Dietary zinc and the control of Streptococcus pneumoniae infection

© 2019 Eijkelkamp et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Human zinc deficiency increases susceptibility to bacterial infection. Although zinc supplementation therapies can reduce the impact of disease, the molecular basis for protection remains unclear. Streptococcus pneumoniae is a major cause of bacterial pneumonia, which is prevalent in regions of zinc deficiency. We report that dietary zinc levels dictate the outcome of S. pneumoniae infection in a murine model. Dietary zinc restriction impacts murine tissue zinc levels with distribution post-infection altered, and S. pneumoniae virulence and infection enhanced. Although the activation and infiltration of murine phagocytic cells was not affected by zinc restriction, their efficacy of bacterial control was compromised. S. pneumoniae was shown to be highly sensitive to zinc intoxication, with this process impaired in zinc restricted mice and isolated phagocytic cells. Collectively, these data show how dietary zinc deficiency increases sensitivity to S. pneumoniae infection while revealing a role for zinc as a component of host antimicrobial defences

Modelling the impact of improving screening and treatment of chronic hepatitis C virus infection on future hepatocellular carcinoma rates and liver-related mortality.

BACKGROUND: The societal, clinical and economic burden imposed by the complications of chronic hepatitis C virus (HCV) infection - including cirrhosis and hepatocellular carcinoma (HCC) - is expected to increase over the coming decades. However, new therapies may improve sustained virological response (SVR) rates and shorten treatment duration. This study aimed to estimate the future burden of HCV-related disease in England if current management strategies remain the same and the impact of increasing diagnosis and treatment of HCV as new therapies become available. METHODS: A previously published model was adapted for England using published literature and government reports, and validated through an iterative process of three meetings of HCV experts. The impact of increasing diagnosis and treatment of HCV as new therapies become available was modelled and compared to the base-case scenario of continuing current management strategies. To assess the 'best case' clinical benefit of new therapies, the number of patients treated was increased by a total of 115% by 2018. RESULTS: In the base-case scenario, total viraemic (HCV RNA-positive) cases of HCV in England will decrease from 144,000 in 2013 to 76,300 in 2030. However, due to the slow progression of chronic HCV, the number of individuals with cirrhosis, decompensated cirrhosis and HCC will continue to increase over this period. The model suggests that the 'best case' substantially reduces HCV-related hepatic disease and HCV-related liver mortality by 2020 compared to the base-case scenario. The number of HCV-related HCC cases would decrease 50% by 2020 and the number progressing from infection to decompensated cirrhosis would decline by 65%. Therefore, compared to projections of current practices, increasing treatment numbers by 115% by 2018 would reduce HCV-related mortality by 50% by 2020. CONCLUSIONS: This analysis suggests that with current treatment practices the number of patients developing HCV-related cirrhosis, decompensated cirrhosis and HCC will increase substantially, with HCV-related liver deaths likely to double by 2030. However, increasing diagnosis and treatment rates could optimise the reduction in the burden of disease produced by the new therapies, potentially halving HCV-related liver mortality and HCV-related HCC by 2020

Amino Acid Usage Is Asymmetrically Biased in AT- and GC-Rich Microbial Genomes.

INTRODUCTION: Genomic base composition ranges from less than 25% AT to more than 85% AT in prokaryotes. Since only a small fraction of prokaryotic genomes is not protein coding even a minor change in genomic base composition will induce profound protein changes. We examined how amino acid and codon frequencies were distributed in over 2000 microbial genomes and how these distributions were affected by base compositional changes. In addition, we wanted to know how genome-wide amino acid usage was biased in the different genomes and how changes to base composition and mutations affected this bias. To carry this out, we used a Generalized Additive Mixed-effects Model (GAMM) to explore non-linear associations and strong data dependences in closely related microbes; principal component analysis (PCA) was used to examine genomic amino acid- and codon frequencies, while the concept of relative entropy was used to analyze genomic mutation rates. RESULTS: We found that genomic amino acid frequencies carried a stronger phylogenetic signal than codon frequencies, but that this signal was weak compared to that of genomic %AT. Further, in contrast to codon usage bias (CUB), amino acid usage bias (AAUB) was differently distributed in AT- and GC-rich genomes in the sense that AT-rich genomes did not prefer specific amino acids over others to the same extent as GC-rich genomes. AAUB was also associated with relative entropy; genomes with low AAUB contained more random mutations as a consequence of relaxed purifying selection than genomes with higher AAUB. CONCLUSION: Genomic base composition has a substantial effect on both amino acid- and codon frequencies in bacterial genomes. While phylogeny influenced amino acid usage more in GC-rich genomes, AT-content was driving amino acid usage in AT-rich genomes. We found the GAMM model to be an excellent tool to analyze the genomic data used in this study

