Partial restoration of pancreatic function in a child with cystic fibrosis.

Lancet Respir Med. 2016 May;4(5):e21-e22

Authors: Howlett C, Ronan NJ, NiChroinin M, Mullane D, Plant BJ

PMID: 27304562 [PubMed - as supplied by publisher]

The phospholipid flippase ATP8B1 mediates apical localization of the Cystic Fibrosis Transmembrane Regulator.

Biochim Biophys Acta. 2016 Jun 11;

Authors: van der Mark VA, de Jonge HR, Chang JC, Ho-Mok KS, Duijst S, Vidović D, Carlon MS, Elferink RP, Paulusma CC

Abstract
Progressive familial intrahepatic cholestasis type 1 (PFIC1) is caused by mutations in the gene encoding the phospholipid flippase ATP8B1. Apart from severe cholestatic liver disease, many PFIC1 patients develop extrahepatic symptoms characteristic of cystic fibrosis (CF), such as pulmonary infection, sweat gland dysfunction and failure to thrive. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel essential for epithelial fluid transport. Previously it was shown that CFTR transcript levels were strongly reduced in livers of PFIC1 patients. Here we have investigated the hypothesis that ATP8B1 is important for proper CFTR expression and function. We analyzed CFTR expression in ATP8B1-depleted intestinal and pulmonary epithelial cell lines and assessed CFTR function by measuring short-circuit currents across transwell-grown ATP8B1-depleted intestinal T84 cells and by a genetically-encoded fluorescent chloride sensor. In addition, we studied CFTR surface expression upon induction of CFTR transcription. We show that CFTR protein levels are strongly reduced in the apical membrane of human ATP8B1-depleted intestinal and pulmonary epithelial cell lines, a phenotype that coincided with reduced CFTR activity. Apical membrane insertion upon induction of ectopically-expressed CFTR was strongly impaired in ATP8B1-depleted cells. We conclude that ATP8B1 is essential for correct apical localization of CFTR in human intestinal and pulmonary epithelial cells, and that impaired CFTR localization underlies some of the extrahepatic phenotypes observed in ATP8B1 deficiency.

PMID: 27301931 [PubMed - as supplied by publisher]

The innate immune protein calprotectin promotes Pseudomonas aeruginosa and Staphylococcus aureus interaction.

Nat Commun. 2016;7:11951

Authors: Wakeman CA, Moore JL, Noto MJ, Zhang Y, Singleton MD, Prentice BM, Gilston BA, Doster RS, Gaddy JA, Chazin WJ, Caprioli RM, Skaar EP

Abstract
Microorganisms form biofilms containing differentiated cell populations. To determine factors driving differentiation, we herein visualize protein and metal distributions within Pseudomonas aeruginosa biofilms using imaging mass spectrometry. These in vitro experiments reveal correlations between differential protein distribution and metal abundance. Notably, zinc- and manganese-depleted portions of the biofilm repress the production of anti-staphylococcal molecules. Exposure to calprotectin (a host protein known to sequester metal ions at infectious foci) recapitulates responses occurring within metal-deplete portions of the biofilm and promotes interaction between P. aeruginosa and Staphylococcus aureus. Consistent with these results, the presence of calprotectin promotes co-colonization of the murine lung, and polymicrobial communities are found to co-exist in calprotectin-enriched airspaces of a cystic fibrosis lung explant. These findings, which demonstrate that metal fluctuations are a driving force of microbial community structure, have clinical implications because of the frequent occurrence of P. aeruginosa and S. aureus co-infections.

PMID: 27301800 [PubMed - in process]

The analysis of the antibiotic resistome offers new opportunities for therapeutic intervention.

