Frontiers in bioscience (Scholar edition)最新文献

{"title":"The Possible Role of Progesterone Receptors in Prostate Cancer Incidences in the Iraqi Population.","authors":"Jaleel Ibrahim Asaad, Khalid S A Alazzawi, Sara S Rasheed, Rebah N Algafari, Rehab S Ramadhan, Marwah Amer Qamandar, Sura S Talib, Rawnaq Z Fadhil","doi":"10.31083/j.fbs1603016","DOIUrl":"10.31083/j.fbs1603016","url":null,"abstract":"<p><strong>Background: </strong>Prostate cancer (PCa) is one of the leading diseases causing mortality. It comes in the third rank of common cancer types. It is considered extremely a complicated cancer type since it occurs in highly steroid-responsive and dependent tissues. Many factors are considered to play an important role in the disease progression of PCa, with some functioning at the molecular level.</p><p><strong>Methodology: </strong>After applying the exclusion criteria, 200 patients who underwent proctectomy were included in this study. Following receiving patient consent, blood samples were withdrawn from patients, DNA was extracted, and precise polymerase chain reaction (PCR) amplification was conducted using specifically designed primers. The resulting amplicons were sequenced and analyzed.</p><p><strong>Results: </strong>The progesterone receptor B (<i>PGRB</i>) DNA from patients showed four distinctive single-nucleotide polymorphisms (SNPs) at sites 11:101128812, 11:101128924, 11:101128949, and 11:101128986, which altered the amino acid sequences to Y>N, A>D, T>I, and C>R, respectively, compared to control. These SNPs resided in sensitive sites that either affected the control elements or promoted alterations in the protein configuration. This DNA change diminished the <i>PGR</i> gene function and promoted an imbalance in the encoded PGR protein structure and expression.</p><p><strong>Conclusions: </strong>Many factors may play a role in PCa manifestation, with steroids and progesterone initially noted as factors. Many studies have dealt with the hormonal effect on PCa; however, few have ultimately determined the molecular impact on disease progression. The presence of pathogenic SNPs in the enhancing region of the gene may impact the expression level of <i>PGR</i>. High or low expression levels may negatively affect gene function, which can be considered a reliable factor in prostate tumorigenesis.</p>","PeriodicalId":73070,"journal":{"name":"Frontiers in bioscience (Scholar edition)","volume":"16 3","pages":"16"},"PeriodicalIF":0.0,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142333810","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}

{"title":"Targeting Molecular Signaling Pathways and Cytokine Responses to Modulate c-MYC in Acute Myeloid Leukemia.","authors":"Kyle Gu, Harry A May, Min H Kang","doi":"10.31083/j.fbs1603015","DOIUrl":"https://doi.org/10.31083/j.fbs1603015","url":null,"abstract":"<p><p>Overexpression of the <i>MYC</i> oncogene, encoding c-MYC protein, contributes to the pathogenesis and drug resistance of acute myeloid leukemia (AML) and many other hematopoietic malignancies. Although standard chemotherapy has predominated in AML therapy over the past five decades, the clinical outcomes and patient response to treatment remain suboptimal. Deeper insight into the molecular basis of this disease should facilitate the development of novel therapeutics targeting specific molecules and pathways that are dysregulated in AML, including fms-like tyrosine kinase 3 (<i>FLT3</i>) gene mutation and cluster of differentiation 33 (CD33) protein expression. Elevated expression of c-MYC is one of the molecular features of AML that determines the clinical prognosis in patients. Increased expression of c-MYC is also one of the cytogenetic characteristics of drug resistance in AML. However, direct targeting of c-MYC has been challenging due to its lack of binding sites for small molecules. In this review, we focused on the mechanisms involving the bromodomain and extra-terminal (BET) and cyclin-dependent kinase 9 (CDK9) proteins, phosphoinositide-Akt-mammalian target of rapamycin (PI3K/AKT/mTOR) and Janus kinase-signal transduction and activation of transcription (JAK/STAT) pathways, as well as various inflammatory cytokines, as an indirect means of regulating MYC overexpression in AML. Furthermore, we highlight Food and Drug Administration (FDA)-approved drugs for AML, and the results of preclinical and clinical studies on novel agents that have been or are currently being tested for efficacy and tolerability in AML therapy. Overall, this review summarizes our current knowledge of the molecular processes that promote leukemogenesis, as well as the various agents that intervene in specific pathways and directly or indirectly modulate c-MYC to disrupt AML pathogenesis and drug resistance.</p>","PeriodicalId":73070,"journal":{"name":"Frontiers in bioscience (Scholar edition)","volume":"16 3","pages":"15"},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142333809","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}

