Related Articles

Mutations in PPCS, Encoding Phosphopantothenoylcystein Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.

Am J Hum Genet. 2018 May 03;:

Authors: Iuso A, Wiersma M, Schüller HJ, Pode-Shakked B, Marek-Yagel D, Grigat M, Schwarzmayr T, Berutti R, Alhaddad B, Kanon B, Grzeschik NA, Okun JG, Perles Z, Salem Y, Barel O, Vardi A, Rubinshtein M, Tirosh T, Dubnov-Raz G, Messias AC, Terrile C, Barshack I, Volkov A, Avivi C, Eyal E, Mastantuono E, Kumbar M, Abudi S, Braunisch M, Strom TM, Meitinger T, Hoffmann GF, Prokisch H, Haack TB, Brundel BJJM, Haas D, Sibon OCM, Anikster Y

Abstract
Coenzyme A (CoA) is an essential metabolic cofactor used by around 4% of cellular enzymes. Its role is to carry and transfer acetyl and acyl groups to other molecules. Cells can synthesize CoA de novo from vitamin B5 (pantothenate) through five consecutive enzymatic steps. Phosphopantothenoylcystein synthetase (PPCS) catalyzes the second step of the pathway during which phosphopantothenate reacts with ATP and cysteine to form phosphopantothenoylcystein. Inborn errors of CoA biosynthesis have been implicated in neurodegeneration with brain iron accumulation (NBIA), a group of rare neurological disorders characterized by accumulation of iron in the basal ganglia and progressive neurodegeneration. Exome sequencing in five individuals from two unrelated families presenting with dilated cardiomyopathy revealed biallelic mutations in PPCS, linking CoA synthesis with a cardiac phenotype. Studies in yeast and fruit flies confirmed the pathogenicity of identified mutations. Biochemical analysis revealed a decrease in CoA levels in fibroblasts of all affected individuals. CoA biosynthesis can occur with pantethine as a source independent from PPCS, suggesting pantethine as targeted treatment for the affected individuals still alive.

PMID: 29754768 [PubMed - as supplied by publisher]

6 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 2018/05/15

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.

43 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2018/05/15

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.

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 2018/05/15

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.

Funding Opportunity RFA-OD-18-005 from the NIH Guide for Grants and Contracts. The purpose of the Mentored Research Scientist Career Development Award in Tobacco Regulatory Research (K01) is to provide support and protected time (three, four, or five years) for an intensive, supervised career development experience in research in biomedical, behavioral, and social science research that will inform the development and evaluation of regulations on tobacco product manufacturing, distribution, and marketing and that will lead to research independence.

Funding Opportunity RFA-OD-18-006 from the NIH Guide for Grants and Contracts. The purpose of the Mentored Research Scientist Career Development Award in Tobacco Regulatory Research (K01) is to provide support and protected time (three, four, or five years) for an intensive, supervised career development experience in research in biomedical, behavioral, and social science research that will inform the development and evaluation of regulations on tobacco product manufacturing, distribution, and marketing and that will lead to research independence

Funding Opportunity RFA-OD-18-008 from the NIH Guide for Grants and Contracts. The purpose of the Pathway to Independence Award in Tobacco Regulatory Research (K99/R00) is to increase and maintain a strong cohort of new and talented independent investigators conducting research that will inform the development and evaluation of regulations on tobacco product manufacturing, distribution, and marketing. The program is designed to facilitate a timely transition from a mentored postdoctoral research position to a stable independent research position with independent NIH or other independent research support at an earlier stage than is currently the norm

Funding Opportunity RFA-OD-18-007 from the NIH Guide for Grants and Contracts. The purpose of the Pathway to Independence Award in Tobacco Regulatory Research (K99/R00) is to increase and maintain a strong cohort of new and talented independent investigators conducting research that will inform the development and evaluation of regulations on tobacco product manufacturing, distribution, and marketing. The program is designed to facilitate a timely transition from a mentored postdoctoral research position to a stable independent research position with independent NIH or other independent research support at an earlier stage than is currently the norm.

