898 research outputs found
Ergothioneine: an underrecognised dietary micronutrient required for healthy ageing?
Ergothioneine is a naturally occurring amino acid and thiol antioxidant found in high amounts in mushrooms and fermented foods. Humans and animals acquire ergothioneine from the diet through the pH-dependent activity of a membrane transporter, the large solute carrier 22A member 4 (SLC22A4), expressed on the apical membrane of the small intestine. The SLC22A4 transporter also functions in the renal reabsorption of ergothioneine in the kidney, with avid absorption and retention of ergothioneine from the diet observed in both animals and humans. Ergothioneine is capable of scavenging a diverse range of reactive oxygen and nitrogen species, has metal chelation properties, and is predicted to directly regulate nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Although not lethal, the genetic knockout of the SLC22A4 gene in multiple organisms increases susceptibility to oxidative stress, damage and inflammation; in agreement with a large body of preclinical data suggesting the physiological function of ergothioneine is as a cellular antioxidant and cytoprotectant agent. In humans, blood levels of ergothioneine decline after the age of 60 years, and lower levels of ergothioneine are associated with more rapid cognitive decline. Conversely, high plasma ergothioneine levels have been associated with significantly reduced cardiovascular mortality and overall mortality risks. In this horizon’s manuscript, we review evidence suggesting critical roles for dietary ergothioneine in healthy ageing and the prevention of cardiometabolic disease. We comment on some of the outstanding research questions in the field and consider the question of whether or not ergothioneine should be considered a conditionally essential micronutrient
Weekend admission and mortality for gastrointestinal disorders across England and Wales
BACKGROUND: Little has been reported on mortality following admissions at weekends for many gastrointestinal (GI) disorders. The aim was to establish whether GI disorders are susceptible to increased mortality following unscheduled admission on weekends compared with weekdays. METHODS: Record linkage was undertaken of national administrative inpatient and mortality data for people in England and Wales who were hospitalized as an emergency for one of 19 major GI disorders. RESULTS: The study included 2 254 701 people in England and 155 464 in Wales. For 11 general surgical and medical GI disorders there were little, or no, significant weekend effects on mortality at 30 days in either country. There were large consistent weekend effects in both countries for severe liver disease (England: 26·2 (95 per cent c.i. 21·1 to 31·6) per cent; Wales: 32·0 (12·4 to 55·1 per cent) and GI cancer (England: 21·8 (19·1 to 24·5) per cent; Wales: 25·0 (15·0 to 35·9) per cent), which were lower in patients managed by surgeons. Admission rates were lower at weekends than on weekdays, most strongly for severe liver disease (by 43·3 per cent in England and 51·4 per cent in Wales) and GI cancer (by 44·6 and 52·8 per cent respectively). Both mortality and the weekend mortality effect for GI cancer were lower for patients managed by surgeons. DISCUSSION: There is little, or no, evidence of a weekend mortality effect for most major general surgical or medical GI disorders, but large weekend effects for GI cancer and severe liver disease. Lower admission rates at weekends indicate more severe cases. The findings for severe liver disease may suggest a lack of specialist hepatological resources. For cancers, reduced availability of end-of-life care in the community at weekends may be the cause
MaxAlign: maximizing usable data in an alignment
<p>Abstract</p> <p>Background</p> <p>The presence of gaps in an alignment of nucleotide or protein sequences is often an inconvenience for bioinformatical studies. In phylogenetic and other analyses, for instance, gapped columns are often discarded entirely from the alignment.</p> <p>Results</p> <p>MaxAlign is a program that optimizes the alignment prior to such analyses. Specifically, it maximizes the number of nucleotide (or amino acid) symbols that are present in gap-free columns – the alignment area – by selecting the optimal subset of sequences to exclude from the alignment.</p> <p>MaxAlign can be used prior to phylogenetic and bioinformatical analyses as well as in other situations where this form of alignment improvement is useful. In this work we test MaxAlign's performance in these tasks and compare the accuracy of phylogenetic estimates including and excluding gapped columns from the analysis, with and without processing with MaxAlign. In this paper we also introduce a new simple measure of tree similarity, Normalized Symmetric Similarity (NSS) that we consider useful for comparing tree topologies.</p> <p>Conclusion</p> <p>We demonstrate how MaxAlign is helpful in detecting misaligned or defective sequences without requiring manual inspection. We also show that it is not advisable to exclude gapped columns from phylogenetic analyses unless MaxAlign is used first. Finally, we find that the sequences removed by MaxAlign from an alignment tend to be those that would otherwise be associated with low phylogenetic accuracy, and that the presence of gaps in any given sequence does not seem to disturb the phylogenetic estimates of <it>other </it>sequences.</p> <p>The MaxAlign web-server is freely available online at http://www.cbs.dtu.dk/services/MaxAlign where supplementary information can also be found. The program is also freely available as a Perl stand-alone package.</p
Phytosterols Inhibit Side-Chain Oxysterol Mediated Activation of LXR in Breast Cancer Cells