{"title":"GWAS-Identified Loci are Associated with Obesity and Type 2 Diabetes Mellitus in Patients with Severe COVID-19.","authors":"Alexey Loktionov, Ksenia Kobzeva, Anna Dorofeeva, Vera Sergeeva, Olga Bushueva","doi":"10.31083/j.fbs1603014","DOIUrl":"https://doi.org/10.31083/j.fbs1603014","url":null,"abstract":"<p><strong>Background: </strong>Comorbidities such as obesity and type 2 diabetes mellitus (T2DM) have emerged as critical risk factors exacerbating the severity and mortality of COVID-19. Meanwhile, numerous genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with increased susceptibility to severe COVID-19.</p><p><strong>Aim: </strong>This study investigated whether SNPs previously identified by GWAS as risk factors for severe COVID-19 also correlate with common comorbidities-obesity and T2DM-in hospitalized patients with severe COVID-19.</p><p><strong>Methods: </strong>DNA samples from 199 hospitalized COVID-19 patients were genotyped using probe-based PCR for 10 GWAS SNPs previously implicated in severe COVID-19 outcomes (rs143334143 <i>CCHCR1</i>, rs111837807 <i>CCHCR1</i>, rs17078346 <i>SLC6A20</i>-<i>LZTFL1</i>, rs17713054 <i>SLC6A20</i>-<i>LZTFL1</i>, rs7949972 <i>ELF5</i>, rs61882275 <i>ELF5</i>, rs12585036 <i>ATP11A</i>, rs67579710 <i>THBS3</i>, <i>THBS3</i>-<i>AS1</i>, rs12610495 <i>DPP9</i>, rs9636867 <i>IFNAR2</i>).</p><p><strong>Results: </strong>The analysis revealed significant associations between certain SNPs and the increased risk of obesity and T2DM in severe COVID-19 patients. Specifically, rs17713054 <i>SLC6A20</i>-<i>LZTFL1</i> (risk allele A; odds ratio (OR) = 2.34, 95% confidence interval (CI) = 1.24-4.4, <i>p</i> = 0.007) and rs7949972 <i>ELF5</i> SNP (risk allele T; OR = 1.79, 95% CI = 1.11-2.91, <i>p</i> = 0.015) were associated with increased risk of obesity. SNP rs9636867 <i>IFNAR2</i> was associated with a higher risk of T2DM (risk allele G, OR = 8.28, 95% CI = 1.69-40.64, <i>p</i> = 0.027). Using the model-based multifactor dimensionality reduction (MB-MDR) approach, the six most significant gene-gene interaction patterns associated with obesity in severe COVID-19 patients were identified and included five polymorphic loci: rs7949972, rs17713054, rs61882275, rs12585036, and rs143334143, participating in two or more of the most significant G-G interactions (<i>pperm</i> < 0.05). In total, the best models of G-G interactions associated with T2DM in patients with severe COVID-19 included eight polymorphic loci, six of which, rs7949972, rs61882275, rs12585036, rs143334143, rs67579710, and rs12610495, were involved in two or more of the most significant G-G interactions.</p><p><strong>Conclusions: </strong>Our study provides novel insights into the genetic associations between GWAS-identified SNPs and the risk of obesity and T2DM in patients with severe COVID-19.</p>","PeriodicalId":73070,"journal":{"name":"Frontiers in bioscience (Scholar edition)","volume":"16 3","pages":"14"},"PeriodicalIF":0.0,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142333806","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}