Stimulation of Host Immune Defenses by a Small Molecule Protects C. elegans from Bacterial Infection

The nematode Caenorhabditis elegans offers currently untapped potential for carrying out high-throughput, live-animal screens of low molecular weight compound libraries to identify molecules that target a variety of cellular processes. We previously used a bacterial infection assay in C. elegans to identify 119 compounds that affect host-microbe interactions among 37,214 tested. Here we show that one of these small molecules, RPW-24, protects C. elegans from bacterial infection by stimulating the host immune response of the nematode. Using transcriptome profiling, epistasis pathway analyses with C. elegans mutants, and an RNAi screen, we show that RPW-24 promotes resistance to Pseudomonas aeruginosa infection by inducing the transcription of a remarkably small number of C. elegans genes (∼1.3% of all genes) in a manner that partially depends on the evolutionarily-conserved p38 MAP kinase pathway and the transcription factor ATF-7. These data show that the immunostimulatory activity of RPW-24 is required for its efficacy and define a novel C. elegans–based strategy to identify compounds with activity against antibiotic-resistant bacterial pathogens

Evidence That Mutation Is Universally Biased towards AT in Bacteria

Mutation is the engine that drives evolution and adaptation forward in that it generates the variation on which natural selection acts. Mutation is a random process that nevertheless occurs according to certain biases. Elucidating mutational biases and the way they vary across species and within genomes is crucial to understanding evolution and adaptation. Here we demonstrate that clonal pathogens that evolve under severely relaxed selection are uniquely suitable for studying mutational biases in bacteria. We estimate mutational patterns using sequence datasets from five such clonal pathogens belonging to four diverse bacterial clades that span most of the range of genomic nucleotide content. We demonstrate that across different types of sites and in all four clades mutation is consistently biased towards AT. This is true even in clades that have high genomic GC content. In all studied cases the mutational bias towards AT is primarily due to the high rate of C/G to T/A transitions. These results suggest that bacterial mutational biases are far less variable than previously thought. They further demonstrate that variation in nucleotide content cannot stem entirely from variation in mutational biases and that natural selection and/or a natural selection-like process such as biased gene conversion strongly affect nucleotide content

VANG-1 and PRKL-1 Cooperate to Negatively Regulate Neurite Formation in Caenorhabditis elegans

Neuritogenesis is a critical early step in the development and maturation of neurons and neuronal circuits. While extracellular directional cues are known to specify the site and orientation of nascent neurite formation in vivo, little is known about the genetic pathways that block inappropriate neurite emergence in order to maintain proper neuronal polarity. Here we report that the Caenorhabditis elegans orthologues of Van Gogh (vang-1), Prickle (prkl-1), and Dishevelled (dsh-1), core components of planar cell polarity (PCP) signaling, are required in a subset of peripheral motor neurons to restrict neurite emergence to a specific organ axis. In loss-of-function mutants, neurons display supernumerary neurites that extend inappropriately along the orthogonal anteroposterior (A/P) body axis. We show that autonomous and non-autonomous gene activities are required early and persistently to inhibit the formation or consolidation of growth cone protrusions directed away from organ precursor cells. Furthermore, prkl-1 overexpression is sufficient to suppress neurite formation and reorient neuronal polarity in a vang-1– and dsh-1–dependent manner. Our findings suggest a novel role for a PCP–like pathway in maintaining polarized neuronal morphology by inhibiting neuronal responses to extrinsic or intrinsic cues that would otherwise promote extraneous neurite formation

Omega-3 fatty acids and vitamin D in immobilisation: Part A - Modulation of appendicular mass content, composition and structure

