Channels (Austin, Tex.)最新文献

{"title":"The endocannabinoid ARA-S facilitates the activation of cardiac Kv7.1/KCNE1 channels from different species.","authors":"Irene Hiniesto-Iñigo, Veronika A Linhart, Ali S Kusay, Sara I Liin","doi":"10.1080/19336950.2024.2420651","DOIUrl":"10.1080/19336950.2024.2420651","url":null,"abstract":"<p><p>The endogenous endocannabinoid-like compound N-arachidonoyl-L-serine (ARA-S) facilitates activation of the human Kv7.1/KCNE1 channel and shortens a prolonged action potential duration and QT interval in guinea pig hearts. Hence, ARA-S is interesting to study further in cardiac models to explore the functional impact of such Kv7.1/KCNE1-mediated effects. To guide which animal models would be suitable for assessing ARA-S effects, and to aid interpretation of findings in different experimental models, it is useful to know whether Kv7.1/KCNE1 channels from relevant species respond similarly to ARA-S. To this end, we used the two-electrode voltage clamp technique to compare the effects of ARA-S on Kv7.1/KCNE1 channels from guinea pig, rabbit, and human Kv7.1/KCNE1, when expressed in <i>Xenopus laevis</i> oocytes. We found that the activation of Kv7.1/KCNE1 channels from all tested species was facilitated by ARA-S, seen as a concentration-dependent shift in the voltage-dependence of channel opening and increase in current amplitude and conductance over a broad voltage range. The rabbit channel displayed quantitatively similar effects as the human channel, whereas the guinea pig channel responded with more prominent increase in current amplitude and maximal conductance. This study suggests that rabbit and guinea pig models are both suitable for studying ARA-S effects mediated via Kv7.1/KCNE1.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"18 1","pages":"2420651"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514023","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":"The role and mechanism of vascular wall cell ion channels in vascular fibrosis remodeling.","authors":"Xiaolin Zhang, Hai Tian, Cheng Xie, Yan Yang, Pengyun Li, Jun Cheng","doi":"10.1080/19336950.2024.2418128","DOIUrl":"10.1080/19336950.2024.2418128","url":null,"abstract":"<p><p>Fibrosis is usually the final pathological state of many chronic inflammatory diseases and may lead to organ malfunction. Excessive deposition of extracellular matrix (ECM) molecules is a characteristic of most fibrotic tissues. The blood vessel wall contains three layers of membrane structure, including the intima, which is composed of endothelial cells; the media, which is composed of smooth muscle cells; and the adventitia, which is formed by the interaction of connective tissue and fibroblasts. The occurrence and progression of vascular remodeling are closely associated with cardiovascular diseases, and vascular remodeling can alter the original structure and function of the blood vessel. Dysregulation of the composition of the extracellular matrix in blood vessels leads to the continuous advancement of vascular stiffening and fibrosis. Vascular fibrosis reaction leads to excessive deposition of the extracellular matrix in the vascular adventitia, reduces vessel compliance, and ultimately alters key aspects of vascular biomechanics. The pathogenesis of fibrosis in the vasculature and strategies for its reversal have become interesting and important challenges. Ion channels are widely expressed in the cardiovascular system; they regulate blood pressure, maintain cardiovascular function homeostasis, and play important roles in ion transport, cell differentiation, proliferation. In blood vessels, different types of ion channels in fibroblasts, smooth muscle cells and endothelial cells may be relevant mediators of the development of fibrosis in organs or tissues. This review discusses the known roles of ion channels in vascular fibrosis remodeling and discusses potential therapeutic targets for regulating remodeling and repair after vascular injury.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"18 1","pages":"2418128"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11492694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482288","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 phenylalanine at the extracellular side of Kir1.1 facilitates potassium permeation.","authors":"Henry Sackin, Mikheil Nanazashvili","doi":"10.1080/19336950.2023.2294661","DOIUrl":"10.1080/19336950.2023.2294661","url":null,"abstract":"<p><p>The Kir1.1 (ROMK) family of weak inward rectifiers controls K secretion in the renal CCT and K recycling in the renal TALH. A single point mutant of the inward rectifier, F127V-Kir1.1b was used to investigate the K transition between the selectivity filter and the outer mouth of the channel. We hypothesize that normally an aromatic <i>Phe</i> at the external entryway of Kir1.1b facilitates outward K secretion. We tested this by replacing F127-Kir1.1b with a small aliphatic <i>Val</i>. Results indicate that removal of the <i>Phe</i> at 127 suppresses outward currents that normally contribute to K secretion. Results with the F127V mutant could be explained by increased polyamine block and/or a decrease in the avidity