Development of a 3D printer using scanning projection stereolithography

We have developed a system for the rapid fabrication of low cost 3D devices and systems in the laboratory with micro-scale features yet cm-scale objects. Our system is inspired by maskless lithography, where a digital micromirror device (DMD) is used to project patterns with resolution up to 10 µm onto a layer of photoresist. Large area objects can be fabricated by stitching projected images over a 5cm2 area. The addition of a z-stage allows multiple layers to be stacked to create 3D objects, removing the need for any developing or etching steps but at the same time leading to true 3D devices which are robust, configurable and scalable. We demonstrate the applications of the system by printing a range of micro-scale objects as well as a fully functioning microfluidic droplet device and test its integrity by pumping dye through the channels

Effects of etelcalcetide on fibroblast growth factor 23 in patients with secondary hyperparathyroidism receiving hemodialysis

Background: Etelcalcetide is an intravenous calcimimetic approved for treatment of secondary hyperparathyroidism (sHPT) in patients receiving hemodialysis. Besides lowering parathyroid hormone (PTH), etelcalcetide also significantly reduces fibroblast growth factor 23 (FGF23), but the mechanisms are unknown. Methods: To investigate potential mediators of etelcalcetide-induced FGF23 reduction, we performed secondary analyses of the 26-week randomized trials that compared the effects on PTH of etelcalcetide (n = 509) versus placebo (n = 514) and etelcalcetide (n = 340) versus cinacalcet (n = 343) in adults with sHPT receiving hemodialysis. We analyzed changes in FGF23 in relation to changes in PTH, calcium, phosphate and bone turnover markers. We also investigated how concomitant treatments aimed at mitigating hypocalcemia altered the FGF23-lowering effects of etelcalcetide. Results: Etelcalcetide reduced FGF23 [median % change (quartile 1-quartile 3)] from baseline to the end of the trial significantly more than placebo [-56% (-85 to -7) versus +2% (-40 to +65); P < 0.001] and cinacalcet [-68% (-87 to -26) versus -41% (-76 to +25); P < 0.001]. Reductions in FGF23 correlated strongly with reductions in calcium and phosphate, but not with PTH; correlations with bone turnover markers were inconsistent and of borderline significance. Increases in concomitant vitamin D administration partially attenuated the FGF23-lowering effect of etelcalcetide, but increased dialysate calcium concentration versus no increase and increased dose of calcium supplementation versus no increase did not attenuate the FGF23-lowering effects of etelcalcetide. Conclusion: These data suggest that etelcalcetide potently lowers FGF23 in patients with sHPT receiving hemodialysis and that the effect remains detectable among patients who receive concomitant treatments aimed at mitigating treatment-associated decreases in serum calcium

Phosphatidylinositol 3-kinase signaling in proliferating cells maintains an anti-apoptotic transcriptional program mediated by inhibition of FOXO and non-canonical activation of NFκB transcription factors

<p>Abstract</p> <p>Background</p> <p>Phosphatidylinositol (PI) 3-kinase is activated by a variety of growth factor receptors and the PI 3-kinase/Akt signaling pathway is a key regulator of cell proliferation and survival. The downstream targets of PI 3-kinase/Akt signaling include direct regulators of cell cycle progression and apoptosis as well as a number of transcription factors. Growth factor stimulation of quiescent cells leads to robust activation of PI 3-kinase, induction of immediate-early genes, and re-entry into the cell cycle. A lower level of PI 3-kinase signaling is also required for the proliferation and survival of cells maintained in the presence of growth factors, but the gene expression program controlled by PI 3-kinase signaling in proliferating cells has not been elucidated.</p> <p>Results</p> <p>We used microarray analyses to characterize the changes in gene expression resulting from inhibition of PI 3-kinase in proliferating cells. The genes regulated by inhibition of PI 3-kinase in proliferating cells were distinct from genes induced by growth factor stimulation of quiescent cells and highly enriched in genes that regulate programmed cell death. Computational analyses followed by chromatin immunoprecipitations demonstrated FOXO binding to both previously known and novel sites in promoter regions of approximately one-third of the up-regulated genes, consistent with activation of FOXO1 and FOXO3a in response to inhibition of PI 3-kinase. NFκB binding sites were similarly identified in promoter regions of over one-third of the down-regulated genes. RelB was constitutively bound to promoter regions in cells maintained in serum, however binding decreased following PI 3-kinase inhibition, indicating that PI 3-kinase signaling activates NFκB via the non-canonical pathway in proliferating cells. Approximately 70% of the genes targeted by FOXO and NFκB regulate cell proliferation and apoptosis, including several regulators of apoptosis that were not previously known to be targeted by these transcription factors.</p> <p>Conclusion</p> <p>PI 3-kinase signaling in proliferating cells regulates a novel transcriptional program that is highly enriched in genes that regulate apoptosis. At least one-third of these genes are regulated either by FOXO transcription factors, which are activated following PI 3-kinase inhibition, or by RelB, which is activated by PI 3-kinase via the non-canonical pathway in proliferating cells.</p

