Literature Watch
Bicarbonate Transport During Enamel Maturation.
Bicarbonate Transport During Enamel Maturation.
Calcif Tissue Int. 2017 Nov;101(5):457-464
Authors: Yin K, Paine ML
Abstract
Amelogenesis (tooth enamel formation) is a biomineralization process consisting primarily of two stages (secretory stage and maturation stage) with unique features. During the secretory stage, the inner epithelium of the enamel organ (i.e., the ameloblast cells) synthesizes and secretes enamel matrix proteins (EMPs) into the enamel space. The protein-rich enamel matrix forms a highly organized architecture in a pH-neutral microenvironment. As amelogenesis transitions to maturation stage, EMPs are degraded and internalized by ameloblasts through endosomal-lysosomal pathways. Enamel crystallite formation is initiated early in the secretory stage, however, during maturation stage the more rapid deposition of calcium and phosphate into the enamel space results in a rapid expansion of crystallite length and mineral volume. During maturation-stage amelogenesis, the pH value of enamel varies considerably from slightly above neutral to acidic. Extracellular acid-base balance during enamel maturation is tightly controlled by ameloblast-mediated regulatory networks, which include significant synthesis and movement of bicarbonate ions from both the enamel papillary layer cells and ameloblasts. In this review we summarize the carbonic anhydrases and the carbonate transporters/exchangers involved in pH regulation in maturation-stage amelogenesis. Proteins that have been shown to be instrumental in this process include CA2, CA6, CFTR, AE2, NBCe1, SLC26A1/SAT1, SLC26A3/DRA, SLC26A4/PDS, SLC26A6/PAT1, and SLC26A7/SUT2. In addition, we discuss the association of miRNA regulation with bicarbonate transport in tooth enamel formation.
PMID: 28795233 [PubMed - indexed for MEDLINE]
Fighting tuberculosis in the EU/EEA: towards the new European Union standards on tuberculosis care.
Fighting tuberculosis in the EU/EEA: towards the new European Union standards on tuberculosis care.
Eur Respir J. 2016 11;48(5):1278-1281
Authors: Sotgiu G, Beer N, Aliberti S, Migliori GB, van der Werf MJ
PMID: 27799382 [PubMed - indexed for MEDLINE]
Profiling of Host Cell Response to Successive Canine Parvovirus Infection Based on Kinetic Proteomic Change Identification.
Profiling of Host Cell Response to Successive Canine Parvovirus Infection Based on Kinetic Proteomic Change Identification.
Sci Rep. 2016 07 13;6:29560
Authors: Zhao H, Cheng Y, Wang J, Lin P, Yi L, Sun Y, Ren J, Tong M, Cao Z, Li J, Deng J, Cheng S
Abstract
Canine parvovirus (CPV) reproduces by co-opting the resources of host cells, inevitably causing cytotoxic effects to the host cells. Feline kidney F81 cells are sensitive to CPV infection and show disparate growing statuses at different time points post-infection. This study analysed the response of F81 cells to CPV infection at successive infection time points by iTRAQ-based quantitative proteomics. Differentially expressed proteins (DEPs) during 60 h of infection and at selected time points post-infection were identified by an analysis of variance test and a two-tailed unpaired t test, respectively. DEPs with similar quantitative changes were clustered by hierarchical clustering and analysed by gene ontology enrichment, revealing that 12 h and 60 h post-infection were the optimal times to analyse the autonomous parvovirus replication and apoptosis processes, respectively. Using the Metacore(TM) database, 29 DEPs were enriched in a network involved in p53 regulation. Besides, a significantly enriched pathway suggests that the CPV-induced cytopathic effect was probably due to the deficiency of functional CFTR caused by CPV infection. This study uncovered the systemic changes in key cellular factors involved in CPV infection and help to understand the molecular mechanisms of the anti-cancer activity of CPV and the cytopathic effects induced by CPV infection.
PMID: 27406444 [PubMed - indexed for MEDLINE]
Cancer astrocytes have a more conserved molecular status in long recurrence free survival (RFS) IDH1 wild-type glioblastoma patients: new emerging cancer players.
Cancer astrocytes have a more conserved molecular status in long recurrence free survival (RFS) IDH1 wild-type glioblastoma patients: new emerging cancer players.