Future Med Chem. 2016 Jun 15;

Authors: Corona F, Blanco P, Alcalde-Rico M, Hernando-Amado S, Lira F, Bernardini A, Sánchez MB, Martínez JL

Abstract
Most efforts in the development of antimicrobials have focused on the screening of lethal targets. Nevertheless, the constant expansion of antimicrobial resistance makes the antibiotic resistance determinants themselves suitable targets for finding inhibitors to be used in combination with antibiotics. Among them, inhibitors of antibiotic inactivating enzymes and of multidrug efflux pumps are suitable candidates for improving the efficacy of antibiotics. In addition, the application of systems biology tools is helping to understand the changes in bacterial physiology associated to the acquisition of resistance, including the increased susceptibility to other antibiotics displayed by some antibiotic-resistant mutants. This information is useful for implementing novel strategies based in metabolic interventions or combination of antibiotics for improving the efficacy of antibacterial therapy.

PMID: 27304087 [PubMed - as supplied by publisher]

Molecular and genetic inflammation networks in major human diseases.

Mol Biosyst. 2016 Jun 15;

Authors: Zhao Y, Forst CV, Sayegh CE, Wang IM, Yang X, Zhang B

Abstract
It has been well-recognized that inflammation alongside tissue repair and damage maintaining tissue homeostasis determines the initiation and progression of complex diseases. Albeit with the accomplishment of having captured the most critical inflammation-involved molecules, genetic susceptibilities, epigenetic factors, and environmental factors, our schemata on the role of inflammation in complex diseases remain largely patchy, in part due to the success of reductionism in terms of research methodology per se. Omics data alongside the advances in data integration technologies have enabled reconstruction of molecular and genetic inflammation networks which shed light on the underlying pathophysiology of complex diseases or clinical conditions. Given the proven beneficial role of anti-inflammation in coronary heart disease as well as other complex diseases and immunotherapy as a revolutionary transition in oncology, it becomes timely to review our current understanding of the molecular and genetic inflammation networks underlying major human diseases. In this review, we first briefly discuss the complexity of infectious diseases and then highlight recently uncovered molecular and genetic inflammation networks in other major human diseases including obesity, type II diabetes, coronary heart disease, late onset Alzheimer's disease, Parkinson's disease, and sporadic cancer. The commonality and specificity of these molecular networks are addressed in the context of genetics based on genome-wide association study (GWAS). The double-sword role of inflammation, such as how the aberrant type 1 and/or type 2 immunity leads to chronic and severe clinical conditions, remains open in terms of the inflammasome and the core inflammatome network features. Increasingly available large Omics and clinical data in tandem with systems biology approaches have offered an exciting yet challenging opportunity toward reconstruction of more comprehensive and dynamic molecular and genetic inflammation networks, which hold great promise in transiting network snapshots to video-style multi-scale interplays of disease mechanisms, in turn leading to effective clinical intervention.

PMID: 27303926 [PubMed - as supplied by publisher]

The natural defense system and the normative self model.

F1000Res. 2016;5:797

Authors: Kourilsky P

Abstract
Infectious agents are not the only agressors, and the immune system is not the sole defender of the organism. In an enlarged perspective, the 'normative self model' postulates that a 'natural defense system' protects man and other complex organisms against the environmental and internal hazards of life, including infections and cancers. It involves multiple error detection and correction mechanisms that confer robustness to the body at all levels of its organization. According to the model, the self relies on a set of physiological norms, and NONself (meaning : Non Obedient to the Norms of the self) is anything 'off-norms'. The natural defense system comprises a set of 'civil defenses' (to which all cells in organs and tissues contribute), and a 'professional army ', made of a smaller set of mobile cells. Mobile and non mobile cells differ in their tuning abilities. Tuning extends the recognition capabilities of NONself by the mobile cells, which increase their defensive function. To prevent them to drift, which would compromise self/NONself discrimination, the more plastic mobile cells need to periodically refer to the more stable non mobile cells to keep within physiological standards.

PMID: 27303629 [PubMed]

A signaling visualization toolkit to support rational design of combination therapies and biomarker discovery: SiViT.

