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Age, serum 25-hydroxyvitamin D and vitamin D receptor (VDR) expression and function in peripheral blood mononuclear cells. - Oncotarget
The relationship between age, vitamin D status, expression and functionality of the vitamin D receptor (VDR), and key genes in the vitamin D pathway in immune cells is unclear. We enrolled adults 50 to 69 years old (20 subjects) and 70+ (20 subjects) and measured: 1) 25(OH)D levels by liquid chromatography/mass spectrometry; and 2) mRNA expression of VDR, 1Î±-OHase, 1,25D3-MARRS, TREM-1, cathelicidin, RIG-I, and interferon-Î² by qRT-PCR. Mean serum 25(OH)D was 30 Â± 4 ng/mL and was not associated with age. Baseline expression of VDR, 1Î±-OHase, 1,25D3-MARRS, TREM-1, and RIG-I also did not differ by age; IFN-Î² expression, however, was higher in the 70+ year old group. 25(OH)D3- and 1,25(OH)2D3-induced VDR, TREM-1 and cathelicidin expression were similar between age groups, as was LPS-induced expression of VDR and of 1Î±-OHase. Ligand-induced 1,25D3-MARRS expression was higher in subjects â‰¥ 70 years. Serum 25(OH)D was inversely associated with LPS-stimulated VDR expression and with baseline or vitamin D-induced TREM-1 expression, adjusting for age, self-rated health, and functional status. In healthy adults â‰¥ 50 years, the expression and functionality of the VDR, 1Î±-OHase and key vitamin D pathway genes were not consistently associated with age.
Reduced serologic sensitivity to influenza A virus illness among inactivated influenza vaccinees. - Vaccine
We compared â‰¥4-fold increases in antibody titers by hemagglutination inhibition assay to RT-PCR results among 42 adults with PCR-confirmed influenza A virus illnesses. Serologic sensitivity was higher among unvaccinated (69%, 95% confidence interval [CI]=48-90%) than vaccinated healthcare personnel (38%, 95% CI=29-46%) in a 2010-11 prospective cohort.Published by Elsevier Ltd.
A novel chemo-mechano-biological model of arterial tissue growth and remodelling. - Journal of biomechanics
Arterial growth and remodelling (G&R) is mediated by vascular cells in response to their chemical and mechanical environment. To date, mechanical and biochemical stimuli tend to be modelled separately, however this ignores their complex interplay. Here, we present a novel mathematical model of arterial chemo-mechano-biology. We illustrate its application to the development of an inflammatory aneurysm in the descending human aorta. The arterial wall is modelled as a bilayer cylindrical non-linear elastic membrane, which is internally pressurised and axially stretched. The medial degradation that accompanies aneurysm development is driven by an inflammatory response. Collagen remodelling is simulated by adaption of the natural reference configuration of constituents; growth is simulated by changes in normalised mass-densities. We account for the distribution of attachment stretches that collagen fibres are configured to the matrix and, innovatively, allow this distribution to remodel. This enables the changing functional role of the adventitia to be simulated. Fibroblast-mediated collagen growth is represented using a biochemical pathway model: a system of coupled non-linear ODEs governs the evolution of fibroblast properties and levels of key biomolecules under the regulation of Transforming Growth Factor (TGF)-Î², a key promoter of matrix deposition. Given physiologically realistic targets, different modes of aneurysm development can be captured, while the predicted evolution of biochemical variables is qualitatively consistent with trends observed experimentally. Interestingly, we observe that increasing the levels of collagen-promoting TGF-Î² results in arrest of aneurysm growth, which seems to be consistent with experimental evidence. We conclude that this novel Chemo-Mechano-Biological (CMB) mathematical model has the potential to provide new mechanobiological insight into vascular disease progression and therapy.Copyright Â© 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.
Modelling superconducting nanowire single photon detectors in a waveguide cavity. - Optics express
In this work we report on a single photon detector system which offers near-unity detection efficiency using waveguide-coupled superconducting nanowires with lengths on the order of 1 Î¼m. This is achieved by embedding the nanowires in a racetrack resonator where the interaction time with the photons trapped in the cavity is increased, thereby allowing for shorter nanowires. We expect this to lead to a higher fabrication yield as the amount of inhomogeneities decreases for shorter nanowires. Our simulations show a system with a 1 Î¼m long superconducting nanowire single photon detector (SNSPD) operating at near-unity detection efficiency using design parameters that can be realistically achieved with conventional fabrication processes. The resonant cavity introduces spectral selectivity to the otherwise broad-band SNSPDs and the cavity induced timing jitter is shown to be insignificant for SNSPDs longer than 1 Î¼m.
