Molecular genetics and metabolism最新文献

{"title":"Neuroectoderm phenotypes in a human stem cell model of O-GlcNAc transferase associated with intellectual disability","authors":"Marta Murray ,&nbsp;Lindsay Davidson ,&nbsp;Andrew T. Ferenbach ,&nbsp;Dirk Lefeber ,&nbsp;Daan M.F. van Aalten","doi":"10.1016/j.ymgme.2024.108492","DOIUrl":"https://doi.org/10.1016/j.ymgme.2024.108492","url":null,"abstract":"<div><p>Pathogenic variants in the O-GlcNAc transferase gene (<em>OGT</em>) have been associated with a congenital disorder of glycosylation (OGT-CDG), presenting with intellectual disability which may be of neuroectodermal origin. To test the hypothesis that pathology is linked to defects in differentiation during early embryogenesis, we developed an OGT-CDG induced pluripotent stem cell line together with isogenic control generated by CRISPR/Cas9 gene-editing. Although the OGT-CDG variant leads to a significant decrease in OGT and O-GlcNAcase protein levels, there were no changes in differentiation potential or stemness. However, differentiation into ectoderm resulted in significant differences in O-GlcNAc homeostasis. Further differentiation to neuronal stem cells revealed differences in morphology between patient and control lines, accompanied by disruption of the O-GlcNAc pathway. This suggests a critical role for O-GlcNAcylation in early neuroectoderm architecture, with robust compensatory mechanisms in the earliest stages of stem cell differentiation.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"142 2","pages":"Article 108492"},"PeriodicalIF":3.8,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224003767/pdfft?md5=d52608713fac9ecbebb266e4897a3884&pid=1-s2.0-S1096719224003767-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140951291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liposome-encapsulated mannose-1-phosphate therapy improves global N-glycosylation in different congenital disorders of glycosylation","authors":"Rohit Budhraja ,&nbsp;Silvia Radenkovic ,&nbsp;Anu Jain ,&nbsp;Irena J.J. Muffels ,&nbsp;Moulay Hicham Alaoui Ismaili ,&nbsp;Tamas Kozicz ,&nbsp;Akhilesh Pandey ,&nbsp;Eva Morava","doi":"10.1016/j.ymgme.2024.108487","DOIUrl":"https://doi.org/10.1016/j.ymgme.2024.108487","url":null,"abstract":"<div><p>Phosphomannomutase 2 (PMM2) converts mannose-6-phospahate to mannose-1-phosphate; the substrate for GDP-mannose, a building block of the glycosylation biosynthetic pathway. Pathogenic variants in the <em>PMM2</em> gene have been shown to be associated with protein hypoglycosylation causing PMM2-congenital disorder of glycosylation (PMM2-CDG). While mannose supplementation improves glycosylation in vitro, but not in vivo, we hypothesized that liposomal delivery of mannose-1-phosphate could increase the stability and delivery of the activated sugar to enter the targeted compartments of cells. Thus, we studied the effect of liposome-encapsulated mannose-1-P (GLM101) on global protein glycosylation and on the cellular proteome in skin fibroblasts from individuals with PMM2-CDG, as well as in individuals with two N-glycosylation defects early in the pathway, namely ALG2-CDG and ALG11-CDG. We leveraged multiplexed proteomics and N-glycoproteomics in fibroblasts derived from different individuals with various pathogenic variants in <em>PMM2, ALG2</em> and <em>ALG11</em> genes. Proteomics data revealed a moderate but significant change in the abundance of some of the proteins in all CDG fibroblasts upon GLM101 treatment. On the other hand, N-glycoproteomics revealed the GLM101 treatment enhanced the expression levels of several high-mannose and complex/hybrid glycopeptides from numerous cellular proteins in individuals with defects in <em>PMM2</em> and <em>ALG2</em> genes. Both PMM2-CDG and ALG2-CDG exhibited several-fold increase in glycopeptides bearing Man₆ and higher glycans and a decrease in Man₅ and smaller glycan moieties, suggesting that GLM101 helps in the formation of mature glycoforms. These changes in protein glycosylation were observed in all individuals irrespective of their genetic variants. ALG11-CDG fibroblasts also showed increase in high mannose glycopeptides upon treatment; however, the improvement was not as dramatic as the other two CDG. Overall, our findings suggest that treatment with GLM101 overcomes the genetic block in the glycosylation pathway and can be used as a potential therapy for CDG with enzymatic defects in early steps in protein N-glycosylation.