Choline-stabilized orthosilicic acid supplementation as an adjunct to calcium/vitamin D3 stimulates markers of bone formation in osteopenic females: a randomized, placebo-controlled trial.

BACKGROUND: Mounting evidence supports a physiological role for silicon (Si) as orthosilicic acid (OSA, Si(OH)4) in bone formation. The effect of oral choline-stabilized orthosilicic acid (ch-OSA) on markers of bone turnover and bone mineral density (BMD) was investigated in a double-blind placebo-controlled trial. METHODS: Over 12-months, 136 women out of 184 randomized (T-score spine < -1.5) completed the study and received, daily, 1000 mg Ca and 20 microg cholecalciferol (Vit D3) and three different ch-OSA doses (3, 6 and 12 mg Si) or placebo. Bone formation markers in serum and urinary resorption markers were measured at baseline, and after 6 and 12 months. Femoral and lumbar BMD were measured at baseline and after 12 months by DEXA. RESULTS: Overall, there was a trend for ch-OSA to confer some additional benefit to Ca and Vit D3 treatment, especially for markers of bone formation, but only the marker for type I collagen formation (PINP) was significant at 12 months for the 6 and 12 mg Si dose (vs. placebo) without a clear dose response effect. A trend for a dose-corresponding increase was observed in the bone resorption marker, collagen type I C-terminal telopeptide (CTX-I). Lumbar spine BMD did not change significantly. Post-hoc subgroup analysis (baseline T-score femur < -1) however was significant for the 6 mg dose at the femoral neck (T-test). There were no ch-OSA related adverse events observed and biochemical safety parameters remained within the normal range. CONCLUSION: Combined therapy of ch-OSA and Ca/Vit D3 had a potential beneficial effect on bone collagen compared to Ca/Vit D3 alone which suggests that this treatment is of potential use in osteoporosis. NTR 1029.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Daily Preventive Zinc Supplementation Decreases Lymphocyte and Eosinophil Concentrations in Rural Laotian Children from Communities with a High Prevalence of Zinc Deficiency: Results of a Randomized Controlled Trial.

BACKGROUND:Zinc deficiency impairs immune function and is common among children in South-East Asia. OBJECTIVES:The effect of zinc supplementation on immune function in young Laotian children was investigated. METHODS:Children (n = 512) aged 6-23 mo received daily preventive zinc tablets (PZ; 7 mg Zn/d), daily multiple micronutrient powder (MNP; 10 mg Zn/d, 6 mg Fe/d, plus 13 other micronutrients), therapeutic dispersible zinc tablets only in association with diarrhea episodes (TZ; 20 mg Zn/d for 10 d after an episode), or daily placebo powder (control). These interventions continued for 9 mo. Cytokine production from whole blood cultures, the concentrations of T-cell populations, and a complete blood count with differential leukocyte count were measured at baseline and endline. Endline means were compared via ANCOVA, controlling for the baseline value of the outcome, child age and sex, district, month of enrollment, and baseline zinc status (below, or above or equal to, the median plasma zinc concentration). RESULTS:T-cell cytokines (IL-2, IFN-γ, IL-13, IL-17), LPS-stimulated cytokines (IL-1β, IL-6, TNF-α, and IL-10), and T-cell concentrations at endline did not differ between intervention groups, nor was there an interaction with baseline zinc status. However, mean ± SE endline lymphocyte concentrations were significantly lower in the PZ than in the control group (5018 ± 158 compared with 5640 ± 160 cells/μL, P = 0.032). Interactions with baseline zinc status were seen for eosinophils (Pixn = 0.0036), basophils (Pixn = 0.023), and monocytes (P = 0.086) but a significant subgroup difference was seen only for eosinophils, where concentrations were significantly lower in the PZ than in the control group among children with baseline plasma zinc concentrations below the overall median (524 ± 44 compared with 600 ± 41 cells/μL, P = 0.012). CONCLUSIONS:Zinc supplementation of rural Laotian children had no effect on cytokines or T-cell concentrations, although zinc supplementation affected lymphocyte and eosinophil concentrations. These cell subsets may be useful as indicators of response to zinc supplementation.This trial was registered at clinicaltrials.gov as NCT02428647

