Related Articles

Genetic and clinical characterization of Pakistani families with Bardet-Biedl syndrome extends the genetic and phenotypic spectrum.

Sci Rep. 2016 10 06;6:34764

Authors: Maria M, Lamers IJ, Schmidts M, Ajmal M, Jaffar S, Ullah E, Mustafa B, Ahmad S, Nazmutdinova K, Hoskins B, van Wijk E, Koster-Kamphuis L, Khan MI, Beales PL, Cremers FP, Roepman R, Azam M, Arts HH, Qamar R

Abstract
Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder that is both genetically and clinically heterogeneous. To date 19 genes have been associated with BBS, which encode proteins active at the primary cilium, an antenna-like organelle that acts as the cell's signaling hub. In the current study, a combination of mutation screening, targeted sequencing of ciliopathy genes associated with BBS, and whole-exome sequencing was used for the genetic characterization of five families including four with classic BBS symptoms and one BBS-like syndrome. This resulted in the identification of novel mutations in BBS genes ARL6 and BBS5, and recurrent mutations in BBS9 and CEP164. In the case of CEP164, this is the first report of two siblings with a BBS-like syndrome with mutations in this gene. Mutations in this gene were previously associated with nephronophthisis 15, thus the current results expand the CEP164-associated phenotypic spectrum. The clinical and genetic spectrum of BBS and BBS-like phenotypes is not fully defined in Pakistan. Therefore, genetic studies are needed to gain insights into genotype-phenotype correlations, which will in turn improve the clinician's ability to make an early and accurate diagnosis, and facilitate genetic counseling, leading to directly benefiting families with affected individuals.

PMID: 27708425 [PubMed - indexed for MEDLINE]

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pharmacogenomics

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Related Articles

Inference of developmental gene regulatory networks beyond classical model systems: new approaches in the post-genomic era.

Integr Comp Biol. 2018 Jun 18;:

Authors: Fernandez-Valverde SL, Aguilera F, Ramos-Díaz RA

Abstract
SYNOPSIS: The advent of high-throughput sequencing technologies has revolutionized the way we understand the transformation of genetic information into morphological traits. Elucidating the network of interactions between genes that govern cell differentiation through development is one of the core challenges in genome research. These networks are known as developmental gene regulatory networks (dGRNs) and consist largely of the functional linkage between developmental control genes, cis-regulatory modules and differentiation genes, which generate spatially and temporally refined patterns of gene expression. Over the last 20 years, great advances have been made in determining these gene interactions mainly in classical model systems, including human, mouse, sea urchin, fruit fly, and worm. This has brought about a radical transformation in the fields of developmental biology and evolutionary biology, allowing the generation of high-resolution gene regulatory maps to analyse cell differentiation during animal development. Such maps have enabled the identification of gene regulatory circuits and have led to the development of network inference methods that can recapitulate the differentiation of specific cell-types or developmental stages. In contrast, dGRN research in non-classical model systems has been limited to the identification of developmental control genes via the candidate gene approach and the characterization of their spatiotemporal expression patterns, as well as to the discovery of cis-regulatory modules via patterns of sequence conservation and/or predicted transcription-factor binding sites. However, thanks to the continuous advances in high-throughput sequencing technologies, this scenario is rapidly changing. Here, we give a historical overview on the architecture and elucidation of the dGRNs. Subsequently, we summarize the approaches available to unravel these regulatory networks, highlighting the vast range of possibilities of integrating multiple technical advances and theoretical approaches to expand our understanding on the global of gene regulation during animal development in non-classical model systems. Such new knowledge will not only lead to greater insights into the evolution of molecular mechanisms underlying cell identity and animal body plans, but also into the evolution of morphological key innovations in animals.

PMID: 29917089 [PubMed - as supplied by publisher]

Related Articles

Predicting drug-disease associations by using similarity constrained matrix factorization.

BMC Bioinformatics. 2018 Jun 19;19(1):233

Authors: Zhang W, Yue X, Lin W, Wu W, Liu R, Huang F, Liu F

Abstract
BACKGROUND: Drug-disease associations provide important information for the drug discovery. Wet experiments that identify drug-disease associations are time-consuming and expensive. However, many drug-disease associations are still unobserved or unknown. The development of computational methods for predicting unobserved drug-disease associations is an important and urgent task.
RESULTS: In this paper, we proposed a similarity constrained matrix factorization method for the drug-disease association prediction (SCMFDD), which makes use of known drug-disease associations, drug features and disease semantic information. SCMFDD projects the drug-disease association relationship into two low-rank spaces, which uncover latent features for drugs and diseases, and then introduces drug feature-based similarities and disease semantic similarity as constraints for drugs and diseases in low-rank spaces. Different from the classic matrix factorization technique, SCMFDD takes the biological context of the problem into account. In computational experiments, the proposed method can produce high-accuracy performances on benchmark datasets, and outperform existing state-of-the-art prediction methods when evaluated by five-fold cross validation and independent testing.
CONCLUSION: We developed a user-friendly web server by using known associations collected from the CTD database, available at http://www.bioinfotech.cn/SCMFDD/ . The case studies show that the server can find out novel associations, which are not included in the CTD database.