Low fruit and vegetable consumption and high saturated fat consumption causes elevated circulating cholesterol and are breast cancer risk factors. During cholesterol metabolism, oxysterols form that bind and activate the liver X receptors (LXRs). Oxysterols halt breast cancer cell proliferation but enhance metastatic colonization, indicating tumour suppressing and promoting roles. Phytosterols and phytostanols in plants, like cholesterol in mammals, are essential components of the plasma membrane and biochemical precursors, and in human cells can alter LXR transcriptional activity. Here, a panel of breast cancer cell lines were treated with four dietary plant sterols and a stanol, alone or in combination with oxysterols. LXR activation and repression were measured by gene expression and LXR-luciferase reporter assays. Oxysterols activated LXR in all cell lines, but surprisingly phytosterols failed to modulate LXR activity. However, phytosterols significantly inhibited the ability of oxysterols to drive LXR transcription. These data support a role for phytosterols in modulating cancer cell behaviour via LXR, and therefore suggest merit in accurate dietary recordings of these molecules in cancer patients during treatment and perhaps supplementation to benefit recovery
Characterization and prognostic value of LXR splice variants in triple-negative breast cancer
Activity of liver x receptor (LXR), the homeostatic regulator of cholesterol metabolism, is elevated in triple-negative breast cancer (BCa) relative to other BCa subtypes, driving drug resistance and metastatic gene signatures. The loci encoding LXRα and LXRβ produce multiple alternatively spliced proteins, but the true range of variants and their relevance to cancer remain poorly defined. Here, we report seven LXR splice variants, three of which have not previously been reported and five that were prognostic for disease-free survival. Expression of full-length LXRα splice variants was associated with poor prognosis, consistent with a role as an oncogenic driver of triple-negative tumor pathophysiology. Contrary to this was the observation that high expression of truncated LXRα splice variants or any LXRβ splice variant was associated with longer survival. These findings indicate that LXR isoform abundance is an important aspect of understanding the link between dysregulated cholesterol metabolism and cancer pathophysiology
Higher Dimensional Cylindrical or Kasner Type Electrovacuum Solutions
We consider a D dimensional Kasner type diagonal spacetime where metric
functions depend only on a single coordinate and electromagnetic field shares
the symmetries of spacetime. These solutions can describe static cylindrical or
cosmological Einstein-Maxwell vacuum spacetimes. We mainly focus on
electrovacuum solutions and four different types of solutions are obtained in
which one of them has no four dimensional counterpart. We also consider the
properties of the general solution corresponding to the exterior field of a
charged line mass and discuss its several properties. Although it resembles the
same form with four dimensional one, there is a difference on the range of the
solutions for fixed signs of the parameters. General magnetic field vacuum
solution are also briefly discussed, which reduces to Bonnor-Melvin magnetic
universe for a special choice of the parameters. The Kasner forms of the
general solution are also presented for the cylindrical or cosmological cases.Comment: 16 pages, Revtex. Text and references are extended, Published versio
Evolutionary distances in the twilight zone -- a rational kernel approach
Phylogenetic tree reconstruction is traditionally based on multiple sequence
alignments (MSAs) and heavily depends on the validity of this information
bottleneck. With increasing sequence divergence, the quality of MSAs decays
quickly. Alignment-free methods, on the other hand, are based on abstract
string comparisons and avoid potential alignment problems. However, in general
they are not biologically motivated and ignore our knowledge about the
evolution of sequences. Thus, it is still a major open question how to define
an evolutionary distance metric between divergent sequences that makes use of
indel information and known substitution models without the need for a multiple
alignment. Here we propose a new evolutionary distance metric to close this
gap. It uses finite-state transducers to create a biologically motivated
similarity score which models substitutions and indels, and does not depend on
a multiple sequence alignment. The sequence similarity score is defined in
analogy to pairwise alignments and additionally has the positive semi-definite
property. We describe its derivation and show in simulation studies and
real-world examples that it is more accurate in reconstructing phylogenies than
competing methods. The result is a new and accurate way of determining
evolutionary distances in and beyond the twilight zone of sequence alignments
that is suitable for large datasets.Comment: to appear in PLoS ON
Ergothioneine supplementation in people with metabolic syndrome (ErgMS): protocol for a randomised, double-blind, placebo-controlled pilot study
Background
Ergothioneine is a naturally occurring metabolite of histidine found in many foods and in high amounts in mushrooms. In vivo, ergothioneine acts as an antioxidant and is widely distributed in most mammalian tissues. While ergothioneine is sold as a dietary supplement for its antioxidant and anti-inflammatory properties, to date there are no published intervention trials examining its health benefits in humans. The aim of this work was to develop a study protocol for a pilot interventional trial that will establish the primary and secondary outcomes, and the power required, for a definitive randomised controlled trial to test the hypothesis that ergothioneine supplementation is beneficial for people with metabolic syndrome.