The FAIR Guiding Principles for scientific data management and stewardship. - Scientific data
There is an urgent need to improve the infrastructure supporting the reuse of scholarly data. A diverse set of stakeholders-representing academia, industry, funding agencies, and scholarly publishers-have come together to design and jointly endorse a concise and measureable set of principles that we refer to as the FAIR Data Principles. The intent is that these may act as a guideline for those wishing to enhance the reusability of their data holdings. Distinct from peer initiatives that focus on the human scholar, the FAIR Principles put specific emphasis on enhancing the ability of machines to automatically find and use the data, in addition to supporting its reuse by individuals. This Comment is the first formal publication of the FAIR Principles, and includes the rationale behind them, and some exemplar implementations in the community.
A hyperelastic fibre-reinforced continuum model of healing tendons with distributed collagen fibre orientations. - Biomechanics and modeling in mechanobiology
The healing process of ruptured tendons is problematic due to scar tissue formation and deteriorated material properties, and in some cases, it may take nearly a year to complete. Mechanical loading has been shown to positively influence tendon healing; however, the mechanisms remain unclear. Computational mechanobiology methods employed extensively to model bone healing have achieved high fidelity. This study aimed to investigate whether an established hyperelastic fibre-reinforced continuum model introduced by Gasser, Ogden and Holzapfel (GOH) can be used to capture the mechanical behaviour of the Achilles tendon under loading during discrete timepoints of the healing process and to assess the model's sensitivity to its microstructural parameters. Curve fitting of the GOH model against experimental tensile testing data of rat Achilles tendons at four timepoints during the tendon repair was used and achieved excellent fits ([Formula: see text]). A parametric sensitivity study using a three-level central composite design, which is a fractional factorial design method, showed that the collagen-fibre-related parameters in the GOH model-[Formula: see text] and [Formula: see text]-had almost equal influence on the fitting. This study demonstrates that the GOH hyperelastic fibre-reinforced model is capable of describing the mechanical behaviour of healing tendons and that further experiments should focus on establishing the structural and material parameters of collagen fibres in the healing tissue.
The Implicitome: A Resource for Rationalizing Gene-Disease Associations. - PloS one
High-throughput experimental methods such as medical sequencing and genome-wide association studies (GWAS) identify increasingly large numbers of potential relations between genetic variants and diseases. Both biological complexity (millions of potential gene-disease associations) and the accelerating rate of data production necessitate computational approaches to prioritize and rationalize potential gene-disease relations. Here, we use concept profile technology to expose from the biomedical literature both explicitly stated gene-disease relations (the explicitome) and a much larger set of implied gene-disease associations (the implicitome). Implicit relations are largely unknown to, or are even unintended by the original authors, but they vastly extend the reach of existing biomedical knowledge for identification and interpretation of gene-disease associations. The implicitome can be used in conjunction with experimental data resources to rationalize both known and novel associations. We demonstrate the usefulness of the implicitome by rationalizing known and novel gene-disease associations, including those from GWAS. To facilitate the re-use of implicit gene-disease associations, we publish our data in compliance with FAIR Data Publishing recommendations [https://www.force11.org/group/fairgroup] using nanopublications. An online tool (http://knowledge.bio) is available to explore established and potential gene-disease associations in the context of other biomedical relations.