{"title":"Epigenetics of Heavy Metal Stress and Response in Plants.","authors":"Gianluigi Giannelli, Elisa Fasani, Giovanni DalCorso","doi":"10.31083/j.fbs1602013","DOIUrl":"https://doi.org/10.31083/j.fbs1602013","url":null,"abstract":"","PeriodicalId":73070,"journal":{"name":"Frontiers in bioscience (Scholar edition)","volume":"16 2","pages":"13"},"PeriodicalIF":0.0,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141473235","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}

{"title":"The Multifaceted Cause of Lipid Storage Myopathies, Genetics, and Treatment.","authors":"Corrado Angelini","doi":"10.31083/j.fbs1602012","DOIUrl":"https://doi.org/10.31083/j.fbs1602012","url":null,"abstract":"<p><p>Several inherited metabolic fatty acid disorders present with myopathies. Skeletal muscle accounts for 40% of the body and is important for metabolism, exercise, and movement. Muscle energy failure is manifested by metabolic crises with muscle weakness, sometimes associated with muscle fatigue and failure resulting in acute necrosis or rhabdomyolysis/myoglobinuria episodes. Lack of energy leads to muscle necrosis. Other presentations are weakness and myalgias with lipid storage myopathies in the biopsy. The biomarkers of such disorders are acyl-carnitine with various profiles and need to be carefully evaluated to plan supplementary therapy and specific diets. If red flags are not distinctly followed and diagnosed in time they might lead to a metabolic or cardiac failure.</p>","PeriodicalId":73070,"journal":{"name":"Frontiers in bioscience (Scholar edition)","volume":"16 2","pages":"12"},"PeriodicalIF":0.0,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141473237","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}

{"title":"Genotyping the <i>BCL11A</i> Single Nucleotide Polymorphism and Associated Levels of Fetal Hemoglobin in Mauritanian Sickle Cell Patients.","authors":"Aminetou Taleb Brahim, Mariem Taleb, Harouna Soumaré, Sidi Mohamed Ghaber, Aminetou Mohamed, Ali Ould Mohamed Salem Boukhary","doi":"10.31083/j.fbs1602011","DOIUrl":"10.31083/j.fbs1602011","url":null,"abstract":"<p><strong>Background: </strong>Sickle cell disease (SCD) is a major heritable genetic disease in sub-Saharan Africa, including Mauritania. Fetal hemoglobin (HbF) can affect the pathophysiology, moderate the clinical course, and offer prospects for curative treatment of SCD. This study aimed to investigate the influence of single nucleotide polymorphisms (SNPs) in the <i>BCL11A</i> gene on the levels of HbF and hematological parameters in Mauritanian sickle cell (<i>HbSS</i>) patients.</p><p><strong>Methods: </strong>Complete blood count was assessed in 565 patients suspected to have SCD. Polymerase chain reaction (PCR)-restriction fragment length polymorphism was performed to identify the <i>HbSS</i>, and sequencing was used for genotyping three SNPs: <i>rs4671393</i> (<i>A>G</i>) and <i>rs11886868</i> (<i>C>T</i>) in the intron 2 and <i>rs1052520</i> (<i>G>A</i>) in the <i>3'UTR</i> regions of the <i>BCL11A</i> gene in 50 sickle cell patients.</p><p><strong>Results: </strong>The prevalence of HbSS among the study population was 8.8% (50/565), and the mean (± standard deviation) of HbF level was 15.0% (± 6.0%). Sequencing showed the presence of three genotypes: AA (13.6%), AG (46.6%), GG (39.6%) in rs4671393; CC (17.6%), CT (48.7%), and TT (33.6%) in <i>rs11886868</i>. All samples from HbSS individuals displayed a wild-type genotype in the rs1052520 allele. The prevalence of minor alleles <i>A</i> (<i>rs4671393</i>) and <i>C</i> (<i>rs11886868</i>) were 37% and 39%, respectively. There was a statistically significant association (<i>p</i> = 0.034) between rs4671393 SNP and elevated HbF (mean 12.72 ± 6.26%).</p><p><strong>Conclusions: </strong>The study of three SNPs in the <i>BCL11A</i> locus in Mauritanian patients with SCD showed a significant association of <i>rs4671393</i> allele with the HbF level. Further research is needed to explore additional SNPs in the <i>BCL11A</i> locus and investigate other genetic markers reported to modulate HbF levels, such as <i>HBS1L-MYB</i> and <i>Xmn1-HBG2</i>, to improve the management of this potentially life-threatening condition in Mauritania.</p>","PeriodicalId":73070,"journal":{"name":"Frontiers in bioscience (Scholar edition)","volume":"16 2","pages":"11"},"PeriodicalIF":0.0,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141473236","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}