Oncotarget. 2016 May 18;

Authors: Bown JL, Shovman M, Robertson P, Boiko A, Goltsov A, Mullen P, Harrison DJ

Abstract
Targeted cancer therapy aims to disrupt aberrant cellular signalling pathways. Biomarkers are surrogates of pathway state, but there is limited success in translating candidate biomarkers to clinical practice due to the intrinsic complexity of pathway networks. Systems biology approaches afford better understanding of complex, dynamical interactions in signalling pathways targeted by anticancer drugs. However, adoption of dynamical modelling by clinicians and biologists is impeded by model inaccessibility. Drawing on computer games technology, we present a novel visualization toolkit, SiViT, that converts systems biology models of cancer cell signalling into interactive simulations that can be used without specialist computational expertise. SiViT allows clinicians and biologists to directly introduce for example loss of function mutations and specific inhibitors. SiViT animates the effects of these introductions on pathway dynamics, suggesting further experiments and assessing candidate biomarker effectiveness. In a systems biology model of Her2 signalling we experimentally validated predictions using SiViT, revealing the dynamics of biomarkers of drug resistance and highlighting the role of pathway crosstalk. No model is ever complete: the iteration of real data and simulation facilitates continued evolution of more accurate, useful models. SiViT will make accessible libraries of models to support preclinical research, combinatorial strategy design and biomarker discovery.

PMID: 27302920 [PubMed - as supplied by publisher]

Advances in targeted proteomics and applications to biomedical research.

Proteomics. 2016 Jun 15;

Authors: Shi T, Song E, Nie S, Rodland KD, Liu T, Qian WJ, Smith RD

Abstract
Targeted proteomics technique has emerged as a powerful protein quantification tool in systems biology, biomedical research, and increasing for clinical applications. The most widely used targeted proteomics approach, selected reaction monitoring (SRM), also known as multiple reaction monitoring (MRM), can be used for quantification of cellular signaling networks and preclinical verification of candidate protein biomarkers. As an extension to our previous review on advances in SRM sensitivity (Shi et al., Proteomics, 12, 1074-1092, 2012) herein we review recent advances in the method and technology for further enhancing SRM sensitivity (from 2012 to present), and highlighting its broad biomedical applications in human bodily fluids, tissue and cell lines. Furthermore, we also review two recently introduced targeted proteomics approaches, parallel reaction monitoring (PRM) and data-independent acquisition (DIA) with targeted data extraction on fast scanning high-resolution accurate-mass (HR/AM) instruments. Such HR/AM targeted quantification with monitoring all target product ions addresses SRM limitations effectively in specificity and multiplexing; whereas when compared to SRM, PRM and DIA are still in the infancy with a limited number of applications. Thus, for HR/AM targeted quantification we focus our discussion on method development, data processing and analysis, and its advantages and limitations in targeted proteomics. Finally, general perspectives on the potential of achieving both high sensitivity and high sample throughput for large-scale quantification of hundreds of target proteins are discussed. This article is protected by copyright. All rights reserved.

PMID: 27302376 [PubMed - as supplied by publisher]

Personalized medicine. Closing the gap between knowledge and clinical practice.

Autoimmun Rev. 2016 Jun 11;

Authors: Anaya JM, Duarte-Rey C, Sarmiento-Monroy JC, Bardey D, Castiblanco J, Rojas-Villarraga A

Abstract
Personalized medicine encompasses a broad and evolving field informed by a patient distinctive information and biomarker profile. Although terminology is evolving and some semantic interpretations exist (e.g., personalized, individualized, precision), in a broad sense personalized medicine can be coined as: "To practice medicine as it once used to be in the past using the current biotechnological tools." A humanized approach to personalized medicine would offer the possibility of exploiting systems biology and its concept of P5 medicine, where predictive factors for developing a disease should be examined within populations in order to establish preventive measures on at-risk individuals, for whom healthcare should be personalized and participatory. Herein, the process of personalized medicine is presented together with the options that can be offered in health care systems with limited resources for diseases like rheumatoid arthritis and type 1 diabetes.

PMID: 27302209 [PubMed - as supplied by publisher]

Dynamic zonation of liver polyploidy.