Funding Opportunity RFA-AG-19-005 from the NIH Guide for Grants and Contracts. Deprescribing, the cessation of long-term therapy under clinician supervision, is a fundamental technique of geriatric practice and palliative medicine to address inappropriate medication use and/or polypharmacy common among older adults with multimorbidity. Important research gaps remain whose resolution may improve approaches to deprescribing and may improve health outcomes by optimizing the goal-directed care of older adults with multiple chronic conditions. This FOA is intended to support a collaborative network to advance scientific research into techniques and outcomes of deprescribing medications for prevention and treatment of older adults with multiple chronic conditions. This network should address the scientific, safety, ethical, and logistical challenges of deprescribing trials and may incorporate focused attention to other relevant and well-justified topics, such as the risks and benefits of target medications, or alternative approaches that may substitute for the deprescribed drugs. This FOA will support the establishment and initial operations of a network over the 5-year grant period including development of collaborations, resources, and infrastructure.

Notice NOT-CA-18-071 from the NIH Guide for Grants and Contracts

Notice NOT-AI-18-038 from the NIH Guide for Grants and Contracts

Related Articles

Targeting transcriptional control of soluble guanylyl cyclase via NOTCH for prevention of cardiovascular disease.

Acta Physiol (Oxf). 2018 May 13;:e13094

Authors: Rippe C, Albinsson S, Guron G, Nilsson H, Swärd K

Abstract
Soluble guanylyl cyclase (sGC) is an effector enzyme of nitric oxide (NO). Recent work has unraveled how levels of this enzyme are controlled, and highlighted a role in vascular disease. We provide a timely summary of available knowledge on transcriptional regulation of sGC, including influences from the NOTCH signaling pathway and genetic variants. It is speculated that hypertension-induced repression of sGC starts a vicious circle that can be initiated by periods of stress, diet or genetic factors, and a key tenet is that reduction of sGC further raises blood pressure. The idea that dysregulation of sGC contributes to syndromes caused by defective NOTCH signaling is advanced, and we discuss drug repositioning for vascular disease prevention. The advantage of targeting sGC expression rather than activity is also considered. It is argued that transcriptional inputs on sGC arise from interactions with other cells, the extracellular matrix, and microRNAs (miRNAs), and concluded that the promise of sGC as a target for prevention of cardiovascular disease has increased in recent time. This article is protected by copyright. All rights reserved.

PMID: 29754438 [PubMed - as supplied by publisher]

Related Articles

Feasibility and biological rationale of repurposing sunitinib and erlotinib for dengue treatment.

Antiviral Res. 2018 May 10;:

Authors: Pu S, Xiao F, Schor S, Bekerman E, Zanini F, Barouch-Bentov R, Nagamine CM, Einav S

Abstract
There is an urgent need for strategies to combat dengue virus (DENV) infection; a major global threat. We reported that the cellular kinases AAK1 and GAK regulate intracellular trafficking of multiple viruses and that sunitinib and erlotinib, approved anticancer drugs with potent activity against these kinases, protect DENV-infected mice from mortality. Nevertheless, further characterization of the therapeutic potential and underlying mechanism of this approach is required prior to clinical evaluation. Here, we demonstrate that sunitinib/erlotinib combination achieves sustained suppression of systemic infection at approved dose in DENV-infected IFN-α/β and IFN-γ receptor-deficient mice. Nevertheless, treatment with these blood-brain barrier impermeable drugs delays, yet does not prevent, late-onset paralysis; a common manifestation in this immunodeficient mouse model but not in humans. Sunitinib and erlotinib treatment also demonstrates efficacy in human primary monocyte-derived dendritic cells. Additionally, DENV infection induces expression of AAK1 transcripts, but not GAK, via single-cell transcriptomics, and these kinases are important molecular targets underlying the anti-DENV effect of sunitinib and erlotinib. Lastly, sunitinib/erlotinib combination alters inflammatory cytokine responses in DENV-infected mice. These findings support feasibility of repurposing sunitinib/erlotinib combination as a host-targeted antiviral approach and contribute to understanding its mechanism of antiviral action.

PMID: 29753658 [PubMed - as supplied by publisher]

Related Articles

Economic Modeling Considerations for Rare Diseases.