Methods
We have designed the ErgMS study as a single-centre, randomised, double-blind, placebo-controlled, 3-arm parallel, pilot intervention trial, which aims to supplement participants with either placebo, 5 or 30 mg/day ergothioneine for 12 weeks. Measurements of metabolic syndrome risk factors, serum markers of oxidative stress (lipid peroxidation), inflammation, blood platelet function and liver function will take place at baseline, and after 6 weeks and 12 weeks of supplementation. In addition, we will examine if there are any changes in the serum metabolome in response to ergothioneine supplementation. Linear regression and two-way ANOVA will be utilised to analyse the association between ergothioneine and measured variables.
Discussion
The ErgMS study will be the first study to address the question does ergothioneine supplementation have health benefits for people with metabolic syndrome. Study results will provide preliminary data as to which dose may improve inflammatory markers in adults with metabolic syndrome and will inform dose and primary outcome selection for a definitive randomised controlled trial.
Trial registration
ISRCTN, ISRCTN25890011 Registered February 10th, 202
Phytosterols and phytostanols and the hallmarks of cancer in model organisms: a systematic review and meta-analysis
Phytosterols and phytostanols are natural products present in vegetable oils, nuts, and seeds, or added to consumer food products whose intake is inversely associated with incidence and prognosis of several cancers. Randomized cancer prevention trials in humans are unfeasible due to time and cost yet the cellular processes and signaling cascades that underpin anti-cancer effects of these phytochemicals have been explored extensively in vitro and in preclinical in vivo models. Here we have performed an original systematic review, meta-analysis, and qualitative interpretation of literature published up to June 2020. MEDLINE, Scopus, and hand-searching identified 408 unique records that were screened leading to 32 original articles that had investigated the effects of phytosterols or phytostanols on cancer biology in preclinical models. Data was extracted from 22 publications for meta-analysis. Phytosterols were most commonly studied and found to reduce primary and metastatic tumor burden in all cancer sites evaluated. Expression of pAKT, and markers of metastasis (alkaline phosphatase, matrix metalloproteases, epithelial to mesenchymal transcription factors, lung and brain colonization), angiogenesis (vascular endothelial growth factor, CD31), and proliferation (Ki67, proliferating cell nuclear antigen) were consistently reduced by phytosterol treatment in breast and colorectal cancer. Very high dose treatment (equivalent to 0.2–1 g/kg body weight not easily achievable through diet or supplementation in humans) was associated with adverse events including poor gut health and intestinal adenoma development. Phytosterols and phytostanols are already clinically recommended for cardiovascular disease risk reduction, and represent promising anti-cancer agents that could be delivered in clinic and to the general population at low cost, with a well understood safety profile, and now with a robust understanding of mechanism-of-action
Accurate reconstruction of insertion-deletion histories by statistical phylogenetics
The Multiple Sequence Alignment (MSA) is a computational abstraction that
represents a partial summary either of indel history, or of structural
similarity. Taking the former view (indel history), it is possible to use
formal automata theory to generalize the phylogenetic likelihood framework for
finite substitution models (Dayhoff's probability matrices and Felsenstein's
pruning algorithm) to arbitrary-length sequences. In this paper, we report
results of a simulation-based benchmark of several methods for reconstruction
of indel history. The methods tested include a relatively new algorithm for
statistical marginalization of MSAs that sums over a stochastically-sampled
ensemble of the most probable evolutionary histories. For mammalian
evolutionary parameters on several different trees, the single most likely
history sampled by our algorithm appears less biased than histories
reconstructed by other MSA methods. The algorithm can also be used for
alignment-free inference, where the MSA is explicitly summed out of the
analysis. As an illustration of our method, we discuss reconstruction of the
evolutionary histories of human protein-coding genes.Comment: 28 pages, 15 figures. arXiv admin note: text overlap with
arXiv:1103.434
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