Cell Tissue Res. 2016 Jun 15;

Authors: Tanami S, Ben-Moshe S, Elkayam A, Mayo A, Bahar Halpern K, Itzkovitz S

Abstract
The liver is a polyploid organ, consisting of hepatocytes with one or two nuclei each containing 2, 4, 8 or more haploid chromosome sets. The dynamic changes in the spatial distributions of polyploid classes across the liver lobule, its repeating anatomical unit, have not been characterized. Identifying these spatial patterns is important for understanding liver homeostatic and regenerative turnover, as well as potential division of labor among ploidy classes. Here, we use single molecule-based tissue imaging to reconstruct the spatial zonation profiles of liver polyploid classes in mice of different ages. We find that liver polyploidy proceeds in spatial waves, advancing more rapidly in the mid-lobule zone compared to the periportal and perivenous zones. We also measure the spatial zonation profiles of S-phase entry at different ages and identify more rapid S-phase entry in the mid-lobule zone at older ages. Our findings reveal fundamental features of liver spatial heterogeneity and highlight their dynamic changes during development and aging.

PMID: 27301446 [PubMed - as supplied by publisher]

Genomic cloud computing: legal and ethical points to consider.

Eur J Hum Genet. 2015 Oct;23(10):1271-8

Authors: Dove ES, Joly Y, Tassé AM, Public Population Project in Genomics and Society (P3G) International Steering Committee, International Cancer Genome Consortium (ICGC) Ethics and Policy Committee, Knoppers BM

Abstract
The biggest challenge in twenty-first century data-intensive genomic science, is developing vast computer infrastructure and advanced software tools to perform comprehensive analyses of genomic data sets for biomedical research and clinical practice. Researchers are increasingly turning to cloud computing both as a solution to integrate data from genomics, systems biology and biomedical data mining and as an approach to analyze data to solve biomedical problems. Although cloud computing provides several benefits such as lower costs and greater efficiency, it also raises legal and ethical issues. In this article, we discuss three key 'points to consider' (data control; data security, confidentiality and transfer; and accountability) based on a preliminary review of several publicly available cloud service providers' Terms of Service. These 'points to consider' should be borne in mind by genomic research organizations when negotiating legal arrangements to store genomic data on a large commercial cloud service provider's servers. Diligent genomic cloud computing means leveraging security standards and evaluation processes as a means to protect data and entails many of the same good practices that researchers should always consider in securing their local infrastructure.

PMID: 25248396 [PubMed - indexed for MEDLINE]

Genetic and metabolic engineering of microorganisms for the development of new flavor compounds from terpenic substrates.

Crit Rev Biotechnol. 2015;35(3):313-25

Authors: Bution ML, Molina G, Abrahão MR, Pastore GM

Abstract
Throughout human history, natural products have been the basis for the discovery and development of therapeutics, cosmetic and food compounds used in industry. Many compounds found in natural organisms are rather difficult to chemically synthesize and to extract in large amounts, and in this respect, genetic and metabolic engineering are playing an increasingly important role in the production of these compounds, such as new terpenes and terpenoids, which may potentially be used to create aromas in industry. Terpenes belong to the largest class of natural compounds, are produced by all living organisms and play a fundamental role in human nutrition, cosmetics and medicine. Recent advances in systems biology and synthetic biology are allowing us to perform metabolic engineering at the whole-cell level, thus enabling the optimal design of microorganisms for the efficient production of drugs, cosmetic and food additives. This review describes the recent advances made in the genetic and metabolic engineering of the terpenes pathway with a particular focus on systems biotechnology.

PMID: 24494701 [PubMed - indexed for MEDLINE]

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

("orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases")

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"Cystic Fibrosis"

These pubmed results were generated on 2016/06/15

PubMed comprises more than 24 million 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.

FALDO: a semantic standard for describing the location of nucleotide and protein feature annotation.