Objectives: Muscle size decreases in response to short-term limb immobilisation. This study set out to determine whether two potential protein-sparing modulators (eicosapentaenoic acid and vitamin D) would attenuate immobilisation-induced changes in muscle characteristics. Design: The study used a randomised, double-blind, placebo-controlled design. Setting: The study took part in a laboratory setting. Participants: Twenty-four male and female healthy participants, aged 23.0±5.8 years. Intervention: The non-dominant arm was immobilised in a sling for a period of nine waking hours a day over two continuous weeks. Participants were randomly assigned to one of three groups: placebo (n=8, Lecithin, 2400 mg daily), omega-3 (ω-3) fatty acids (n=8, eicosapentaenoic acid (EPA); 1770 mg, and docosahexaenoic acid (DHA); 390 mg, daily) or vitamin D (n=8, 1,000 IU daily). Measurements: Muscle and sub-cutaneous adipose thickness (B-mode ultrasonography), body composition (DXA) and arm girth (anthropometry) were measured before immobilisation, immediately on removal of the sling and two weeks after re-mobilisation. Results: Muscle thickness (-5.4±4.3%), upper and lower arm girth (-1.3±0.4 and -0.8±0.8%, respectively), lean mass (-3.6±3.7%) and bone mineral content (BMC) (-2.3±1.5%) decreased significantly with limb immobilisation in the placebo group (P0.05) towards attenuating the decreases in muscle thickness, upper/lower arm girths and BMC observed in the placebo group. The ω-3 supplementation group demonstrated a non-significant attenuation of the decrease in DXA quantified lean mass observed in the placebo group. Sub-cutaneous adipose thickness increased in the placebo group (P<0.05). ω-3 and vitamin D both blunted this response, with ω-3 having a greater effect (P<0.05). All parameters had returned to baseline values at the re-mobilisation phase of the study. Conclusion: Overall, at the current doses, ω-3 and vitamin D supplementation only attenuated one of the changes associated with non-injurious limb immobilisation. These findings would necessitate further research into either a) supplementation linked to injury-induced immobilisation, or b) larger doses of these supplements to confirm/refute the physiological reserve potential of the two supplements

Nothing Lasts Forever: Environmental Discourses on the Collapse of Past Societies

The study of the collapse of past societies raises many questions for the theory and practice of archaeology. Interest in collapse extends as well into the natural sciences and environmental and sustainability policy. Despite a range of approaches to collapse, the predominant paradigm is environmental collapse, which I argue obscures recognition of the dynamic role of social processes that lie at the heart of human communities. These environmental discourses, together with confusion over terminology and the concepts of collapse, have created widespread aporia about collapse and resulted in the creation of mixed messages about complex historical and social processes

Omega-3 fatty acids and vitamin D in immobilisation: Part B- modulation of muscle functional, vascular and activation profiles

Abstract Objectives: This study set out to determine whether two potential protein-sparing modulators (eicosapentaenoic acid and vitamin D) would modulate the anticipated muscle functional and related blood vessels function deleterious effects of immobilisation. Design: The study used a randomised, double-blind, placebo-controlled design. Setting: The study took part in a laboratory setting. Participants: Twenty-four male and female healthy participants, aged 23.0±5.8 years. Intervention: The non-dominant arm was immobilised in a sling for a period of nine waking hours a day over two continuous weeks. Participants were randomly assigned to one of three groups: placebo (n=8, Lecithin, 2400 mg daily), omega-3 (-3) fatty acids (n=8, eicosapentaenoic acid (EPA); 1770 mg, and docosahexaenoic acid (DHA); 390 mg DHA, daily) or vitamin D (n=8, 1,000 IU daily). Measurements: Isometric and isokinetic torque, antagonist muscle co-contraction (activation profile), muscle fatigability indices, and arterial resting blood flow were measured before, at the end of the immobilisation period, and two weeks after re-mobilisation. Results: Muscle elbow flexion and extension isometric and isokinetic torque decreased significantly with limb immobilisation in the placebo group (P0.05) towards attenuating the decreases observed in the placebo group. There was no significant change in muscle fatigue parameters or co-contraction values with immobilisation and no effect of supplementation group (P>0.05). Similarly, this immobilisation model had no impact on the assessed blood flow kinetics. All parameters had returned to baseline values at the re-mobilisation phase of the study. Conclusion: Overall, at the current doses, neither -3 nor vitamin D supplementation significantly attenuated declines in torque associated with immobilisation. It would appear that muscle function (described here in Part B) might not be as useful a marker of the effectiveness of a supplement against the impact of immobilisation compared to tissue composition changes (described in Part A)