Value Health. 2018 May;21(5):515-524

Authors: Pearson I, Rothwell B, Olaye A, Knight C

Abstract
OBJECTIVES: To identify challenges that affect the feasibility and rigor of economic models in rare diseases and strategies that manufacturers have employed in health technology assessment submissions to demonstrate the value of new orphan products that have limited study data.
METHODS: Targeted reviews of PubMed, the National Institute for Health and Care Excellence's (NICE's) Highly Specialised Technologies (HST), and the Scottish Medicines Consortium's (SMC's) ultra-orphan submissions were performed.
RESULTS: A total of 19 PubMed studies, 3 published NICE HSTs, and 11 ultra-orphan SMC submissions were eligible for inclusion. In rare diseases, a number of different factors may affect the model's ability to comply with good practice recommendations. Many products for the treatment of rare diseases have an incomplete efficacy and safety profile at product launch. In addition, there is often limited available natural history and epidemiology data. Information on the direct and indirect cost burden of an orphan disease also may be limited, making it difficult to estimate the potential economic benefit of treatment. These challenges can prevent accurate estimation of a new product's benefits in relation to costs. Approaches that can address such challenges include using patient and/or clinician feedback to inform model assumptions; data from disease analogues; epidemiological techniques, such as matching-adjusted indirect comparison; and long-term data collection.
CONCLUSIONS: Modeling in rare diseases is often challenging; however, a number of approaches are available to support the development of model structures and the collation of input parameters and to manage uncertainty.

PMID: 29753347 [PubMed - in process]

Related Articles

Pathophysiology and Genetics of Bronchiectasis Unrelated to Cystic Fibrosis.

Lung. 2018 May 12;:

Authors: Nikolic A

Abstract
Bronchiectasis is characterized by deregulated inflammatory response and recurrent bacterial infection resulting in progressive lung damage and an irreversible dilatation of bronchi and bronchioles. Generally accepted model of the development of bronchiectasis is the "vicious cycle hypothesis" that proposes compromising of the mucociliary clearance by an initial event, which leads to the infection of the respiratory tract followed by further impairment of mucociliary function, bacterial proliferation, and more inflammation. Bronchiectasis is a very common symptom in patients with cystic fibrosis (CF), while bronchiectasis unrelated to CF is heterogeneous pathology of unknown cause with a large number of potential contributory factors and poorly understood pathogenesis. It is presumed that bronchiectasis unrelated to CF is a multifactorial condition predisposed by genetic factors. Different molecules have been implicated in the onset and development of idiopathic bronchiectasis, as well as modulation of the disease severity and response to therapy. Most of these molecules are involved in the processes that contribute to the homeostasis of the lung tissue, especially mucociliary clearance, protease-antiprotease balance, and immunomodulation. Evaluation of the studies performed towards investigation of the role these molecules play in bronchiectasis identifies genetic variants that may be of potential importance for clinical management of the disease, and also of interest for future research efforts. This review focuses on the molecules with major roles in lung homeostasis and their involvement in bronchiectasis unrelated to CF.

PMID: 29754320 [PubMed - as supplied by publisher]

Related Articles

Imaging Mass Spectrometry for Characterization of Atrial Fibrillation Subtypes.

Proteomics Clin Appl. 2018 May 13;:e1700155

Authors: Klein O, Hanke T, Nerbrich G, Yan J, Schubert B, Giavalisco P, Noack F, Thiele H, Mohamed SA

Abstract
PURPOSE: Atrial fibrillation (AF) is a cardiac arrhythmia characterized by a rapid and irregular heart rhythm. AF types, paroxysmal (PX), persistent (PE) and long-lasting persistent (LSP), requires differences in clinical management. Unfortunately, a significant proportion of AF patients are clinical misclassified. Therefore, our study aim that MALDI-Imaging (IMS) is valuable as a diagnostic aid in AF subtypes assessment.
EXPERIMENTAL DESIGN: Patients were clinically classified according guidelines of the European Society of Cardiology. FFPE tissue specimens from PE, PX and LSP subtype were analysed by MALDI-IMS and evaluated by multi-statistical testing. Proteins were subsequent identified using LC-MS/MS and findings were confirmed by immunohistochemistry and through the determination of potential fibrosis via histopathology RESULT: : Determined characteristic peptide signatures and peptide values facilitate to distinguish between PE, PE and LSP arterial fibrillation subtypes. In particular, peptide values from alpha 1 type I collagen were identified that were significantly higher in LSP and PE tissue but not in PX myocardial AF tissue. These findings were confirmed by immunohistochemistry and through the determination of potential fibrosis via histopathology.
CONCLUSION AND RELEVANCE: Our results represent an improvement in AF risk stratification by using MALDI-IMS as a promising approach for AF tissue assessment. This article is protected by copyright. All rights reserved.

PMID: 29754423 [PubMed - as supplied by publisher]

Related Articles

Targeting TWIST1 through loss of function inhibits tumorigenicity of human glioblastoma.