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"142 2","pages":"Article 108487"},"PeriodicalIF":3.8,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140905502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantification of N-acetyl-l-aspartate in dried blood spots: A simple and fast LC-MS/MS neonatal screening method for the diagnosis of Canavan disease","authors":"Christian Posern ,&nbsp;Benjamin Dreyer ,&nbsp;Sarah L. Maier ,&nbsp;Florian Eichler ,&nbsp;Michael H. Gelb ,&nbsp;René Santer ,&nbsp;Annette Bley ,&nbsp;Simona Murko","doi":"10.1016/j.ymgme.2024.108489","DOIUrl":"https://doi.org/10.1016/j.ymgme.2024.108489","url":null,"abstract":"<div><h3>Background</h3><p>Canavan disease is a devastating neurometabolic disorder caused by accumulation of <em>N</em> acetylaspartate in brain and body fluids due to genetic defects in the aspartoacylase gene (<em>ASPA</em>). New gene therapies are on the horizon but will require early presymptomatic diagnosis to be fully effective.</p></div><div><h3>Methods</h3><p>We therefore developed a fast and highly sensitive liquid chromatography mass spectrometry (LC-MS/MS)-based method for quantification of <em>N</em>-acetylaspartate in dried blood spots and established reference ranges for neonates and older controls. With this test, we investigated 45 samples of 25 Canavan patients including 8 with a neonatal sample.</p></div><div><h3>Results</h3><p>Measuring <em>N</em>-acetylaspartate concentration in dried blood with this novel test, all Canavan patients (with variable severity) were well separated from the control group (median; range: 5.7; 1.6–13.6 μmol/L [<em>n</em> = 45] <em>vs</em> 0.44; 0.24–0.99 μmol/L [<em>n</em> = 59] (<em>p</em> &lt; 0.05)). There was also no overlap when comparing neonatal samples of Canavan patients (7.3; 5.1–9.9 μmol/L [<em>n</em> = 8]) and neonatal controls (0.93; 0.4–1.8 μmol/L [<em>n</em> = 784]) (p &lt; 0.05).</p></div><div><h3>Conclusions</h3><p>We have developed a new LC-MS/MS-based screening test for early postnatal diagnosis of Canavan disease that should be further evaluated in a population-based study once a promising treatment becomes available. The method meets the general requirements of newborn screening and should be appropriate for multiplexing with other screening approaches that combine chromatographic and mass spectrometry techniques.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"142 2","pages":"Article 108489"},"PeriodicalIF":3.8,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224003731/pdfft?md5=1dea0f8fc69b0aeaadc13dc8e0e625fa&pid=1-s2.0-S1096719224003731-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140879429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"It's time to reconsider the newborn screening RUSP prospective pilot study “N of 1” rule","authors":"Michael H. Gelb ,&nbsp;Dietrich Matern ,&nbsp;Matthew Ellinwood ,&nbsp;Amy Gaviglio","doi":"10.1016/j.ymgme.2024.108352","DOIUrl":"10.1016/j.ymgme.2024.108352","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"142 1","pages":"Article 108352"},"PeriodicalIF":3.8,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140013019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover 2 / Ed. Board","authors":"","doi":"10.1016/S1096-7192(24)00363-9","DOIUrl":"https://doi.org/10.1016/S1096-7192(24)00363-9","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"142 1","pages":"Article 108479"},"PeriodicalIF":3.8,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224003639/pdfft?md5=e12b3a94b249dc6ab488a2ed022fc39e&pid=1-s2.0-S1096719224003639-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140825439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Empagliflozin for treating neutropenia and neutrophil dysfunction in 21 infants with glycogen storage disease 1b","authors":"Sarah C. Grünert ,&nbsp;Matthias Gautschi ,&nbsp;Joshua Baker ,&nbsp;Monica Boyer ,&nbsp;Alberto Burlina ,&nbsp;Thomas Casswall ,&nbsp;Willemijn Corpeleijn ,&nbsp;Kismet Çıki ,&nbsp;Melanie Cotter ,&nbsp;Ellen Crushell ,&nbsp;Terry G.J. Derks ,&nbsp;Dorothea Haas ,&nbsp;Sebile Kilavuz ,&nbsp;Sandra D.K. Kingma ,&nbsp;Stanley H. Korman ,&nbsp;Anne Kozek ,&nbsp;Corinne de Laet ,&nbsp;Helen Mundy ,&nbsp;Marie Cecile Nassogne ,&nbsp;Victor Quintero ,&nbsp;Saskia B. Wortmann","doi":"10.1016/j.ymgme.2024.108486","DOIUrl":"https://doi.org/10.1016/j.ymgme.2024.108486","url":null,"abstract":"<div><p>Empagliflozin has been successfully repurposed for treating neutropenia and neutrophil dysfunction in patients with glycogen storage disease type 1b (GSD 1b), however, data in infants are missing. We report on efficacy and safety of empagliflozin in infants with GSD 1b.