their mode of action was characterized by the addition of glutathione, using a fourfold cysteine 5-LO mutant and mass spectrometry analysis. SAR studies revealed several members of the tyrphostin family containing a Michael-reactive cyanoacrylate to efficiently inhibit 5-LO. We identified degrasyn (IC₅₀ 0.11 µM), tyrphostin A9 (IC₅₀ 0.8 µM), AG879 (IC₅₀ 78 nM), and AG556 (IC₅₀ 64 nM) as potent 5-LO inhibitors. Mass spectrometry analysis revealed that degrasyn and AG556 covalently bound to up to four cysteines, including C416 and/or C418 which surround the substrate entry site. Furthermore, the 5-LO inhibitory effect of degrasyn was remarkably impaired by the addition of glutathione or by the mutation of cysteines to serines at the surface of 5-LO. We successfully identified several tyrphostins as potent inhibitors of human 5-LO. Degrasyn and AG556 were able to covalently bind to 5-LO via their cyanoacrylate moiety. This provides a promising mechanism for targeting 5-LO by Michael acceptors, leading to new therapeutic opportunities in the field of inflammation and cancer.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"1913-1928"},"PeriodicalIF":2.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11582101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142351800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipid signaling: facets of a versatile cell communication strategy in health and disease.","authors":"Erich Gulbins, Josef Pfeilschifter","doi":"10.1007/s00424-024-03034-8","DOIUrl":"10.1007/s00424-024-03034-8","url":null,"abstract":"","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"1777-1778"},"PeriodicalIF":2.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11582111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyperglucagonemia and glucagon hypersecretion in early type 2 diabetes result from multifaceted dysregulation of pancreatic mouse α-cells.","authors":"Antonia Ruiz-Pino, Arianna Goncalves-Ramírez, Margarita Jiménez-Palomares, Beatriz Merino, Manuel Castellano-Muñoz, Jean F Vettorazzi, Alex Rafacho, Laura Marroquí, Ángel Nadal, Paloma Alonso-Magdalena, Germán Perdomo, Irene Cózar-Castellano, Ivan Quesada","doi":"10.1007/s00424-024-03045-5","DOIUrl":"https://doi.org/10.1007/s00424-024-03045-5","url":null,"abstract":"<p><p>Hyperglucagonemia has been implicated in the pathogenesis of type 2 diabetes (T2D). In contrast to β-cells, studies on the function of the pancreatic α-cell in T2D are scarce. Consequently, the processes underlying hyperglucagonemia and α-cell dysfunction are largely unknown, limiting the appropriate design of specific pharmacological and therapeutic strategies. In the current study, we aimed to analyze the alterations of the pancreatic α-cell and its glucagon responses in diabetic db/db mice at early stages of the disease. In this context of glucose intolerance, hyperinsulinemia, and β-cell dysfunction, hyperglucagonemia was only present at fed conditions and was associated with insulin resistance. Yet, we found that the glucagon-to-insulin ratio in db/db mice did not change with fed or fasted states, further supporting that the metabolic regulation of glucagon release was impaired. Pancreatic β-cell dysfunction in db/db mice was manifested by increased basal secretion from isolated islets along with reduced insulin content. In contrast, α-cells from diabetic animals presented upregulated secretion and islet content of glucagon compared with controls. Electrophysiological analysis of dispersed α-cells revealed that altered secretion was not the result of impaired exocytosis. Instead, we found defective regulation of Ca²⁺ signaling by glucose. Besides these functional alterations, we also observed augmented α-cell mass in diabetic mice, which was accompanied by disrupted islet cytoarchitecture as well as increased α-cell size and number, without pieces of evidence of upregulated proliferation. Overall, these findings indicate that hyperglucagonemia in early T2D results from multifaceted α-cell deregulation in mice.