{"title":"Enoxaparin Effect on Interleukin-10 Levels in Iraqi Patients with COVID-19: A Case-Control Study.","authors":"Nawal Haider Al-Hashimi, Mohammed S Al-Hindawi, Ali M Mohsen, Abdulnasser M Al-Gebori","doi":"10.31083/j.fbs1602009","DOIUrl":"10.31083/j.fbs1602009","url":null,"abstract":"<p><strong>Background: </strong>Coronavirus disease 19 (COVID-19), an infectious disease resulting from a virus known as severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), was discovered in China in 2019 and causes several mild to moderate respiratory conditions. This study aimed to reveal the changes in serum interleukin-10 (IL-10) and other parameters in Iraqi COVID-19 patients compared with healthy controls by studying the effects of enoxaparin and evaluating the potential of IL-10 as a disease activity marker.</p><p><strong>Methods: </strong>This was a case-control study that included 180 samples: 90 patients hospitalized with COVID-19 from November 2022 to 20 April 2023 (40 patients had never used enoxaparin, whereas 50 patients had taken enoxaparin) and 90 healthy, age- and sex-matched control. There were 44 female patients and 46 male patients. The mean age of the patients and controls was 53.8 years <i>vs.</i> 50.8 years, respectively. The sandwich enzyme-linked immunosorbent assay (ELISA) method was used to measure IL-10 levels, while other parameters were assessed using the colorimetric method.</p><p><strong>Results: </strong>The results of the study indicated highly significant changes between the patients and healthy controls in IL-10, D-dimer, and C-reactive protein (CRP) levels, as well as liver and renal functions. These findings elucidated a significant change between enoxaparin patients and non-enoxaparin patients in IL-10, D-dimer, and CRP levels. However, the liver and renal functions were not significantly altered. The Spearman's rank correlation test investigated the relationship between serum IL-10 and CRP.</p><p><strong>Conclusions: </strong>The results displayed a strong positive relationship between IL-10 and CRP. There were no significant differences between the other analyzed parameters; consequently, the patients had higher concentrations of IL-10, D-dimer, and some other parameters than the healthy controls. Additionally, IL-10 may be used as a marker of disease activity. Enoxaparin will likely help control IL-10 and D-dimer concentrations in patients since IL-10 levels decreased in patients treated with enoxaparin.</p>","PeriodicalId":73070,"journal":{"name":"Frontiers in bioscience (Scholar edition)","volume":"16 2","pages":"9"},"PeriodicalIF":0.0,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141473234","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}