J Biomed Semantics. 2016;7:39

Authors: Bolleman JT, Mungall CJ, Strozzi F, Baran J, Dumontier M, Bonnal RJ, Buels R, Hoehndorf R, Fujisawa T, Katayama T, Cock PJ

Abstract
BACKGROUND: Nucleotide and protein sequence feature annotations are essential to understand biology on the genomic, transcriptomic, and proteomic level. Using Semantic Web technologies to query biological annotations, there was no standard that described this potentially complex location information as subject-predicate-object triples.
DESCRIPTION: We have developed an ontology, the Feature Annotation Location Description Ontology (FALDO), to describe the positions of annotated features on linear and circular sequences. FALDO can be used to describe nucleotide features in sequence records, protein annotations, and glycan binding sites, among other features in coordinate systems of the aforementioned "omics" areas. Using the same data format to represent sequence positions that are independent of file formats allows us to integrate sequence data from multiple sources and data types. The genome browser JBrowse is used to demonstrate accessing multiple SPARQL endpoints to display genomic feature annotations, as well as protein annotations from UniProt mapped to genomic locations.
CONCLUSIONS: Our ontology allows users to uniformly describe - and potentially merge - sequence annotations from multiple sources. Data sources using FALDO can prospectively be retrieved using federalised SPARQL queries against public SPARQL endpoints and/or local private triple stores.

PMID: 27296299 [PubMed - in process]

Review on Pharmacogenetics and Pharmacogenomics Applied to the Study of Asthma.

Methods Mol Biol. 2016;1434:255-272

Authors: Sánchez-Martín A, García-Sánchez A, Isidoro-García M

Abstract
Nearly one-half of asthmatic patients do not respond to the most common therapies. Evidence suggests that genetic factors may be involved in the heterogeneity in therapeutic response and adverse events to asthma therapies. We focus on the three major classes of asthma medication: β-adrenergic receptor agonist, inhaled corticosteroids, and leukotriene modifiers. Pharmacogenetics and pharmacogenomics studies have identified several candidate genes associated with drug response.In this chapter, the main pharmacogenetic and pharmacogenomic studies in addition to the future perspectives in personalized medicine will be reviewed. The ideal treatment of asthma would be a tailored approach to health care in which adverse effects are minimized and the therapeutic benefit for an individual asthmatic is maximized leading to a more cost-effective care.

PMID: 27300544 [PubMed - as supplied by publisher]

Verification of five pharmacogenomics-based warfarin administration models.

Indian J Pharmacol. 2016 May-Jun;48(3):258-63

Authors: Lin M, Yu L, Qiu H, Wang Q, Zhang J, Song H

Abstract
OBJECTIVE: This study aims to screen and validate five individual warfarin dosing models (four Asian model algorithms, namely, Ohno, Wen, Miao, Huang, and the algorithm of International Warfarin Pharmacogenetic Consortium, namely IWPC algorithm) with the aim of evaluating their accuracy, practicality, and safety.
MATERIALS AND METHODS: Patients' CYP2C9*3 and VKORC1-1639G >A genes were genotyped, and patient-related information and steady warfarin doses were recorded. The difference between the predicted dose and actual maintenance dose of each model was compared.
RESULTS: The prediction accuracies of the Huang and Wen models were the highest. In terms of clinical practicality, the Huang model rated the highest for the low-dose group, whereas the Ohno and IWPC models rated the highest for the middle-dose group. The models tended to markedly overpredict the doses in the low-dose group, especially the IWPC model. The Miao model tended to severely underpredict the doses in the middle-dose group, whereas no model exhibited severe overprediction.
CONCLUSIONS: Since none of the models ranked high for all the three criteria considered, the impact of various factors should be thoroughly considered before selecting the most appropriate model for the region's population.

PMID: 27298494 [PubMed - in process]

Individualized network-based drug repositioning infrastructure for precision oncology in the panomics era.