Fracture behavior of inlay and onlay fixed partial dentures - An in-vitro experimental and XFEM modeling study. - Journal of the mechanical behavior of biomedical materials
This study aimed to explore the "sensitivity" of the fracture load and initiation site to loading position on the central occlusal surface of a pontic tooth for both all-ceramic inlay retained and onlay supported partial denture systems.Three dimensional (3D) finite element (FE) inlay retained and onlay supported partial denture models were established for simulating crack initiation and propagation by using the eXtended Finite Element Method (XFEM). The models were subjected to a mastication force up to 500N on the central fossa of the pontic. The loading position was varied to investigate its influence on fracture load and crack path.Small perturbation of the loading position caused the fracture load and crack pattern to vary considerably. For the inlay fixed partial dentures (FPDs), the fracture origins changed from the bucco-gingival aspect of the molar embrasure to the premolar embrasure when the indenter force location is slightly shifted from the mesial to distal side. In contrast, for onlay FPDs, cracking initiated from bucco-gingival aspect of the premolar embrasure when the indenter is slightly shifted to the buccal side and from molar embrasure when the indenter is shifted to the lingual side.The fracture load and cracking path were found to be very sensitive to loading position in the all-ceramic inlay and onlay FPDs. The study provides a basis for improved understanding on the role of localized contact loading of the cusp surface in all-ceramic FPDs.Copyright Â© 2016 Elsevier Ltd. All rights reserved.
DNA and Protein Requirements for Substrate Conformational Changes Necessary for Human Flap Endonuclease-1-catalyzed Reaction. - The Journal of biological chemistry
Human flap endonuclease-1 (hFEN1) catalyzes the essential removal of single-stranded flaps arising at DNA junctions during replication and repair processes. hFEN1 biological function must be precisely controlled, and consequently, the protein relies on a combination of protein and substrate conformational changes as a prerequisite for reaction. These include substrate bending at the duplex-duplex junction and transfer of unpaired reacting duplex end into the active site. When present, 5'-flaps are thought to thread under the helical cap, limiting reaction to flaps with free 5'-terminiin vivo Here we monitored DNA bending by FRET and DNA unpairing using 2-aminopurine exciton pair CD to determine the DNA and protein requirements for these substrate conformational changes. Binding of DNA to hFEN1 in a bent conformation occurred independently of 5'-flap accommodation and did not require active site metal ions or the presence of conserved active site residues. More stringent requirements exist for transfer of the substrate to the active site. Placement of the scissile phosphate diester in the active site required the presence of divalent metal ions, a free 5'-flap (if present), a Watson-Crick base pair at the terminus of the reacting duplex, and the intact secondary structure of the enzyme helical cap. Optimal positioning of the scissile phosphate additionally required active site conserved residues Tyr(40), Asp(181), and Arg(100)and a reacting duplex 5'-phosphate. These studies suggest a FEN1 reaction mechanism where junctions are bound and 5'-flaps are threaded (when present), and finally the substrate is transferred onto active site metals initiating cleavage.Â© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
Efficacy, Safety, and Dose of Pafuramidine, a New Oral Drug for Treatment of First Stage Sleeping Sickness, in a Phase 2a Clinical Study and Phase 2b Randomized Clinical Studies. - PLoS neglected tropical diseases
Sleeping sickness (human African trypanosomiasis [HAT]) is caused by protozoan parasites and characterized by a chronic progressive course, which may last up to several years before death. We conducted two Phase 2 studies to determine the efficacy and safety of oral pafuramidine in African patients with first stage HAT.The Phase 2a study was an open-label, non-controlled, proof-of-concept study where 32 patients were treated with 100 mg of pafuramidine orally twice a day (BID) for 5 days at two trypanosomiasis reference centers (Angola and the Democratic Republic of the Congo [DRC]) between August 2001 and November 2004. The Phase 2b study compared pafuramidine in 41 patients versus standard pentamidine therapy in 40 patients. The Phase 2b study was open-label, parallel-group, controlled, randomized, and conducted at two sites in the DRC between April 2003 and February 2007. The Phase 2b study was then amended to add an open-label sequence (Phase 2b-2), where 30 patients received pafuramidine for 10 days. The primary efficacy endpoint was parasitologic cure at 24 hours (Phase 2a) or 3 months (Phase 2b) after treatment completion. The primary safety outcome was the rate of occurrence of World Health Organization Toxicity Scale Grade 3 or higher adverse events. All subjects provided written informed consent.Pafuramidine for the treatment of first stage HAT was comparable in efficacy to pentamidine after 10 days of dosing. The cure rates 3 months post-treatment were 79% in the 5-day pafuramidine, 100% in the 7-day pentamidine, and 93% in the 10-day pafuramidine groups. In Phase 2b, the percentage of patients with at least 1 treatment-emergent adverse event was notably higher after pentamidine treatment (93%) than pafuramidine treatment for 5 days (25%) and 10 days (57%). These results support continuation of the development program for pafuramidine into Phase 3.
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