</p><p>This is an international retrospective case series on 21 GSD 1b infants treated with empagliflozin (total treatment time 20.6 years). Before starting empagliflozin (at a median age of 8.1 months with a median dose of 0.3 mg/kg/day) 12 patients had clinical signs and symptoms of neutrophil dysfunction. Six of these previously symptomatic patients had no further neutropenia/neutrophil dysfunction-associated findings on empagliflozin. Eight patients had no signs and symptoms of neutropenia/neutrophil dysfunction before start and during empagliflozin treatment. One previously asymptomatic individual with a horseshoe kidney developed a central line infection with pyelonephritis and urosepsis during empagliflozin treatment. Of the 10 patients who were treated with G-CSF before starting empagliflozin, this was stopped in four and decreased in another four. Eleven individuals were never treated with G-CSF.</p><p>While in 17 patients glucose homeostasis remained stable on empagliflozin, four showed glucose homeostasis instability in the introductory phase. In 17 patients, no other side effects were reported, while genital (<em>n</em> = 2) or oral (<em>n</em> = 1) candidiasis and skin infection (n = 1) were reported in the remaining four.</p><p>Empagliflozin had a good effect on neutropenia/neutrophil dysfunction–related signs and symptoms and a favourable safety profile in infants with GSD 1b and therefore qualifies for further exploration as first line treatment.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"142 2","pages":"Article 108486"},"PeriodicalIF":3.8,"publicationDate":"2024-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140900920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ALG13-Congenital Disorder of Glycosylation (ALG13-CDG): Updated clinical and molecular review and clinical management guidelines","authors":"Rameen Shah ,&nbsp;Erik A. Eklund ,&nbsp;Silvia Radenkovic ,&nbsp;Mustafa Sadek ,&nbsp;Ibrahim Shammas ,&nbsp;Sanne Verberkmoes ,&nbsp;Bobby G. Ng ,&nbsp;Hudson H. Freeze ,&nbsp;Andrew C. Edmondson ,&nbsp;Miao He ,&nbsp;Tamas Kozicz ,&nbsp;Ruqaiah Altassan ,&nbsp;Eva Morava","doi":"10.1016/j.ymgme.2024.108472","DOIUrl":"10.1016/j.ymgme.2024.108472","url":null,"abstract":"<div><p>ALG13-Congenital Disorder of Glycosylation (CDG), is a rare X-linked CDG caused by pathogenic variants in ALG13 (OMIM <span>300776</span><svg><path></path></svg>) that affects the N-linked glycosylation pathway. Affected individuals present with a predominantly neurological manifestation during infancy. Epileptic spasms are a common presenting symptom of ALG13-CDG. Other common phenotypes include developmental delay, seizures, intellectual disability, microcephaly, and hypotonia. Current management of ALG13-CDG is targeted to address patients’ symptoms. To date, less than 100 individuals have been reported with ALG13-CDG.</p><p>In this article, an international group of experts in CDG reviewed all reported individuals affected with ALG13-CDG and suggested diagnostic and management guidelines for ALG13-CDG. The guidelines are based on the best available data and expert opinion. Neurological symptoms dominate the phenotype of ALG13-CDG where epileptic spasm is confirmed to be the most common presenting symptom of ALG13-CDG in association with hypotonia and developmental delay. We propose that ACTH/prednisolone treatment should be trialed first, followed by vigabatrin, however ketogenic diet has been shown to have promising results in ALG13-CDG. In order to optimize medical management, we also suggest early cardiac, gastrointestinal, skeletal, and behavioral assessments in affected patients.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"142 2","pages":"Article 108472"},"PeriodicalIF":3.8,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140763358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SSR4-CDG, an ultra-rare X-linked congenital disorder of glycosylation affecting the TRAP complex: Review of 22 affected individuals including the first adult patient","authors":"Christin Johnsen ,&nbsp;Nazi Tabatadze ,&nbsp;Silvia Radenkovic ,&nbsp;Grace Botzo ,&nbsp;Bryce Kuschel ,&nbsp;Gia Melikishvili ,&nbsp;Eva Morava","doi":"10.1016/j.ymgme.2024.108477","DOIUrl":"10.1016/j.ymgme.2024.108477","url":null,"abstract":"<div><p>Congenital disorders of glycosylation (CDG) are a group of rare, often multi-systemic genetic disorders that result from disturbed protein and lipid glycosylation. SSR4-CDG is an ultra-rare, comparably mild subtype of CDG, presenting mostly in males. It is caused by pathogenic variants in the <em>SSR4</em> gene, which is located on the X chromosome. SSR4 (signal sequence receptor protein 4) is a subunit of the translocon-associated protein (TRAP) complex, a structure that is needed for the translocation of proteins across the ER membrane. A deficiency of SSR4 leads to disturbed N-linked glycosylation of proteins in the endoplasmic reticulum. Here, we review the most common clinical, biochemical and genetic features of 18 previously published individuals and report four