Brief Bioinform. 2016 Jun 12;

Authors: Cheng F, Hong H, Yang S, Wei Y

Abstract
Advances in next-generation sequencing technologies have generated the data supporting a large volume of somatic alterations in several national and international cancer genome projects, such as The Cancer Genome Atlas and the International Cancer Genome Consortium. These cancer genomics data have facilitated the revolution of a novel oncology drug discovery paradigm from candidate target or gene studies toward targeting clinically relevant driver mutations or molecular features for precision cancer therapy. This focuses on identifying the most appropriately targeted therapy to an individual patient harboring a particularly genetic profile or molecular feature. However, traditional experimental approaches that are used to develop new chemical entities for targeting the clinically relevant driver mutations are costly and high-risk. Drug repositioning, also known as drug repurposing, re-tasking or re-profiling, has been demonstrated as a promising strategy for drug discovery and development. Recently, computational techniques and methods have been proposed for oncology drug repositioning and identifying pharmacogenomics biomarkers, but overall progress remains to be seen. In this review, we focus on introducing new developments and advances of the individualized network-based drug repositioning approaches by targeting the clinically relevant driver events or molecular features derived from cancer panomics data for the development of precision oncology drug therapies (e.g. one-person trials) to fully realize the promise of precision medicine. We discuss several potential challenges (e.g. tumor heterogeneity and cancer subclones) for precision oncology. Finally, we highlight several new directions for the precision oncology drug discovery via biotherapies (e.g. gene therapy and immunotherapy) that target the 'undruggable' cancer genome in the functional genomics era.

PMID: 27296652 [PubMed - as supplied by publisher]

Resolving the etiology of atopic disorders by using genetic analysis of racial ancestry.

J Allergy Clin Immunol. 2016 Jun 10;

Authors: Gupta J, Johansson E, Bernstein JA, Chakraborty R, Khurana Hershey GK, Rothenberg ME, Mersha TB

Abstract
Atopic dermatitis (AD), food allergy, allergic rhinitis, and asthma are common atopic disorders of complex etiology. The frequently observed atopic march from early AD to asthma, allergic rhinitis, or both later in life and the extensive comorbidity of atopic disorders suggest common causal mechanisms in addition to distinct ones. Indeed, both disease-specific and shared genomic regions exist for atopic disorders. Their prevalence also varies among races; for example, AD and asthma have a higher prevalence in African Americans when compared with European Americans. Whether this disparity stems from true genetic or race-specific environmental risk factors or both is unknown. Thus far, the majority of the genetic studies on atopic diseases have used populations of European ancestry, limiting their generalizability. Large-cohort initiatives and new analytic methods, such as admixture mapping, are currently being used to address this knowledge gap. Here we discuss the unique and shared genetic risk factors for atopic disorders in the context of ancestry variations and the promise of high-throughput "-omics"-based systems biology approach in providing greater insight to deconstruct their genetic and nongenetic etiologies. Future research will also focus on deep phenotyping and genotyping of diverse racial ancestry, gene-environment, and gene-gene interactions.

PMID: 27297995 [PubMed - as supplied by publisher]

Can stable isotope mass spectrometry replace ‎radiolabelled approaches in metabolic studies?

Plant Sci. 2016 Aug;249:59-69

Authors: Batista Silva W, Daloso DM, Fernie AR, Nunes-Nesi A, Araújo WL

Abstract
Metabolic pathways and the key regulatory points thereof can be deduced using isotopically labelled substrates. One prerequisite is the accurate measurement of the labeling pattern of targeted metabolites. The subsequent estimation of metabolic fluxes following incubation in radiolabelled substrates has been extensively used. Radiolabelling is a sensitive approach and allows determination of total label uptake since the total radiolabel content is easy to detect. However, the incubation of cells, tissues or the whole plant in a stable isotope enriched environment and the use of either mass spectrometry or nuclear magnetic resonance techniques to determine label incorporation within specific metabolites offers the possibility to readily obtain metabolic information with higher resolution. It additionally also offers an important complement to other post-genomic strategies such as metabolite profiling providing insights into the regulation of the metabolic network and thus allowing a more thorough description of plant cellular function. Thus, although safety concerns mean that stable isotope feeding is generally preferred, the techniques are in truth highly complementary and application of both approaches in tandem currently probably provides the best route towards a comprehensive understanding of plant cellular metabolism.

PMID: 27297990 [PubMed - in process]