Oncotarget. 2018 May 08;9(35):24014-24027
Authors: Franceschi S, Lessi F, Aretini P, Ortenzi V, Scatena C, Menicagli M, La Ferla M, Civita P, Zavaglia K, Scopelliti C, Apollo A, Carbone FG, Vannozzi R, Bevilacqua G, Pasqualetti F, Naccarato AG, Mazzanti CM
Abstract
Glioblastoma is a devastating disease that despite all the information gathered so far, its optimal management remains elusive due to the absence of validated targets from clinical studies. A better clarification of the molecular mechanisms is needed. In this study, having access to IDH1 wild-type glioblastoma of patients with exceptionally long recurrence free survival (RFS), we decided to compare their mutational and gene expression profile to groups of IDH1 wild-type glioblastoma of patients with shorter RFS, by using NGS technology. The exome analysis revealed that Long-RFS tumors have a lower mutational rate compared to the other groups. A total of 158 genes were found differentially expressed among the groups, 112 of which distinguished the two RFS extreme groups. Overall, the exome data suggests that shorter RFS tumors could be, chronologically, in a more advanced state in the muli-step tumor process of sequential accumulation of mutations. New players in this kind of cancer emerge from the analysis, confirmed at the RNA/DNA level, identifying, therefore, possible oncodrivers or tumor suppressor genes.
PMID: 29844869 [PubMed]
Distinct mutations with different inheritance mode caused similar retinal dystrophies in one family: a demonstration of the importance of genetic annotations in complicated pedigrees.
Distinct mutations with different inheritance mode caused similar retinal dystrophies in one family: a demonstration of the importance of genetic annotations in complicated pedigrees.
J Transl Med. 2018 May 29;16(1):145
Authors: Chen X, Sheng X, Liu Y, Li Z, Sun X, Jiang C, Qi R, Yuan S, Wang X, Zhou G, Zhen Y, Xie P, Liu Q, Yan B, Zhao C
Abstract
BACKGROUND: Retinitis pigmentosa (RP) is the most common form of inherited retinal dystrophy presenting remarkable genetic heterogeneity. Genetic annotations would help with better clinical assessments and benefit gene therapy, and therefore should be recommended for RP patients. This report reveals the disease causing mutations in two RP pedigrees with confusing inheritance patterns using whole exome sequencing (WES).
METHODS: Twenty-five participants including eight patients from two families were recruited and received comprehensive ophthalmic evaluations. WES was applied for mutation identification. Bioinformatics annotations, intrafamilial co-segregation tests, and in silico analyses were subsequently conducted for mutation verification.
RESULTS: All patients were clinically diagnosed with RP. The first family included two siblings born to parents with consanguineous marriage; however, no potential pathogenic variant was found shared by both patients. Further analysis revealed that the female patient carried a recurrent homozygous C8ORF37 p.W185*, while the male patient had hemizygous OFD1 p.T120A. The second family was found to segregate mutations in two genes, TULP1 and RP1. Two patients born to consanguineous marriage carried homozygous TULP1 p.R419W, while a recurrent heterozygous RP1 p.L762Yfs*17 was found in another four patients presenting an autosomal dominant inheritance pattern. Crystal structural analysis further indicated that the substitution from arginine to tryptophan at the highly conserved residue 419 of TULP1 could lead to the elimination of two hydrogen bonds between residue 419 and residues V488 and S534. All four genes, including C8ORF37, OFD1, TULP1 and RP1, have been previously implicated in RP etiology.
CONCLUSIONS: Our study demonstrates the coexistence of diverse inheritance modes and mutations affecting distinct disease causing genes in two RP families with consanguineous marriage. Our data provide novel insights into assessments of complicated pedigrees, reinforce the genetic complexity of RP, and highlight the need for extensive molecular evaluations in such challenging families with diverse inheritance modes and mutations.
PMID: 29843741 [PubMed - in process]
Clinical and genetic characteristics of pulmonary arterial hypertension in Lebanon.
Clinical and genetic characteristics of pulmonary arterial hypertension in Lebanon.
BMC Med Genet. 2018 May 30;19(1):89
Authors: Abou Hassan OK, Haidar W, Nemer G, Skouri H, Haddad F, BouAkl I
Abstract
BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an incidence rate of 2-6 cases per million per year. Our knowledge of the disease in the Middle East and North Africa (MENA) region is limited by the small number of clinical studies and the complete absence of genetic studies.
METHODS: Our aim was to shed light on the clinical and genetic characteristics of PAH in Lebanon and the region by using exome sequencing on PAH patients referred to the American University of Beirut Medical Center (AUBMC). Twenty-one idiopathic, hereditary and Congenital Heart Disease (CHD) PAH patients were prospectively recruited, their clinical data summarized, and sequencing performed.
RESULTS: The mean age at diagnosis was 33 years with a female preponderance of 70%. The mean pulmonary artery pressure at the time of diagnosis was 55. Genetic testing showed that 5 out of 19 idiopathic and Congenital Heart Disease PAH patients had Bone Morphogenetic Protein Receptor 2 (BMPR2) mutations at 25% prevalence, with 2 of these patients exhibiting a novel mutation. It also showed the presence of 1 BMPR2 mutation with 100% penetrance in a heritable PAH family. In the remaining cases, the lack of a complete genotype/phenotype correlation entailed a multigenic inheritance; suspected interactions involved previously associated genes T-box transcription factor 4 (TBX4), Bone Morphogenic Protein 10 (BMP10) and Growth Differentiation Factor 2 (GDF2).