Mol Oncol. 2018 May 13;:

Authors: Mikheev AM, Mikheeva SA, Severs LJ, Funk CC, Huang L, McFaline-Figueroa JL, Schwensen J, Trapnell C, Price ND, Wong S, Rostomily RC

Abstract
Twist1 (TW) is a bHLH transcription factor (TF) and master regulator of the epithelial to mesenchymal transition (EMT). In vitro, TW promotes mesenchymal change, invasion and self-renewal in glioblastoma (GBM) cells. However the potential therapeutic relevance of TW has not been established through loss of function studies in human GBM cell xenograft models. The effects of TW loss of function (gene editing and knock down) on inhibition of tumorigenicity of U87MG and GBM4 glioma stem cells were tested in orthotopic xenograft models and conditional knockdown in established flank xenograft tumors. RNAseq and the analysis of tumors investigated putative TW associated mechanisms. Multiple bioinformatics tools revealed significant alteration of ECM, membrane receptors, signaling transduction kinases and cytoskeleton dynamics leading to identification of PI3K/AKT signaling. We experimentally show alteration of AKT activity and periostin (POSTN) expression in vivo and/or in vitro. For the first time we show that effect of TW knockout inhibits AKT activity in U87MG cells in vivo independent of PTEN mutation. The clinical relevance of TW and candidate mechanisms was established by analysis of the TCGA and ENCODE databases. TW expression was associated with decreased patient survival and LASSO regression analysis identified POSTN as one of top targets of TW in human GBM. While we previously demonstrated the role of TW in promoting EMT and invasion of glioma cells, these studies provide direct experimental evidence supporting pro-tumorigenic role of TW independent of invasion in vivo and the therapeutic relevance of targeting TW in human GBM. Further, the role of TW driving POSTN expression and AKT signaling suggests actionable targets, which could be leveraged to mitigate the oncogenic effects of TW in GBM.

PMID: 29754406 [PubMed - as supplied by publisher]

Related Articles

Automated Visualization of Genetic Designs Using DNAplotlib.

Methods Mol Biol. 2018;1772:399-409

Authors: Bartoli V, Dixon DOR, Gorochowski TE

Abstract
Visualization of complex genetic systems can help efficiently communicate important design features and clearly illustrate overall structures. To aid in the creation of such diagrams, standards such as the Synthetic Biology Open Language Visual (SBOLv) have been established to ensure that specific symbols and shapes convey the same meaning for genetic parts across the field. Here, we describe several ways that the computational tool DNAplotlib can be used to automate the generation of SBOLv standard-compliant diagrams covering simple genetic designs to large libraries of genetic constructs.

PMID: 29754241 [PubMed - in process]

Related Articles

Bio-Algorithmic Workflows for Standardized Synthetic Biology Constructs.

Methods Mol Biol. 2018;1772:363-372

Authors: Goñi-Moreno A, de Lorenzo V

Abstract
A synthetic biology workflow covers the roadmap from conceptualization of a genetic device to its construction and measurement. It is composed of databases that provide DNA parts/plasmids, wet-lab methods , software tools to design circuits, simulation packages , and tools to analyze circuit performance. The interdisciplinary nature of such a workflow requires that experimental results and their in-silico counterparts proceed alongside, with constant feedback between them. We present an end-to-end use case for engineering a simple synthetic device, where information standards maintain coherence throughout the workflow. These are the Standard European Vector Architecture (SEVA), the Synthetic Biology Open Language (SBOL), and the Systems Biology Markup Language (SBML).

PMID: 29754239 [PubMed - in process]

Related Articles

Construction and Integration of a Synthetic MicroRNA Cluster for Multiplex RNA Interference in Mammalian Cells.

Methods Mol Biol. 2018;1772:347-359

Authors: Wang T, Xie Z

Abstract
Basic biological research and biomedical applications often require studying the multiple interactions between genes or proteins while multiplex RNA interference (RNAi) technology is still challenging in mammalian cells. In mammalian genomes, the natural microRNA (miRNA) clusters, of which the miRNAs often share similar expression patterns and target diverse genes, would provide a potential multiplex RNAi scaffold. Based on the natural pri-miR-155 precursor, we have developed and characterized a multiplex RNAi method by engineering synthetic miRNA clusters, among which the maturation and function of individual miRNA precursors are independent of their positions in the cluster. And the synthetic miRNA clusters are assembled by an efficient hierarchical Golden-Gate cloning method. Here, we describe the design rules and the hierarchical cloning methods to construct synthetic miRNA cluster, and the brief protocol for the integration of synthetic miRNA clusters into the mammalian genome.

PMID: 29754238 [PubMed - in process]