of Kir1.1 for K ions near the outer mouth of the channel. The latter is supported by F127V-Kir1.1b having a lower affinity (K_m = 33 mM) for K than wild-type Kir1.1b (K_m = 7 mM) during external K elevation. Conversely, chelation of K with 18-Crown-6 ether reduced K conductance faster in F127V (half-time = 6s) than in wt-Kir1.1b (half-time = 120s), implying that F127V is less hospitable to external K. In other experiments, positive membrane potentials gated the F127V mutant channel closed at physiological levels of external Ca, possibly by electrostatically depleting K adjacent to the membrane, suggesting that the <i>Phe</i> residue is critical for outward K secretion at physiological Ca. We speculate that the avidity of wt-Kir1.1b for external K could result from a cation-Pi interaction between K and the aromatic F127.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"18 1","pages":"2294661"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10773671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139111385","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 structural atlas of druggable sites on Na_v channels.","authors":"Zhangqiang Li, Qiurong Wu, Nieng Yan","doi":"10.1080/19336950.2023.2287832","DOIUrl":"10.1080/19336950.2023.2287832","url":null,"abstract":"<p><p>Voltage-gated sodium (Na_v) channels govern membrane excitability by initiating and propagating action potentials. Consistent with their physiological significance, dysfunction, or mutations in these channels are associated with various channelopathies. Na_v channels are thereby major targets for various clinical and investigational drugs. In addition, a large number of natural toxins, both small molecules and peptides, can bind to Na_v channels and modulate their functions. Technological breakthrough in cryo-electron microscopy (cryo-EM) has enabled the determination of high-resolution structures of eukaryotic and eventually human Na_v channels, alone or in complex with auxiliary subunits, toxins, and drugs. These studies have not only advanced our comprehension of channel architecture and working mechanisms but also afforded unprecedented clarity to the molecular basis for the binding and mechanism of action (MOA) of prototypical drugs and toxins. In this review, we will provide an overview of the recent advances in structural pharmacology of Na_v channels, encompassing the structural map for ligand binding on Na_v channels. These findings have established a vital groundwork for future drug development.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"18 1","pages":"2287832"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10732651/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138464760","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":"Evaluation of four <i>KCNMA1</i> channelopathy variants on BK channel current under Ca_V1.2 activation.","authors":"Ria L Dinsdale, Andrea L Meredith","doi":"10.1080/19336950.2024.2396346","DOIUrl":"10.1080/19336950.2024.2396346","url":null,"abstract":"<p><p>Variants in <i>KCNMA1</i>, encoding the voltage- and calcium-activated K⁺ (BK) channel, are associated with human neurological disease. The effects of gain-of-function (GOF) and loss-of-function (LOF) variants have been predominantly studied on BK channel currents evoked under steady-state voltage and Ca²⁺ conditions. However, in their physiological context, BK channels exist in partnership with voltage-gated Ca²⁺ channels and respond to dynamic changes in intracellular Ca²⁺ (Ca²⁺_i). In this study, an L-type voltage-gated Ca²⁺ channel present in the brain, Ca_V1.2, was co-expressed with wild type and mutant BK channels containing GOF (D434G, N999S) and LOF (H444Q, D965V) patient-associated variants in HEK-293T cells. Whole-cell BK currents were recorded under Ca_V1.2 activation using buffering conditions that restrict Ca²⁺_i to nano- or micro-domains. Both conditions permitted wild type BK current activation in response to Ca_V1.2 Ca²⁺ influx, but differences in behavior between wild type and mutant BK channels were reduced compared to prior studies in clamped Ca²⁺_i. Only the N999S mutation produced an increase in BK current in both micro- and nano-domains using square voltage commands and was also detectable in BK current evoked by a neuronal action potential within a microdomain. These data corroborate the GOF effect of N999S on BK channel activity under dynamic voltage and Ca²⁺ stimuli, consistent with its pathogenicity in neurological disease. However, the patient-associated mutations D434G, H444Q, and D965V did not exhibit significant effects on BK current under Ca_V1.2-mediated Ca²⁺ influx, in contrast with prior steady-state protocols. These results demonstrate a differential potential for <i>KCNMA1</i> variant pathogenicity compared under diverse voltage and Ca²⁺ conditions.