Saturday, June 25, 2016

Cellular Selenoprotein mRNA Tethering via Antisense Interactions with Ebola and HIV-1 mRNAs May Impact Host Selenium Biochemistry

Author(s):

Ethan Will Taylor, Jan A. Ruzicka, Lakmini Premadasa and Lijun ZhaoPages 1530-1535 (6)

Abstract:


Regulation of protein expression by non-coding RNAs typically involves effects on mRNA degradation and/or ribosomal translation. The possibility of virus-host mRNA-mRNA antisense tethering interactions (ATI) as a gain-of-function strategy, via the capture of functional RNA motifs, has not been hitherto considered. We present evidence that ATIs may be exploited by certain RNA viruses in order to tether the mRNAs of host selenoproteins, potentially exploiting the proximity of a captured host selenocysteine insertion sequence (SECIS) element to enable the expression of virally-encoded selenoprotein modules, via translation of in-frame UGA stop codons as selenocysteine. Computational analysis predicts thermodynamically stable ATIs between several widely expressed mammalian selenoprotein mRNAs (e.g., isoforms of thioredoxin reductase) and specific Ebola virus mRNAs, and HIV-1 mRNA, which we demonstrate via DNA gel shift assays. The probable functional significance of these ATIs is further supported by the observation that, in both viruses, they are located in close proximity to highly conserved in-frame UGA stop codons at the 3′ end of open reading frames that encode essential viral proteins (the HIV-1 nef protein and the Ebola nucleoprotein). Significantly, in HIV/AIDS patients, an inverse correlation between serum selenium and mortality has been repeatedly documented, and clinical benefits of selenium in the context of multi-micronutrient supplementation have been demonstrated in several well-controlled clinical trials. Hence, in the light of our findings, the possibility of a similar role for selenium in Ebola pathogenesis and treatment merits serious investigation.

Keywords:

Antisense, Ebola, mRNA, Selenium, Selenoprotein, HIV, Tethering, Thioredoxin reductase

Affiliation:

Dept. of Nanoscience, University of North Carolina at Greensboro, Joint School of Nanoscience and Nanoengineering, 2907 E. Gate City Blvd., Greensboro, NC 27401 USA

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Biomarkers in the Management of Difficult Asthma

Author(s):

Florence Schleich, Demarche Sophie and Louis RenaudPages 1561-1573 (13)

Abstract:


Difficult asthma is a heterogeneous disease of the airways including various types of bronchial inflammation and various degrees of airway remodeling. Therapeutic response of severe asthmatics can be predicted by the use of biomarkers of Type2-high or Type2-low inflammation. Based on sputum cell analysis, four inflammatory phenotypes have been described. As induced sputum is timeconsuming and expensive technique, surrogate biomarkers are useful in clinical practice.
Eosinophilic phenotype is likely to reflect ongoing adaptive immunity in response to allergen. Several biomarkers of eosinophilic asthma are easily available in clinical practice (blood eosinophils, serum IgE, exhaled nitric oxyde, serum periostin). Neutrophilic asthma is thought to reflect innate immune system activation in response to pollutants or infectious agents while paucigranulocytic asthma is thought to be not inflammatory and characterized by smooth muscle dysfunction. We currently lack of user-friendly biomarkers of neutrophilic asthma and airway remodeling.
In this review, we summarize the biomarkers available for the management of difficult asthma.

Keywords:

Airway remodeling, Biomarker, Difficult asthma, Inflammation, Phenotype, Severe.

Affiliation:

Respiratory Medicine, CHU Sart-Tilman B35, 4000 Li├Ęge, Belgium.

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Linking Biosynthetic Gene Clusters to their Metabolites via Pathway- Targeted Molecular Networking

Author(s):

Eric P. Trautman and Jason M. CrawfordPages 1705-1716 (12)

Abstract:


The connection of microbial biosynthetic gene clusters to the small molecule metabolites they encode is central to the discovery and characterization of new metabolic pathways with ecological and pharmacological potential. With increasing microbial genome sequence information being deposited into publicly available databases, it is clear that microbes have the coding capacity for many more biologically active small molecules than previously realized. Of increasing interest are the small molecules encoded by the human microbiome, as these metabolites likely mediate a variety of currently uncharacterized human-microbe interactions that influence health and disease. In this mini-review, we describe the ongoing biosynthetic, structural, and functional characterizations of the genotoxic colibactin pathway in gut bacteria as a thematic example of linking biosynthetic gene clusters to their metabolites. We also highlight other natural products that are produced through analogous biosynthetic logic and comment on some current disconnects between bioinformatics predictions and experimental structural characterizations. Lastly, we describe the use of pathway-targeted molecular networking as a tool to characterize secondary metabolic pathways within complex metabolomes and to aid in downstream metabolite structural elucidation efforts.

Keywords:

Biosynthesis, Colibactin, Pathway-Targeted Molecular Networking

Affiliation:

Department of Chemistry, Faculty of Yale University, P.O. Box: 27392, West Haven, CT, 06516, USA

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The Unexpected Advantages of Using D-Amino Acids for Peptide Self- Assembly into Nanostructured Hydrogels for Medicine

Author(s):

Michele Melchionna, Katie E. Styan and Silvia MarchesanPages 2009-2018 (10)

Abstract:


Self-assembled peptide hydrogels have brought innovation to the medicinal field, not only as responsive biomaterials but also as nanostructured therapeutic agents or as smart drug delivery systems. D-amino acids are typically introduced to increase the peptide enzymatic stability. However, there are several reports of unexpected effects on peptide conformation, self-assembly behavior, cytotoxicity and even therapeutic activity. This mini-review discusses all the surprising twists of heterochiral self-assembled peptide hydrogels, and delineates emerging key findings to exploit all the benefits of D-amino acids in this novel medicinal area.

Keywords:

Chirality, D-Amino acids, Enantiomers, Heterochiral, Hydrogels, Nanomaterials, Peptides, Self-assembly.

Affiliation:

Department of Chemical and Pharmaceutical Sciences, University of Trieste, 34127 Trieste, Italy.

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