{"title":"Mitochondrial Dysfunction as a Factor of Energy Metabolism Disorders in Type 2 Diabetes Mellitus.","authors":"Alexander Blagov, Ludmila Nedosugova, Tatiana Kirichenko, Vasily Sukhorukov, Alexandra Melnichenko, Alexander Orekhov","doi":"10.31083/j.fbs1601005","DOIUrl":"10.31083/j.fbs1601005","url":null,"abstract":"<p><p>The pathogenesis of type 2 diabetes mellitus (T2DM) is based on the development of insulin resistance, which is a disruption to the ability of the tissues to bind to insulin, leading to a general metabolic disorder. Mitochondria are the main participants in cellular energy metabolism, meaning their dysfunction is associated with the development of insulin resistance in T2DM. Mitochondrial function is affected by insulin resistance in various tissues, including skeletal muscle and the liver, which greatly influence glucose homeostasis throughout the body. This review studies mitochondrial dysfunction in T2DM and its impact on disease progression. In addition, it considers the causes underlying the development of mitochondrial dysfunction in T2DM, including mutations in the mitochondrial genome, mitochondrial DNA methylation, and other epigenetic influences, as well as the impact of impaired mitochondrial membrane potential. New therapeutic strategies for diabetes that have been developed to target the mitochondria will also be presented.</p>","PeriodicalId":73070,"journal":{"name":"Frontiers in bioscience (Scholar edition)","volume":"16 1","pages":"5"},"PeriodicalIF":0.0,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140308192","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}

{"title":"Genetics and Age-Related Macular Degeneration: A Practical Review for Clinicians.","authors":"Julia Nguyen, Milam A Brantley, Stephen G Schwartz","doi":"10.31083/j.fbs1601003","DOIUrl":"10.31083/j.fbs1601003","url":null,"abstract":"<p><p>Age-related macular degeneration (AMD) is a multifactorial genetic disease, with at least 52 identifiable associated gene variants at 34 loci, including variants in <i>complement factor H</i> (<i>CFH</i>) and <i>age-related maculopathy susceptibility 2/high-temperature requirement A serine peptidase-1</i> (<i>ARMS2/HTRA1</i>). Genetic factors account for up to 70% of disease variability. However, population-based genetic risk scores are generally more helpful for clinical trial design and stratification of risk groups than for individual patient counseling. There is some evidence of pharmacogenetic influences on various treatment modalities used in AMD patients, including Age-Related Eye Disease Study (AREDS) supplements, photodynamic therapy (PDT), and anti-vascular endothelial growth factor (anti-VEGF) agents. However, there is currently no convincing evidence that genetic information plays a role in routine clinical care.</p>","PeriodicalId":73070,"journal":{"name":"Frontiers in bioscience (Scholar edition)","volume":"16 1","pages":"3"},"PeriodicalIF":0.0,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140308191","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}

{"title":"CpG Islands, Gene Expression and Pseudogenization: A Case for a Potential Trilogy.","authors":"Ammad Aslam Khan, Anees Fatima","doi":"10.31083/j.fbs1601002","DOIUrl":"10.31083/j.fbs1601002","url":null,"abstract":"<p><strong>Background: </strong>The promoters of mammalian genes contain clusters of CG dinucleotides known as CpG islands. Most mammalian housekeeping genes predominantly contain CpG islands (CGIs), facilitating gene transcription. Numerous studies have explored the physiological implications of the relationship between CGIs and gene expression. However, the evolutionary implications of this relationship remain largely unexplored. Pseudogenes, in contrast, are genomic remnants that have lost their function over evolutionary time.</p><p><strong>Methods: </strong>In our current research, we employed comparative genomic techniques to demonstrate a correlation between the absence of gene expression due to a lack of CGIs in the gene promoters and pseudogenization.</p><p><strong>Results: </strong>We showed that there is a significant enrichment of tissue-specific genes in the functional orthologs of pseudogenes. We also found a significant correlation between the lack of CGIs and enriched tissue specificity in these functional orthologs of pseudogenes.</p><p><strong>Conclusions: </strong>We inferred that perhaps tissue-specific genes are more prone to the process of pseudogenization. In this way, because of their impact on gene expression, CGIs may affect the fate of a gene. To our knowledge, this is the first study to propose a connection between CGIs, gene expression, and the pseudogenization process and discuss the evolutionary implications of this potential trilogy.</p>","PeriodicalId":73070,"journal":{"name":"Frontiers in bioscience (Scholar edition)","volume":"16 1","pages":"2"},"PeriodicalIF":0.0,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140308190","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}