CONCLUSIONS: This is the first study that looks into the genetic causes of PAH, including known and new BMPR2 mutations, in the MENA region. It is also the first study to characterize the clinical features of the disease in Lebanon.
PMID: 29843651 [PubMed - in process]
Increased yield of full GBA sequencing in Ashkenazi Jews with Parkinson's disease.
Increased yield of full GBA sequencing in Ashkenazi Jews with Parkinson's disease.
Eur J Med Genet. 2018 May 26;:
Authors: Ruskey JA, Greenbaum L, Roncière L, Alam A, Spiegelman D, Liong C, Levy OA, Waters C, Fahn S, Marder KS, Chung W, Yahalom G, Israeli-Korn S, Livneh V, Fay-Karmon T, Alcalay RN, Hassin-Baer S, Gan-Or Z
Abstract
BACKGROUND: Variants in GBA are the most common genetic risk factor for Parkinson's disease (PD), and are especially prevalent in the Ashkenazi Jewish (AJ) population. However, most studies on GBA in AJ genotype only seven selected Gaucher-associated pathogenic variants rather than sequencing the whole gene, which may leave carriers of PD-associated GBA variants undiscovered.
METHODS: GBA was fully sequenced using molecular inversion probes (MIPs) and Sanger sequencing in 735 AJ PD patients and 662 AJ controls, from Israel and New York. Additional AJ control data (n = 3044) from the Inflammatory Bowel Disease Exome Portal was used.
RESULTS: Full GBA sequencing increased the number of variants discovered by 17.4%, compared to targeted genotyping. An additional 17 PD patients were identified with GBA-associated PD. The p.E326K variant was found in 1.6% of AJ PD patients, making it the second most common PD-associated GBA variant in AJ. GBA variants were found in 18% of PD patients and 7.5% of controls (OR = 2.7, 95%CI = 1.9-3.8, p < 0.0001).
CONCLUSION: Without full sequencing of GBA, or at minimum including p.E326K in the genotyping panel, a significant proportion of variant carriers go undiscovered and may be incorrectly assigned as non-carriers in studies or clinical trials.
PMID: 29842932 [PubMed - as supplied by publisher]
Aggregation of population-based genetic variation over protein domain homologues and its potential use in genetic diagnostics.
Aggregation of population-based genetic variation over protein domain homologues and its potential use in genetic diagnostics.
Hum Mutat. 2017 Nov;38(11):1454-1463
Authors: Wiel L, Venselaar H, Veltman JA, Vriend G, Gilissen C
Abstract
Whole exomes of patients with a genetic disorder are nowadays routinely sequenced but interpretation of the identified genetic variants remains a major challenge. The increased availability of population-based human genetic variation has given rise to measures of genetic tolerance that have been used, for example, to predict disease-causing genes in neurodevelopmental disorders. Here, we investigated whether combining variant information from homologous protein domains can improve variant interpretation. For this purpose, we developed a framework that maps population variation and known pathogenic mutations onto 2,750 "meta-domains." These meta-domains consist of 30,853 homologous Pfam protein domain instances that cover 36% of all human protein coding sequences. We find that genetic tolerance is consistent across protein domain homologues, and that patterns of genetic tolerance faithfully mimic patterns of evolutionary conservation. Furthermore, for a significant fraction (68%) of the meta-domains high-frequency population variation re-occurs at the same positions across domain homologues more often than expected. In addition, we observe that the presence of pathogenic missense variants at an aligned homologous domain position is often paired with the absence of population variation and vice versa. The use of these meta-domains can improve the interpretation of genetic variation.
PMID: 28815929 [PubMed - indexed for MEDLINE]
Identification of autism-related MECP2 mutations by whole-exome sequencing and functional validation.
Identification of autism-related MECP2 mutations by whole-exome sequencing and functional validation.
Mol Autism. 2017;8:43
Authors: Wen Z, Cheng TL, Li GZ, Sun SB, Yu SY, Zhang Y, Du YS, Qiu Z
Abstract
BACKGROUND: Methyl-CpG-binding protein-2 (MeCP2) is a critical regulator for neural development. Either loss- or gain-of-function leads to severe neurodevelopmental disorders, such as Rett syndrome (RTT) and autism spectrum disorder (ASD). We set out to screen for MECP2 mutations in patients of ASD and determine whether these autism-related mutations may compromise the proper function of MeCP2.