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142731788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of the estrous cycle on brain monoamines and behavioral and respiratory responses to CO₂ in mice.","authors":"Beatriz Dominiquini-Moraes, Mariana Bernardes-Ribeiro, Luis Gustavo A Patrone, Elisa M Fonseca, Alana T Frias, Kaoma S Costa Silva, Roberta Araujo-Lopes, Raphael E Szawka, Kênia C Bícego, Hélio Zangrossi, Luciane H Gargaglioni","doi":"10.1007/s00424-024-03040-w","DOIUrl":"https://doi.org/10.1007/s00424-024-03040-w","url":null,"abstract":"<p><p>The prevalence of panic disorder is two to four times higher in women compared to that in men, and hormonal changes during the menstrual cycle play a role in the occurrence of panic attacks. Here, we investigated the effect of the estrous cycle on the ventilatory and behavioral responses to CO₂ in mice. Female mice in proestrus, estrus, metestrus, or diestrus were exposed to 20% CO₂, and their escape behaviors, brain monoamines, and plasma levels of 17β-estradiol (E₂) and progesterone (P₄) were measured. Pulmonary ventilation (V̇_E), oxygen consumption (V̇O₂), and body core temperature (T_B) were also measured during normocapnia followed by CO₂. Females exposed to 20% CO₂ exhibited an escape behavior, but the estrous cycle did not affect this response. Females in all phases of the estrous cycle showed higher V̇_E and lower T_B during hypercapnia. In diestrus, there was an attenuation of CO₂-induced hyperventilation with no change in V̇O₂, whereas in estrus, this response was accompanied by a reduction in V̇O₂. Hypercapnia also increased the concentration of plasma P₄ and central DOPAC, the main dopamine metabolite, in all females. There was an estrous cycle effect on brainstem serotonin, with females in estrus showing a higher concentration than females in the metestrus and diestrus phases. Therefore, our data suggest that hypercapnia induces panic-related behaviors and ventilatory changes that lead to an increase in P₄ secretion in female mice, likely originating from the adrenals. The estrous cycle does not affect the behavioral response but interferes in the ventilatory and metabolic responses to CO₂ in mice.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142731789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Controlled dietary phosphate loading in healthy young men elevates plasma phosphate and FGF23 levels.","authors":"Jennifer Scotti Gerber, Eva Maria Pastor Arroyo, Johanne Pastor, Miguel Correia, Stefan Rudloff, Orson W Moe, Daniela Egli-Spichtig, Nilufar Mohebbi, Carsten A Wagner","doi":"10.1007/s00424-024-03046-4","DOIUrl":"https://doi.org/10.1007/s00424-024-03046-4","url":null,"abstract":"<p><p>Increased dietary inorganic phosphate (P_i) intake stimulates renal P_i excretion, in part, by parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23) or dopamine. High dietary P_i may also stimulate sympathetic outflow. Rodent studies provided evidence for these regulatory loops, while controlled experiments in healthy humans examined periods of either a few hours or several weeks, and often varied dietary calcium intake. The effects of controlled, isolated changes in dietary P_i intake over shorter periods are unknown. We studied the effects of a low or high P_i diet on parameters of mineral metabolism in 10 healthy young men. Participants received a standardized diet (1000 mg phosphorus equivalent/day) supplemented with either a phosphate binder (low P_i diet) or phosphate capsules (750 mg phosphorus, high P_i diet) in a randomized cross-over trial for 5 days with a 7-day washout between diets. High P_i intake increased plasma P_i levels and 24-h excretion and decreased urinary calcium excretion. High P_i intake increased intact FGF23 (iFGF23) and suppressed plasma Klotho without affecting cFGF23, PTH, calcidiol, calcitriol, Fetuin-A, dopamine, epinephrine, norepinephrine, metanephrine, or aldosterone. Higher iFGF23 correlated with lower calcitriol and higher PTH. These data support a role for iFGF23 in increasing renal P_i excretion and reducing calcitriol in healthy young men during steady-state high dietary P_i intake. High dietary P_i intake elevated blood P_i levels in healthy young subjects with normal renal function and may therefore be a health risk, as higher serum P_i levels are associated with cardiovascular risk in the general population.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142731753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Intertwined regulators: hypoxia pathway proteins, microRNAs, and phosphodiesterases in the control of steroidogenesis.","authors":"Stephen Ariyeloye, Susanne Kämmerer, Erik Klapproth, Ben Wielockx, Ali El-Armouche","doi":"10.1007/s00424-024-03044-6","DOIUrl":"https://doi.org/10.1007/s00424-024-03044-6","url":null,"abstract":"","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142731755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}