Localisation of the human hSuv3p helicase in the mitochondrial matrix and its preferential unwinding of dsDNA

We characterised the human hSuv3p protein belonging to the family of NTPases/helicases. In yeast mitochondria the hSUV3 orthologue is a component of the degradosome complex and participates in mtRNA turnover and processing, while in Caenorhabditis elegans the hSUV3 orthologue is necessary for viability of early embryos. Using immunofluorescence analysis, an in vitro mitochondrial uptake assay and sub‐fractionation of human mitochondria we show hSuv3p to be a soluble protein localised in the mitochondrial matrix. We expressed and purified recombinant hSuv3p protein from a bacterial expression system. The purified enzyme was capable of hydrolysing ATP with a Km of 41.9 µM and the activity was only modestly stimulated by polynucleotides. hSuv3p unwound partly hybridised dsRNA and dsDNA structures with a very strong preference for the latter. The presented analysis of the hSuv3p NTPase/helicase suggests that new functions of the protein have been acquired in the course of evolution

Lythrum salicaria Ellagitannins Stimulate IPEC-J2 Cells Monolayer Formation and Inhibit Enteropathogenic Escherichia coli Growth and Adhesion

Lythrum salicaria herb (LSH) was applied in diarrhea therapy since ancient times. Despite empirically referenced therapeutic effects, the bioactivity mechanisms and chemical constituents responsible for pharmacological activity remain not fully resolved. Taking into consideration the historical use of LSH in treatment of diarrhea in humans and farm animals, the aim of the study was to examine in vitro the influence of LSH and its C-glycosylic ellagitannins on processes associated with maintaining intestinal epithelium integrity and enteropathogenic Escherichia coli (EPEC) growth and adhesion. LSH was not only inhibiting EPEC growth in a concentration dependent manner but also its adhesion to IPEC-J2 intestinal epithelial cell monolayers. Inhibitory activity toward EPEC growth was additionally confirmed ex vivo in distal colon samples of postweaning piglets. LSH and its dominating C-glycosylic ellagitannins, castalagin (1), vescalagin (2), and salicarinins A (3) and B (4) were stimulating IPEC-J2 monolayer formation by enhancing claudin 4 production. Parallelly tested gut microbiota metabolites of LSH ellagitannins, urolithin C (5), urolithin A (6), and its glucuronides (7) were inactive. The activities of LSH and the isolated ellagitannins support its purported antidiarrheal properties and indicate potential mechanisms responsible for its beneficial influence on the intestinal epithelium

Concepts and Their Dynamics: A Quantum-Theoretic Modeling of Human Thought

We analyze different aspects of our quantum modeling approach of human concepts, and more specifically focus on the quantum effects of contextuality, interference, entanglement and emergence, illustrating how each of them makes its appearance in specific situations of the dynamics of human concepts and their combinations. We point out the relation of our approach, which is based on an ontology of a concept as an entity in a state changing under influence of a context, with the main traditional concept theories, i.e. prototype theory, exemplar theory and theory theory. We ponder about the question why quantum theory performs so well in its modeling of human concepts, and shed light on this question by analyzing the role of complex amplitudes, showing how they allow to describe interference in the statistics of measurement outcomes, while in the traditional theories statistics of outcomes originates in classical probability weights, without the possibility of interference. The relevance of complex numbers, the appearance of entanglement, and the role of Fock space in explaining contextual emergence, all as unique features of the quantum modeling, are explicitly revealed in this paper by analyzing human concepts and their dynamics.Comment: 31 pages, 5 figure

Comparative studies of urolithins and their phase II metabolites on macrophage and neutrophil functions

Purpose Ellagitannins are high molecular weight polyphenols present in high quantities in various food products. They are metabolized by human and animal gut microbiota to postbiotic metabolites-urolithins, bioavailable molecules of a low molecular weight. Following absorption in the gut, urolithins rapidly undergo phase II metabolism. Thus, to fully evaluate the mechanisms of their biological activity, the in vitro studies should be conducted for their phase II conjugates, mainly glucuronides. The aim of the study was to comparatively determine the influence of urolithin A, iso-urolithin A, and urolithin B together with their respective glucuronides on processes associated with the inflammatory response. Methods The urolithins obtained by chemical synthesis or isolation from microbiota cultures were tested with their respective glucuronides isolated from human urine towards modulation of inflammatory response in THP-1-derived macrophages, RAW 264.7 macrophages, PBMCs-derived macrophages, and primary neutrophils. Results Urolithin A was confirmed to be the most active metabolite in terms of LPS-induced inflammatory response inhibition (TNF-alpha attenuation, IL-10 induction). The observed strong induction of ERK1/2 phosphorylation has been postulated as the mechanism of its action. None of the tested glucuronide conjugates was active in terms of pro-inflammatory TNF-alpha inhibition and anti-inflammatory IL-10 and TGF-beta 1 induction. Conclusion Comparative studies of the most abundant urolithins and their phase II conjugates conducted on human and murine immune cells unambiguously confirmed urolithin A to be the most active metabolite in terms of inhibition of the inflammatory response. Phase II metabolism was shown to result in the loss of urolithins' pharmacological properties

Therapeutic Effects of Oral Application of Menthol and Extracts from Tormentil (Potentilla erecta), Raspberry Leaves (Rubus idaeus), and Loosestrife (Lythrum salicaria) during Acute Murine Campylobacteriosis