Cholera Toxin Regulates a Signaling Pathway Critical for the Expansion of Neural Stem Cell Cultures from the Fetal and Adult Rodent Brains

Background: New mechanisms that regulate neural stem cell (NSC) expansion will contribute to improved assay systems and the emerging regenerative approach that targets endogenous stem cells. Expanding knowledge on the control of stem cell self renewal will also lead to new approaches for targeting the stem cell population of cancers. Methodology/Principal Findings: Here we show that Cholera toxin regulates two recently characterized NSC markers, the Tie2 receptor and the transcription factor Hes3, and promotes the expansion of NSCs in culture. Cholera toxin increases immunoreactivity for the Tie2 receptor and rapidly induces the nuclear localization of Hes3. This is followed by powerful cultured NSC expansion and induction of proliferation both in the presence and absence of mitogen. Conclusions/Significance: Our data suggest a new cell biological mechanism that regulates the self renewal and differentiation properties of stem cells, providing a new logic to manipulate NSCs in the context of regenerative disease and cancer

Identification of O-Linked Glycoproteins Binding to the Lectin Helix pomatia Agglutinin as Markers of Metastatic Colorectal Cancer

Background Protein glycosylation is an important post-translational modification shown to be altered in all tumour types studied to date. Mucin glycoproteins have been established as important carriers of O-linked glycans but other glycoproteins exhibiting altered glycosylation repertoires have yet to be identified but offer potential as biomarkers for metastatic cancer. Methodology In this study a glycoproteomic approach was used to identify glycoproteins exhibiting alterations in glycosylation in colorectal cancer and to evaluate the changes in O-linked glycosylation in the context of the p53 and KRAS (codon 12/13) mutation status. Affinity purification with the carbohydrate binding protein from Helix pomatia agglutinin (HPA) was coupled to 2-dimensional gel electrophoresis with mass spectrometry to enable the identification of low abundance O-linked glycoproteins from human colorectal cancer specimens. Results Aberrant O-linked glycosylation was observed to be an early event that occurred irrespective of the p53 and KRAS status and correlating with metastatic colorectal cancer. Affinity purification using the lectin HPA followed by proteomic analysis revealed annexin 4, annexin 5 and CLCA1 to be increased in the metastatic colorectal cancer specimens. The results were validated using a further independent set of specimens and this showed a significant association between the staining score for annexin 4 and HPA and the time to metastasis; independently (annexin A4: Chi square 11.45, P = 0.0007; HPA: Chi square 9.065, P = 0.0026) and in combination (annexin 4 and HPA combined: Chi square 13.47; P = 0.0002). Conclusion Glycoproteins showing changes in O-linked glycosylation in metastatic colorectal cancer have been identified. The glycosylation changes were independent of p53 and KRAS status. These proteins offer potential for further exploration as biomarkers and potential targets for metastatic colorectal cancer

Bacteriophage Lysin Mediates the Binding of Streptococcus mitis to Human Platelets through Interaction with Fibrinogen

The binding of bacteria to human platelets is a likely central mechanism in the pathogenesis of infective endocarditis. We have previously found that platelet binding by Streptococcus mitis SF100 is mediated by surface components encoded by a lysogenic bacteriophage, SM1. We now demonstrate that SM1-encoded lysin contributes to platelet binding via its direct interaction with fibrinogen. Far Western blotting of platelets revealed that fibrinogen was the major membrane-associated protein bound by lysin. Analysis of lysin binding with purified fibrinogen in vitro confirmed that these proteins could bind directly, and that this interaction was both saturable and inhibitable. Lysin bound both the Aα and Bβ chains of fibrinogen, but not the γ subunit. Binding of lysin to the Bβ chain was further localized to a region within the fibrinogen D fragment. Disruption of the SF100 lysin gene resulted in an 83±3.1% reduction (mean ± SD) in binding to immobilized fibrinogen by this mutant strain (PS1006). Preincubation of this isogenic mutant with purified lysin restored fibrinogen binding to wild type levels. When tested in a co-infection model of endocarditis, loss of lysin expression resulted in a significant reduction in virulence, as measured by achievable bacterial densities (CFU/g) within vegetations, kidneys, and spleens. These results indicate that bacteriophage-encoded lysin is a multifunctional protein, representing a new class of fibrinogen-binding proteins. Lysin appears to be cell wall-associated through its interaction with choline. Once on the bacterial surface, lysin can bind fibrinogen directly, which appears to be an important interaction for the pathogenesis of endocarditis