PMID: 29914348 [PubMed - in process]

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Immunosuppressive drug therapy for preventing rejection following lung transplantation in cystic fibrosis.

Cochrane Database Syst Rev. 2018 Jun 18;6:CD009421

Authors: Saldanha IJ, Akinyede O, Robinson KA

Abstract
BACKGROUND: For people with cystic fibrosis and advanced pulmonary damage, lung transplantation is an available and viable option. However, graft rejection is an important potential consequence after lung transplantation. Immunosuppressive therapy is needed to prevent episodes of graft rejection and thus subsequently reduce morbidity and mortality in this population. There are a number of classes of immunosuppressive drugs which act on different components of the immune system. There is considerable variability in the use of immunosuppressive agents after lung transplantation in cystic fibrosis. While much of the research in immunosuppressive drug therapy has focused on the general population of lung transplant recipients, little is known about the comparative effectiveness and safety of these agents in people with cystic fibrosis. This is an update of a previously published review.
OBJECTIVES: To assess the effects of individual drugs or combinations of drugs compared to placebo or other individual drugs or combinations of drugs in preventing rejection following lung transplantation in people with cystic fibrosis.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register and scanned references of the potentially eligible study. We also searched the www.clinicaltrials.gov registry and the World Health Organisation (WHO) International Clinical Trials Registry Platform (ICTRP) to obtain information on unpublished and ongoing studies.Date of latest search: 29 May 2018.
SELECTION CRITERIA: Randomised and quasi-randomised studies.
DATA COLLECTION AND ANALYSIS: We independently assessed the studies identified from our searches for inclusion in the review. Should eligible studies be identified and included in future updates of the review, we will independently extract data and assess the risk of bias. We will use GRADE to summarize our results through a summary of findings table for each comparison we present in the review.
MAIN RESULTS: While five studies addressed the interventions of interest, we did not include them in the review because the investigators of the studies did not report any information specific to people with cystic fibrosis. Our attempts to obtain this information have not yet been successful. We will include any provided data in future updates of the review.
AUTHORS' CONCLUSIONS: The lack of currently available evidence makes it impossible to draw conclusions about the comparative efficacy and safety of the various immunosuppressive drugs among people with cystic fibrosis after lung transplantation. A 2013 Cochrane Review comparing tacrolimus with cyclosporine in all lung transplant recipients (not restricted to those with cystic fibrosis) reported no significant difference in mortality and risk of acute rejection. However, tacrolimus use was associated with lower risk of broncholitis obliterans syndrome and arterial hypertension and higher risk of diabetes mellitus. It should be noted that this wider review contained only a small number of included studies (n = 3) with a high risk of bias. Additional randomised studies are required to provide evidence for the benefit and safety of the use of immunosuppressive therapy among people with cystic fibrosis after lung transplantation.

PMID: 29921013 [PubMed - as supplied by publisher]

Related Articles

Is an FEV1 of 80% predicted a normal spirometry in Cystic Fibrosis children and adults?

Clin Respir J. 2018 Jun 19;:

Authors: König P, Ner Z, Acton JD, Ge B, Hewett J

Abstract
Introduction- FEV1 is considered the gold standard spirometric measure for the assessment and management of cystic fibrosis lung disease. Recent evidence suggests that tests at lower lung volumes may be more sensitive. Objectives- To assess how many other spirometric tests are abnormal in the presence of a normal FEV1 (≥80%) and which spirometric tests are most sensitive in detecting airway obstruction. Methods -This was a retrospective analysis of 3,169 spirometry tests on 184 patients with cystic fibrosis aged 6 - 57 years. Tests were acceptable if they met ATS criteria. Results- Tests with normal FEV1 , FEF75 showed obstruction in 58% of tests, FEF25-75 in 31% and FEV1 /FVC ratio in 72%. Overall 75% of tests had an abnormality. FEF75 , FEF25-75 , FEF50 , and FEV1 /FVC ratio were all significantly more sensitive in identifying obstruction than FEV1 . The FEV1 /FVC ratio was the most sensitive of all tests in identifying obstruction except in adults (> 20 years), in whom FEF75 at 90%, was more sensitive than the ratio at 85%. FEF25-75 was also at 85% sensitive. Even though the FEV1 /FVC ratio was the most sensitive of all tests, in the presence of a normal ratio, 35% other tests were abnormal. Conclusions - Normal FEV1 , is not indicative of normal spirometry. FEV1 /FVC is the most sensitive measure of early or mild airway obstruction in children with cystic fibrosis. If only the FEV1 /FVC ratio was considered, many cases of obstruction would be missed, therefore all spirometric measures should be considered in the clinical evaluation of airway obstruction. This article is protected by copyright. All rights reserved.