Three-Dimensional Simulations of a Starburst-Driven Galactic Wind

We have performed a series of three-dimensional simulations of a starburst-driven wind in an inhomogeneous interstellar medium. The introduction of an inhomogeneous disk leads to differences in the formation of a wind, most noticeably the absence of the ``blow-out'' effect seen in homogeneous models. A wind forms from a series of small bubbles that propagate into the tenuous gas between dense clouds in the disk. These bubbles merge and follow the path of least resistance out of the disk, before flowing freely into the halo. Filaments are formed from disk gas that is broken up and accelerated into the outflow. These filaments are distributed throughout a biconical structure within a more spherically distributed hot wind. The distribution of the inhomogeneous interstellar medium in the disk is important in determining the morphology of this wind, as well as the distribution of the filaments. While higher resolution simulations are required in order to ascertain the importance of mixing processes, we find that soft X-ray emission arises from gas that has been mass-loaded from clouds in the disk, as well as from bow shocks upstream of clouds, driven into the flow by the ram pressure of the wind, and the interaction between these shocks.Comment: 37 pages, 16 figures, mpg movie can be obtained at http://www.mso.anu.edu.au/~jcooper/movie/video16.mpg, accepted for publication in Ap

Integrated synthesis of nucleotide and nucleosides influenced by amino acids

Research on prebiotic chemistry and the origins of nucleic acids and proteins has traditionally been focussed on only one or the other. However, if nucleotides and amino acids co-existed on the early Earth, their mutual interactions and reactivity should be considered explicitly. Here we set out to investigate nucleotide/nucleoside formation by simple dehydration reactions of constituent building blocks (sugar, phosphate, and nucleobase) in the presence of different amino acids. We demonstrate the simultaneous formation of glycosidic bonds between ribose, purines, and pyrimidines under mild conditions without catalysts or activated reagents, as well as nucleobase exchange, in addition to the simultaneous formation of nucleotide and nucleoside isomers from several nucleobases. Clear differences in the distribution of glycosylation products are observed when glycine is present. This work demonstrates that reaction networks of nucleotides and amino acids should be considered when exploring the emergence of catalytic networks in the context of molecular evolution

Environmental control programs the emergence of distinct functional ensembles from unconstrained chemical reactions

Many approaches to the origin of life focus on how the molecules found in biology might be made in the absence of biological processes, from the simplest plausible starting materials. Another approach could be to view the emergence of the chemistry of biology as process whereby the environment effectively directs “primordial soups” toward structure, function, and genetic systems over time. This does not require the molecules found in biology today to be made initially, and leads to the hypothesis that environment can direct chemical soups toward order, and eventually living systems. Herein, we show how unconstrained condensation reactions can be steered by changes in the reaction environment, such as order of reactant addition, and addition of salts or minerals. Using omics techniques to survey the resulting chemical ensembles we demonstrate there are distinct, significant, and reproducible differences between the product mixtures. Furthermore, we observe that these differences in composition have consequences, manifested in clearly different structural and functional properties. We demonstrate that simple variations in environmental parameters lead to differentiation of distinct chemical ensembles from both amino acid mixtures and a primordial soup model. We show that the synthetic complexity emerging from such unconstrained reactions is not as intractable as often suggested, when viewed through a chemically agnostic lens. An open approach to complexity can generate compositional, structural, and functional diversity from fixed sets of simple starting materials, suggesting that differentiation of chemical ensembles can occur in the wider environment without the need for biological machinery

The Energetic Particle Detector (EPD) Investigation and the Energetic Ion Spectrometer (EIS) for the Magnetospheric Multiscale (MMS) Mission