A genomic catalog of Earth’s microbiomes

The reconstruction of bacterial and archaeal genomes from shotgun metagenomes has enabled insights into the ecology and evolution of environmental and host-associated microbiomes. Here we applied this approach to >10,000 metagenomes collected from diverse habitats covering all of Earth’s continents and oceans, including metagenomes from human and animal hosts, engineered environments, and natural and agricultural soils, to capture extant microbial, metabolic and functional potential. This comprehensive catalog includes 52,515 metagenome-assembled genomes representing 12,556 novel candidate species-level operational taxonomic units spanning 135 phyla. The catalog expands the known phylogenetic diversity of bacteria and archaea by 44% and is broadly available for streamlined comparative analyses, interactive exploration, metabolic modeling and bulk download. We demonstrate the utility of this collection for understanding secondary-metabolite biosynthetic potential and for resolving thousands of new host linkages to uncultivated viruses. This resource underscores the value of genome-centric approaches for revealing genomic properties of uncultivated microorganisms that affect ecosystem processes

Epigenomic analysis of aberrantly methylated genes in colorectal cancer identifies genes commonly affected by epigenetic alterations.

Methylation profiling based on bead-chip arrays is an effective method for screening aberrantly methylated genes in CRC. In addition, we identified novel methylated genes that are candidate diagnostic or prognostic markers for CRC

Genomic analysis and relatedness of P2-like phages of the Burkholderia cepacia complex

<p>Abstract</p> <p>Background</p> <p>The <it>Burkholderia cepacia </it>complex (BCC) is comprised of at least seventeen Gram-negative species that cause infections in cystic fibrosis patients. Because BCC bacteria are broadly antibiotic resistant, phage therapy is currently being investigated as a possible alternative treatment for these infections. The purpose of our study was to sequence and characterize three novel BCC-specific phages: KS5 (vB_BceM-KS5 or vB_BmuZ-ATCC 17616), KS14 (vB_BceM-KS14) and KL3 (vB_BamM-KL3 or vB_BceZ-CEP511).</p> <p>Results</p> <p>KS5, KS14 and KL3 are myoviruses with the A1 morphotype. The genomes of these phages are between 32317 and 40555 base pairs in length and are predicted to encode between 44 and 52 proteins. These phages have over 50% of their proteins in common with enterobacteria phage P2 and so can be classified as members of the <it>Peduovirinae </it>subfamily and the "P2-like viruses" genus. The BCC phage proteins similar to those encoded by P2 are predominantly structural components involved in virion morphogenesis. As prophages, KS5 and KL3 integrate into an AMP nucleosidase gene and a threonine tRNA gene, respectively. Unlike other P2-like viruses, the KS14 prophage is maintained as a plasmid. The P2 <it>E+E' </it>translational frameshift site is conserved among these three phages and so they are predicted to use frameshifting for expression of two of their tail proteins. The <it>lysBC </it>genes of KS14 and KL3 are similar to those of P2, but in KS5 the organization of these genes suggests that they may have been acquired via horizontal transfer from a phage similar to λ. KS5 contains two sequence elements that are unique among these three phages: an IS<it>Bmu</it>2-like insertion sequence and a reverse transcriptase gene. KL3 encodes an EcoRII-C endonuclease/methylase pair and Vsr endonuclease that are predicted to function during the lytic cycle to cleave non-self DNA, protect the phage genome and repair methylation-induced mutations.</p> <p>Conclusions</p> <p>KS5, KS14 and KL3 are the first BCC-specific phages to be identified as P2-like. As KS14 has previously been shown to be active against <it>Burkholderia cenocepacia in vivo</it>, genomic characterization of these phages is a crucial first step in the development of these and similar phages for clinical use against the BCC.</p