PMID: 29920961 [PubMed - as supplied by publisher]

Related Articles

Isolated Nonvisualization of the Fetal Gallbladder Should Be Considered for the Prenatal Diagnosis of Cystic Fibrosis.

Fetal Diagn Ther. 2018 Jun 19;:1-5

Authors: Bergougnoux A, Jouannic JM, Verneau F, Bienvenu T, Gaitch N, Raynal C, Girodon E

Abstract
BACKGROUND: Cystic fibrosis (CF) can be revealed during fetal life by diverse ultrasound digestive abnormalities (USDA) such as fetal echogenic bowel or fetal intestinal loop dilatation, nonvisualization of the fetal gallbladder (NVFGB) being rarely observed in isolation. Only 6 cases of CF revealed by isolated NVFGB have been reported so far in the literature. Furthermore, recent studies suggested that this sign is of poor predictive value for CF.
METHODS: We report on the results of a 6-year French tricenter study on 1,124 cases of fetal USDA for whom a comprehensive molecular study was performed for CF.
RESULTS: Among the 37 CF fetuses, 5 (13.5%) presented with isolated NVFGB at ultrasound (US) examination at 24-31 weeks of gestation. This sign was more frequently observed in CF fetuses than in non-CF fetuses, with a likelihood ratio of 2.7. The genotypes included three c.1521_1523del (F508del) homozygous cases and two compound heterozygous cases for a frequent and a rare CF-causing variant.
DISCUSSION: These observations highlight the importance to report on the presence and aspect of the fetal gallbladder at the second trimester US scan and to consider prenatal CFTR molecular analysis in cases of isolated NVFGB.

PMID: 29920495 [PubMed - as supplied by publisher]

Related Articles

Kcnn4 is a modifier gene of intestinal cystic fibrosis preventing lethality in the Cftr-F508del mouse.

Sci Rep. 2018 Jun 18;8(1):9320

Authors: Philp AR, Riquelme TT, Millar-Büchner P, González R, Sepúlveda FV, Cid LP, Flores CA

Abstract
Nearly 70% of cystic fibrosis (CF) patients bear the phenylalanine-508 deletion but disease severity differs greatly, and is not explained by the existence of different mutations in compound heterozygous. Studies demonstrated that genes other than CFTR relate to intestinal disease in humans and CF-mouse. Kcnn4, the gene encoding the calcium-activated potassium channel KCa3.1, important for intestinal secretion, is present in a locus linked with occurrence of intestinal CF-disease in mice and humans. We reasoned that it might be a CF-modifier gene and bred a CF-mouse with Kcnn4 silencing, finding that lethality was almost abolished. Silencing of Kcnn4 did not improve intestinal secretory functions, but rather corrected increased circulating TNF-α level and reduced intestinal mast cell increase. Given the importance of mast cells in intestinal disease additional double mutant CF-animals were tested, one lacking mast cells (C-kitW-sh/W-sh) and Stat6-/- to block IgE production. While mast cell depletion had no effect, silencing Stat6 significantly reduced lethality. Our results show that Kcnn4 is an intestinal CF modifier gene partially acting through a STAT6-dependent mechanism.

PMID: 29915289 [PubMed - in process]

Related Articles

OmpR regulator of Burkholderia multivorans controls mucoid-to-nonmucoid transition and other cell envelope properties associated with persistence in the cystic fibrosis lung.