METHODS: Whole-exome sequencing was performed to screen MECP2 and other ASD candidate genes for 120 patients diagnosed with ASD. The parents of patients who were identified with MECP2 mutation were selected for further Sanger sequencing. Each patient accomplished the case report form including general information and clinical scales applied to assess their clinical features. Mouse cortical neurons and HEK-293 cells were cultured and transfected with MeCP2 wild-type (WT) or mutant to examine the function of autism-associated MeCP2 mutants. HEK-293 cells were used to examine the expression of MeCP2 mutant constructs with Western blot. Mouse cortical neurons were used to analyze neurites and axon outgrowth by immunofluorescence experiments.
RESULTS: We identified three missense mutations of MECP2 from three autism patients by whole-exome sequencing: p.P152L (c.455C>T), p.P376S (c.1162C>T), and p.R294X (c.880C>T). Among these mutations, p.P152L and p.R294X were de novo mutations, whereas p.P376S was inherited maternally. The diagnosis of RTT was excluded in all three autism patients. Abnormalities of dendritic and axonal growth were found after autism-related MeCP2 mutants were expressed in mouse cortical neurons; suggesting that autism-related MECP2 mutations impair the proper development of neurons.
CONCLUSIONS: Our study identified genetic mutations of the MECP2 gene in autism patients, which were previously considered to be associated primarily with RTT. This finding suggests that loss-of-function mutations of MECP2 may also lead to autism spectrum disorders.
PMID: 28785396 [PubMed - indexed for MEDLINE]
pharmacogenomics; +12 new citations
12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:
These pubmed results were generated on 2018/05/31
PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects"); +11 new citations
11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:
("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")
These pubmed results were generated on 2018/05/31
PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
Notice of Early Expiration of PAR-17-053 "Research Education: Initiative for Maximizing Student Development (IMSD) Program (R25)"
Notice of Intent to Publish a Funding Opportunity Announcement for the Maximizing Access to Research Careers (MARC) (T34) Program
Notice of Intent to Publish a Funding Opportunity Announcement for the Graduate Research Initiative for Student Enhancement (G-RISE) (T32) Program
Notice of Intent to Publish a Funding Opportunity Announcement for the Undergraduate Research Initiative for Student Enhancement (U-RISE) (T34) Program
Notice of Intent to Publish a Funding Opportunity Announcement for the Initiative for Maximizing Student Development (IMSD) (T32) Program
Occupational Safety and Health Research (R01)
"Rare Diseases"[Mesh] OR "orphan disease"; +8 new citations
8 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:
"Rare Diseases"[Mesh] OR "orphan disease"
These pubmed results were generated on 2018/05/29
PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
GDA, a web-based tool for Genomics and Drugs integrated analysis.
GDA, a web-based tool for Genomics and Drugs integrated analysis.
Nucleic Acids Res. 2018 May 25;:
Authors: Caroli J, Sorrentino G, Forcato M, Del Sal G, Bicciato S
Abstract
Several major screenings of genetic profiling and drug testing in cancer cell lines proved that the integration of genomic portraits and compound activities is effective in discovering new genetic markers of drug sensitivity and clinically relevant anticancer compounds. Despite most genetic and drug response data are publicly available, the availability of user-friendly tools for their integrative analysis remains limited, thus hampering an effective exploitation of this information. Here, we present GDA, a web-based tool for Genomics and Drugs integrated Analysis that combines drug response data for >50 800 compounds with mutations and gene expression profiles across 73 cancer cell lines. Genomic and pharmacological data are integrated through a modular architecture that allows users to identify compounds active towards cancer cell lines bearing a specific genomic background and, conversely, the mutational or transcriptional status of cells responding or not-responding to a specific compound. Results are presented through intuitive graphical representations and supplemented with information obtained from public repositories. As both personalized targeted therapies and drug-repurposing are gaining increasing attention, GDA represents a resource to formulate hypotheses on the interplay between genomic traits and drug response in cancer. GDA is freely available at http://gda.unimore.it/.
PMID: 29800349 [PubMed - as supplied by publisher]
Polypharmacological Drug-target Inference for Chemogenomics.
Polypharmacological Drug-target Inference for Chemogenomics.
Mol Inform. 2018 May 24;:
Authors: Schneider P, Schneider G
Abstract
Pharmacological drug actions are often caused by multi-target effects. While most of the currently approved synthetic drugs were designed to interact with a single 'on-target', these chemical agents often interact with additional 'off-targets'. Understanding and rationalizing these multiple interactions will be indispensable for the design of future precision medicines. We employed computational predictions of drug-target interactions to analyze functional drug-drug relationships. 900 approved drugs were represented in terms of their predicted activity fingerprints, considering 1158 potential target activities. A drug relationship network was constructed based on fingerprint similarity. The resulting network graph highlights clusters of compounds sharing similar predicted on- and off-targets, and allows to identify mutual targets of drugs that were originally developed for different therapeutic indications. Such an analysis offers straightforward access to spotting potential off-target liabilities and drug-drug interactions, as well as drug repurposing opportunities.
PMID: 29797496 [PubMed - as supplied by publisher]
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