Human food-borne infections with the enteropathogen Campylobacter jejuni are becoming increasingly prevalent worldwide. Since antibiotics are usually not indicated in campylobacteriosis, alternative treatment regimens are important. We here investigated potential disease-alleviating effects of menthol and of extracts from tormentil, raspberry leaves, and loosestrife in acute murine campylobacteriosis. Therefore, C. jejuni-infected microbiota-depleted IL-10−/− mice were orally treated with the compounds alone or all in combination from day 2 until day 6 post-infection. Whereas neither treatment regimen affected gastrointestinal pathogen loads, the combination of compounds alleviated C. jejuni-induced diarrheal symptoms in diseased mice on day 6 post-infection. Furthermore, the therapeutic application of tormentil and menthol alone and the combination of the four compounds resulted in lower colonic T cell numbers in infected mice when compared to placebo counterparts. Notably, pro-inflammatory cytokines measured in mesenteric lymph nodes taken from C. jejuni-infected mice following tormentil, menthol, and combination treatment did not differ from basal concentrations. However, neither treatment regimen could dampen extra-intestinal immune responses, including systemic pro-inflammatory cytokine secretion on day 6 post-infection. In conclusion, the combination of menthol and of extracts from tormentil, raspberry leaves, and loosestrife constitutes an antibiotic-independent approach to alleviate campylobacteriosis symptoms

Human mitochondrial RNA turnover caught in flagranti: involvement of hSuv3p helicase in RNA surveillance

The mechanism of human mitochondrial RNA turnover and surveillance is still a matter of debate. We have obtained a cellular model for studying the role of hSuv3p helicase in human mitochondria. Expression of a dominant-negative mutant of the hSUV3 gene which encodes a protein with no ATPase or helicase activity results in perturbations of mtRNA metabolism and enables to study the processing and degradation intermediates which otherwise are difficult to detect because of their short half-lives. The hSuv3p activity was found to be necessary in the regulation of stability of mature, properly formed mRNAs and for removal of the noncoding processing intermediates transcribed from both H and L-strands, including mirror RNAs which represent antisense RNAs transcribed from the opposite DNA strand. Lack of hSuv3p function also resulted in accumulation of aberrant RNA species, molecules with extended poly(A) tails and degradation intermediates truncated predominantly at their 3′-ends. Moreover, we present data indicating that hSuv3p co-purifies with PNPase; this may suggest participation of both proteins in mtRNA metabolism

Novel AlkB Dioxygenases—Alternative Models for In Silico and In Vivo Studies

Background: ALKBH proteins, the homologs of Escherichia coli AlkB dioxygenase, constitute a direct, single-protein repair system, protecting cellular DNA and RNA against the cytotoxic and mutagenic activity of alkylating agents, chemicals significantly contributing to tumor formation and used in cancer therapy. In silico analysis and in vivo studies have shown the existence of AlkB homologs in almost all organisms. Nine AlkB homologs (ALKBH1–8 and FTO) have been identified in humans. High ALKBH levels have been found to encourage tumor development, questioning the use of alkylating agents in chemotherapy. The aim of this work was to assign biological significance to multiple AlkB homologs by characterizing their activity in the repair of nucleic acids in prokaryotes and their subcellular localization in eukaryotes. Methodology and Findings: Bioinformatic analysis of protein sequence databases identified 1943 AlkB sequences with eight new AlkB subfamilies. Since Cyanobacteria and Arabidopsis thaliana contain multiple AlkB homologs, they were selected as model organisms for in vivo research. Using E. coli alkB2 mutant and plasmids expressing cyanobacterial AlkBs, we studied the repair of methyl methanesulfonate (MMS) and chloroacetaldehyde (CAA) induced lesions in ssDNA, ssRNA, and genomic DNA. On the basis of GFP fusions, we investigated the subcellular localization of ALKBHs in A. thaliana and established its mostly nucleo-cytoplasmic distribution. Some of the ALKBH proteins were found to change their localization upon MMS treatment. Conclusions: Our in vivo studies showed highly specific activity of cyanobacterial AlkB proteins towards lesions and nucleic acid type. Subcellular localization and translocation of ALKBHs in A. thaliana indicates a possible role for these proteins in the repair of alkyl lesions. We hypothesize that the multiplicity of ALKBHs is due to their involvement in the metabolism of nucleo-protein complexes; we find their repair by ALKBH proteins to be economical and effective alternative to degradation and de novo synthesis

Mind the Gap: Transitions Between Concepts of Information in Varied Domains

The concept of 'information' in five different realms – technological, physical, biological, social and philosophical – is briefly examined. The 'gaps' between these conceptions are dis‐ cussed, and unifying frameworks of diverse nature, including those of Shannon/Wiener, Landauer, Stonier, Bates and Floridi, are examined. The value of attempting to bridge the gaps, while avoiding shallow analogies, is explained. With information physics gaining general acceptance, and biology gaining the status of an information science, it seems rational to look for links, relationships, analogies and even helpful metaphors between them and the library/information sciences. Prospects for doing so, involving concepts of complexity and emergence, are suggested

Resolvins suppress tumor growth and enhance cancer therapy

National Cancer Institute grants RO1 01CA170549-02 (to D. Panigrahy and C.N. Serhan), ROCA148633-01A4 (to D. Panigrahy), and GM095467 (to C.N. Serhan); the Stop and Shop Pediatric Brain Tumor Fund (to M.W. Kieran); the CJ Buckley Pediatric Brain Tumor Fund (to M.W. Kieran); Alex Lemonade Stand (to M.W. Kieran); Molly’s Magic Wand for Pediatric Brain Tumors (to M.W. Kieran); the Markoff Foundation Art-In-Giving Foundation (to M.W. Kieran); the Kamen Foundation (to M.W. Kieran); Jared Branfman Sunflowers for Life (to M.W.K.); and The Wellcome Trust program 086867/Z/08 (to M. Perretti)