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"18 1","pages":"2396346"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11370921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142115579","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 benzoylurea derivative decreases TRPM7 channel function and inhibits cancer cells migration.","authors":"Xiaoding Zhang, Rui Zong, Yu Han, Xiaoming Li, Shuangyu Liu, Yixue Cao, Nan Jiang, Pingping Chen, Haixia Gao","doi":"10.1080/19336950.2024.2396339","DOIUrl":"10.1080/19336950.2024.2396339","url":null,"abstract":"<p><p>The transient receptor potential melastatin 7 channel (TRPM7) is a nonselective cation channel highly expressed in some human cancer tissues. TRPM7 is involved in the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of cancer cells. Modulation of TRPM7 could be a promising therapeutic strategy for treating cancer; however, efficient and selective pharmacological TRPM7 modulators are lacking. In this study we investigated N- [4- (4, 6-dimethyl- 2-pyrimidinyloxy) - 3- methylphenyl] -N' - [2 -(dimethylamino)] benzoylurea (SUD), a newly synthesized benzoylurea derivative, for its effects on cancer cell migration and EMT and on functional expression of TRPM7. Our previous studies showed that SUD induces cell cycle arrest and apoptosis of MCF-7 and BGC-823 cells (human breast cancer and gastric cancer cell lines, respectively). Here, we show that SUD significantly decreased the migration of both types of cancer cells. Moreover, SUD decreased vimentin expression and increased E-cadherin expression in both cell types, indicating that EMT is also decreased by SUD. Importantly, SUD potentially reduced the TRPM7-like current in a concentration-dependent manner and decreased TRPM7 expression through the PI3K/Akt signaling pathway. Finally, molecular docking simulations were used to investigate potential SUD binding sites on TRPM7. In summary, our research demonstrated that SUD is an effective TRPM7 inhibitor and a potential agent to suppress the metastasis of breast and gastric cancer by inhibiting TRPM7 expression and function.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"18 1","pages":"2396339"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11370923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142115580","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 insights into voltage-gated ion channels: Translational breakthroughs in medical oncology.","authors":"Minas Sakellakis, Sung Mi Yoon, Jashan Reet, Athanasios Chalkias","doi":"10.1080/19336950.2023.2297605","DOIUrl":"10.1080/19336950.2023.2297605","url":null,"abstract":"<p><p>Preclinical evidence suggests that voltage gradients can act as a kind of top-down master regulator during embryogenesis and orchestrate downstream molecular-genetic pathways during organ regeneration or repair. Moreover, electrical stimulation shifts response to injury toward regeneration instead of healing or scarring. Cancer and embryogenesis not only share common phenotypical features but also commonly upregulated molecular pathways. Voltage-gated ion channel activity is directly or indirectly linked to the pathogenesis of cancer hallmarks, while experimental and clinical studies suggest that their modulation, e.g., by anesthetic agents, may exert antitumor effects. A large recent clinical trial served as a proof-of-principle for the benefit of preoperative use of topical sodium channel blockade as a potential anticancer strategy against early human breast cancers. Regardless of whether ion channel aberrations are primary or secondary cancer drivers, understanding the functional consequences of these events may guide us toward the development of novel therapeutic approaches.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"18 1","pages":"2297605"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10761148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139059243","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":"Cell size induced bias of current density in hypertrophic cardiomyocytes.","authors":"Elena Lilliu, Benjamin Hackl, Eva Zabrodska, Stefanie Gewessler, Tobias Karge, Jessica Marksteiner, Jakob Sauer, Eva M Putz, Hannes Todt, Karlheinz Hilber, Xaver Koenig","doi":"10.1080/19336950.2024.2361416","DOIUrl":"10.1080/19336950.2024.2361416","url":null,"abstract":"<p><p>Alterations in ion channel expression and function known as \"electrical remodeling\" contribute to the development of hypertrophy and to the emergence of arrhythmias and sudden cardiac death. However, comparing current density values - an electrophysiological parameter commonly utilized to assess ion channel function - between normal and hypertrophied cells may be flawed when current amplitude does not scale with cell size. Even more, common routines to study equally sized cells or to discard measurements when large currents do not allow proper voltage-clamp control may introduce a selection bias and thereby confound direct comparison. To test a possible dependence of current density on cell size and shape, we employed whole-cell patch-clamp recording of voltage-gated sodium and calcium currents in Langendorff-isolated ventricular cardiomyocytes and Purkinje myocytes, as well as in cardiomyocytes derived from trans-aortic constriction operated mice. Here, we describe a distinct inverse relationship between voltage-gated sodium and calcium current densities and cell capacitance both in normal and hypertrophied cells. This inverse relationship was well fit by an exponential function and may be due to physiological adaptations that do not scale proportionally with cell size or may be explained by a selection bias. Our study emphasizes the need to consider cell size bias when comparing current densities in cardiomyocytes of different sizes, particularly in hypertrophic cells. Conventional comparisons based solely on mean current density may be inadequate for groups with unequal cell size or non-proportional current amplitude and cell size scaling.