J Bacteriol. 2018 Jun 18;:

Authors: Silva IN, Pessoa FD, Ramires MJ, Santos MR, Becker JD, Cooper VS, Moreira LM

Abstract
Bacteria from the Burkholderia cepacia complex grow in different natural and man-made environments and are feared opportunistic pathogens that cause chronic respiratory infections in cystic fibrosis patients. Previous studies showed that Burkholderia mucoid clinical isolates grown under stress conditions give rise to nonmucoid variants devoid of the exopolysaccharide cepacian. Here, we have determined that a major cause of the nonmucoid morphotype involves nonsynonymous mutations and small indels in the ompR gene encoding a response regulator of a two-component regulatory system. In trans complementation of nonmucoid variants (NMVs) with the native gene restored exopolysaccharide production. Loss of functional B. multivorans OmpR had a positive effect on growth, adhesion to lung epithelial cells and biofilm formation in high osmolarity medium, as well as an increase in swimming and swarming motilities. In contrast, phenotypes such as antibiotic resistance, biofilm formation at low osmolarity and virulence in Galleria mellonella were compromised by the absence of functional OmpR. Transcriptomic studies indicated that loss of ompR gene affects the expression of 701 genes, many associated with outer membrane composition, motility, stress response, iron acquisition, and uptake of nutrients consistent with starvation tolerance. Since stresses here imposed to B. multivorans may strongly resemble the ones found in the CF airways, and mutations in ompR gene from longitudinally collected CF isolates have been found, this regulator might be important for production of NMVs in the CF environment.IMPORTANCE Within the cystic fibrosis (CF) lung, bacteria experience high osmolarity conditions due to ion unbalance resulting from defects in the CFTR protein activity in epithelial cells. Understanding how bacterial CF pathogens thrive in this environment might help to develop new therapeutic interventions to prevent chronic respiratory infections. Here, we show that the OmpR response regulator of one of the species found in CF respiratory infections, Burkholderia multivorans, is involved in the emergence of nonmucoid colony variants and is important for osmoadaptation by regulating several cell envelope components. Specifically, genetic, phenotypic, genomic and transcriptomic approaches uncover OmpR as a regulator of cell wall remodeling under stress conditions, with implications in several phenotypes like exopolysaccharide production, motility, antibiotic resistance, adhesion, and virulence.

PMID: 29914989 [PubMed - as supplied by publisher]

Related Articles

In vitro susceptibility of Burkholderia cepacia complex isolated from cystic fibrosis patients to ceftazidime-avibactam and ceftolozane-tazobactam.

Antimicrob Agents Chemother. 2018 Jun 18;:

Authors: Van Dalem A, Herpol M, Echahidi F, Peeters C, Wybo I, De Wachter E, Vandamme P, Piérard D

Abstract
We tested the in vitro susceptibility of ceftazidime-avibactam and ceftolozane-tazobactam and 13 other antibiotics against 91 Burkholderia cepacia complex (BCC) strains isolated from cystic fibrosis patients since 2012. Highest susceptibility (82%) was found for trimethoprim-sulfamethoxazole. Respectively, 81% and 63% of all BCC strains were susceptible to ceftazidime-avibactam and ceftolozane-tazobactam. For temocillin, ceftazidime, piperacillin-tazobactam and meropenem, at least 50% of the strains were susceptible. B. stabilis seems to be more resistant than other BCC species.

PMID: 29914964 [PubMed - as supplied by publisher]

Related Articles

Activity of Telavancin against S. aureus isolated from cystic fibrosis patients including those with decreased susceptibility to Ceftaroline.

Antimicrob Agents Chemother. 2018 Jun 18;:

Authors: Roch M, Varela MC, Taglialegna A, Rose WE, Rosato AE

Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) acquisition in cystic fibrosis (CF) patients confers a worse clinical outcome with increased rate of declined lung function. Telavancin, an approved lipoglycopeptide used to treat infections due to S. aureus has a dual mode of action causing inhibition of the peptidoglycan synthesis and membrane depolarization. CF-associated MRSA infections remain an important problem with no foreseeable decline in prevalence rates. Although telavancin is currently in clinical use for complicated skin infections and hospital-acquired pneumonia, the activity against CF- associated S. aureus infections has not been investigated. In this work, we studied the activity of telavancin against CF S. aureus strains collected from diverse geographical CF centers in the USA. We found that telavancin-MIC90 was 0.06 μg/ml, 8-fold lower than ceftaroline or daptomycin and 25-fold lower than linezolid and vancomycin. We demonstrate that telavancin at serum-free concentrations has rapid bactericidal activity with a decrease of more than 3 log10 CFU/ml during the first 4 to 6 hours of treatment, performing better in this assay than vancomycin and ceftaroline, including S. aureus resistant to ceftaroline.Telavancin resistance was infrequent (0.3%), although we found that it can occur in- vitro in both CF- and non-CF S. aureus strains by progressive passages with sub-inhibitory concentrations. Genetic analysis of telavancin in-vitro mutants showed gene polymorphisms in cell wall and virulence genes, and increased survival in a Galleria mellonella infection model. Thus, we conclude that telavancin represents a promising therapeutic option for CF infections with potent in-vitro activity and low resistance potential.

PMID: 29914961 [PubMed - as supplied by publisher]