Abstract The Energetic Particle Detector (EPD) Investigation is one of 5 fields-and-particles investigations on the Magnetospheric Multiscale (MMS) mission. MMS comprises 4 spacecraft flying in close formation in highly elliptical, near-Earth-equatorial orbits targeting understanding of the fundamental physics of the important physical process called magnetic reconnection using Earth’s magnetosphere as a plasma laboratory. EPD comprises two sensor types, the Energetic Ion Spectrometer (EIS) with one instrument on each of the 4 spacecraft, and the Fly’s Eye Energetic Particle Spectrometer (FEEPS) with 2 instruments on each of the 4 spacecraft. EIS measures energetic ion energy, angle and elemental compositional distributions from a required low energy limit of 20 keV for protons and 45 keV for oxygen ions, up to \u3e0.5 MeV (with capabilities to measure up to \u3e1 MeV). FEEPS measures instantaneous all sky images of energetic electrons from 25 keV to \u3e0.5 MeV, and also measures total ion energy distributions from 45 keV to \u3e0.5 MeV to be used in conjunction with EIS to measure all sky ion distributions. In this report we describe the EPD investigation and the details of the EIS sensor. Specifically we describe EPD-level science objectives, the science and measurement requirements, and the challenges that the EPD team had in meeting these requirements. Here we also describe the design and operation of the EIS instruments, their calibrated performances, and the EIS in-flight and ground operations. Blake et al. (The Flys Eye Energetic Particle Spectrometer (FEEPS) contribution to the Energetic Particle Detector (EPD) investigation of the Magnetospheric Magnetoscale (MMS) Mission, this issue) describe the design and operation of the FEEPS instruments, their calibrated performances, and the FEEPS in-flight and ground operations. The MMS spacecraft will launch in early 2015, and over its 2-year mission will provide comprehensive measurements of magnetic reconnection at Earth’s magnetopause during the 18 months that comprise orbital phase 1, and magnetic reconnection within Earth’s magnetotail during the about 6 months that comprise orbital phase 2

Comparison between noncontrast computed tomography and magnetic resonance imaging for detection and characterization of thoracolumbar myelopathy caused by intervertebral disk herniation in dogs

Magnetic resonance imaging (MRI) and computed tomography (CT) are commonly used to evaluate dogs with thoracolumbar myelopathy; however, relative diagnostic sensitivities for these two modalities have not been previously reported. The purpose of this prospective study was to compare diagnostic sensitivity and observer agreement for MRI and CT in a group of dogs with thoracolumbar myelopathy due to surgically confirmed intervertebral disk herniation (IVDH). All included dogs had magnetic resonance (MR) imaging followed by noncontrast CT using standardized protocols. Three experienced observers interpreted each imaging study independently without knowledge of clinical or surgical findings. The operating surgeon was aware of MR findings but not CT findings at the time surgical findings were recorded. Forty-four dogs met the inclusion criteria. The sensitivity of CT was 88.6% (79.5%–94.2%) and of MR was 98.5% (95% confidence interval, 94.1%–99.7%) for diagnosis of intervertebral disk herniation. Specificity was not calculated, as all dogs had IVDH at surgery. Magnetic resonance imaging was more accurate than CT for identifying the site of intervertebral disk herniation-associated spinal cord compression and differentiating disk extrusion vs. protrusion. Computed tomography was less accurate for lesion localization in per acute cases, as well as for chondrodystrophic, female, older and smaller (<7 kg) dogs. Inter-rater agreement was good for lesion lateralization for bothMR and CT (κ = 0.687, 95% CI = 0.552, 0.822, P = 0.002, and κ = 0.692, 95% CI = 0.542, 0.842, P = 0.003). Findings from the current study indicated that MR imaging was more sensitive and accurate than noncontrast CT for diagnosis and characterization of thoracolumbar myelopathy due to IVDH in dogs. Chttp://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1740-8261hb201

Evidence of selection in mineral mediated polymerization reactions executed in a robotic Chemputer system

It has long been thought that abiogenesis requires a process of selection and evolution at the molecular level, but this process is hard to explore experimentally. One solution could be the use of automation in experiments which could allow for traceability and the ability to explore a larger reaction space. We report a fully programmable and automated platform to explore the reactions of amino acids in the presence of mineral environments. The robotic system is based upon the Chemputer system which has well defined modules, software, and a chemical programming language to orchestrate the chemical processes, including analysis. The reaction mixtures were analysed with tandem mass spectrometry and a peptide sequencing algorithm. Each experiment was screened for 1,398,100 possible unique sequences, and more than 550 specifically defined sequences were confirmed experimentally. This work aimed to develop a new understanding of selection in repeated cycles of polymerisation reactions to explore the emergence of well-defined amino acid sequences. We found that the outcome of oligomerisation was significantly influenced by the presence of different minerals, and that a serpentine environment selects glycine and phenylalanine rich fragments that enable the formation of longer oligomers with well-defined sequences as a function of cycle number