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"18 1","pages":"2361416"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11155701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141249093","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":"Role of the Ca_V1.2 distal carboxy terminus in the regulation of L-type current.","authors":"Felipe Arancibia, Daniela De Giorgis, Franco Medina, Tamara Hermosilla, Felipe Simon, Diego Varela","doi":"10.1080/19336950.2024.2338782","DOIUrl":"https://doi.org/10.1080/19336950.2024.2338782","url":null,"abstract":"<p><p>L-type calcium channels are essential for the excitation-contraction coupling in cardiac muscle. The Ca_V1.2 channel is the most predominant isoform in the ventricle which consists of a multi-subunit membrane complex that includes the Ca_V1.2 pore-forming subunit and auxiliary subunits like Ca_Vα₂δ and Ca_Vβ_2b. The Ca_V1.2 channel's C-terminus undergoes proteolytic cleavage, and the distal C-terminal domain (DC_termD) associates with the channel core through two domains known as proximal and distal C-terminal regulatory domain (PCRD and DCRD, respectively). The interaction between the DC_termD and the remaining C-terminus reduces the channel activity and modifies voltage- and calcium-dependent inactivation mechanisms, leading to an autoinhibitory effect. In this study, we investigate how the interaction between DCRD and PCRD affects the inactivation processes and Ca_V1.2 activity. We expressed a 14-amino acid peptide miming the DCRD-PCRD interaction sequence in both heterologous systems and cardiomyocytes. Our results show that overexpression of this small peptide can displace the DC_termD and replicate the effects of the entire DC_termD on voltage-dependent inactivation and channel inhibition. However, the effect on calcium-dependent inactivation requires the full DC_termD and is prevented by overexpression of calmodulin. In conclusion, our results suggest that the interaction between DCRD and PCRD is sufficient to bring about the current inhibition and alter the voltage-dependent inactivation, possibly in an allosteric manner. Additionally, our data suggest that the DC_termD competitively modifies the calcium-dependent mechanism. The identified peptide sequence provides a valuable tool for further dissecting the molecular mechanisms that regulate L-type calcium channels' basal activity in cardiomyocytes.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"18 1","pages":"2338782"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11067984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140873666","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":"The activation thresholds and inactivation kinetics of poking-evoked PIEZO1 and PIEZO2 currents are sensitive to subtle variations in mechanical stimulation parameters.","authors":"Nadja Zeitzschel, Stefan G Lechner","doi":"10.1080/19336950.2024.2355123","DOIUrl":"https://doi.org/10.1080/19336950.2024.2355123","url":null,"abstract":"<p><p>PIEZO1 and PIEZO2 are mechanically activated ion channels that confer mechanosensitivity to various cell types. PIEZO channels are commonly examined using the so-called poking technique, where currents are recorded in the whole-cell configuration of the patch-clamp technique, while the cell surface is mechanically stimulated with a small fire-polished patch pipette. Currently, there is no gold standard for mechanical stimulation, and therefore, stimulation protocols differ significantly between laboratories with regard to stimulation velocity, angle, and size of the stimulation probe. Here, we systematically examined the impact of variations in these three stimulation parameters on the outcomes of patch-clamp recordings of PIEZO1 and PIEZO2. We show that the inactivation kinetics of PIEZO1 and, to a lesser extent, of PIEZO2 change with the angle at which the probe that is used for mechanical stimulation is positioned and, even more prominently, with the size of its tip. Moreover, we found that the mechanical activation threshold of PIEZO2, but not PIEZO1, decreased with increasing stimulation speeds. Thus, our data show that two key outcome parameters of PIEZO-related patch-clamp studies are significantly affected by common variations in the mechanical stimulation protocols, which calls for caution when comparing data from different laboratories and highlights the need to establish a gold standard for mechanical stimulation to improve comparability and reproducibility of data obtained with the poking technique.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"18 1","pages":"2355123"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140961341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}