new cases diagnosed with SSR4-CDG, including the first adult affected by this disorder. Based on our review, developmental delay, speech delay, intellectual disability, muscular hypotonia, microcephaly and distinct facial features are key symptoms of SSR4-CDG that are present in all affected individuals. Although these symptoms overlap with many other neurodevelopmental disorders, their combination with additional clinical features, and a quite distinguishable facial appearance of affected individuals make this disorder a potentially recognizable type of CDG. Additional signs and symptoms include failure to thrive, feeding difficulties, connective tissue involvement, gastrointestinal problems, skeletal abnormalities, seizures and, in some cases, significant behavioral abnormalities. Due to lack of awareness of this rare disorder, and since biochemical testing can be normal in affected individuals, most are diagnosed through genetic studies, such as whole exome sequencing. With this article, we expand the phenotype of SSR4-CDG to include cardiac symptoms, laryngeal abnormalities, and teleangiectasia. We also provide insights into the prognosis into early adulthood and offer recommendations for adequate management and care. We emphasize the great need for causal therapies, as well as effective symptomatic therapies addressing the multitude of symptoms in this disease. In particular, behavioral problems can severely affect quality of life in individuals diagnosed with SSR4-CDG and need special attention. Finally, we aim to improve guidance and education for affected families and treating physicians and create a basis for future research in this disorder.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"142 3","pages":"Article 108477"},"PeriodicalIF":3.8,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224003615/pdfft?md5=cbac4fcf9dc6c5bd3013437dc057cfa3&pid=1-s2.0-S1096719224003615-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140793036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and biochemical footprints of congenital disorders of glycosylation: Proposed nosology","authors":"Bobby G. Ng ,&nbsp;Hudson H. Freeze ,&nbsp;Nastassja Himmelreich ,&nbsp;Nenad Blau ,&nbsp;Carlos R. Ferreira","doi":"10.1016/j.ymgme.2024.108476","DOIUrl":"https://doi.org/10.1016/j.ymgme.2024.108476","url":null,"abstract":"<div><p>We have identified 200 congenital disorders of glycosylation (CDG) caused by 189 different gene defects and have proposed a classification system for CDG based on the mode of action. This classification includes 8 categories: 1. Disorders of monosaccharide synthesis and interconversion, 2. Disorders of nucleotide sugar synthesis and transport, 3. Disorders of N-linked protein glycosylation, 4. Disorders of O-linked protein glycosylation, 5. Disorders of lipid glycosylation, 6. Disorders of vesicular trafficking, 7. Disorders of multiple glycosylation pathways and 8. Disorders of glycoprotein/glycan degradation. Additionally, using information from IEMbase, we have described the clinical involvement of 19 organs and systems, as well as essential laboratory investigations for each type of CDG. Neurological, dysmorphic, skeletal, and ocular manifestations were the most prevalent, occurring in 81%, 56%, 53%, and 46% of CDG, respectively. This was followed by digestive, cardiovascular, dermatological, endocrine, and hematological symptoms (17–34%). Immunological, genitourinary, respiratory, psychiatric, and renal symptoms were less frequently reported (8–12%), with hair and dental abnormalities present in only 4–7% of CDG. The information provided in this study, including our proposed classification system for CDG, may be beneficial for healthcare providers caring for individuals with metabolic conditions associated with CDG.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"142 1","pages":"Article 108476"},"PeriodicalIF":3.8,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224003603/pdfft?md5=df97e0cc675c7986b7c0a9d961271f3d&pid=1-s2.0-S1096719224003603-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140632537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dietary management in MPV17-related depletion syndrome pre- and post- liver transplant: A case study","authors":"Kiera Batten ,&nbsp;Senior Metabolic Dietitian ,&nbsp;Arthavan Selvanathan ,&nbsp;Michael Stormon ,&nbsp;Gordon Thomas ,&nbsp;John Preddy ,&nbsp;Kaustuv Bhattacharya","doi":"10.1016/j.ymgme.2024.108207","DOIUrl":"https://doi.org/10.1016/j.ymgme.2024.108207","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"141 4","pages":"Article 108207"},"PeriodicalIF":3.8,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140346682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}