Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Aeroacoustics and Flow Dynamics of an airfoil with a Gurney flap using TR-PIV

Aircraft noise has come under severe scrutiny due to growing number of airports and airline operations. The noise generated by high lift devices is now comparable to the turbofan engines due to increasing bypass ratios. A Gurney flap is a suitable starting point to study trailing edge flap aeroacoustics due to additional lift characteristics and a simple geometry. The thesis aims in using Time-Resolved Particle Image Velocimetry to understand the dynamics of flow as well as identifying structures responsible for the tonal noise in a Gurney flap. TR-PIV was used to obtain, at a high spatial and temporal resolution, the flow dynamics associated with a Gurney flap at low Mach and high Reynolds number. A part of the thesis focussed on validating the two modes of shedding as an additional lift increment mechanism in a Gurney flap in case of a fully developed turbulent boundary layer. Flow statistics showed an upstream recirculation region, upper and lower separating shear layers and a main recirculation region whose size varied with Gurney flap size and angle of attack downstream of the flap. The instantaneous velocity and vorticity fields showed the flapping motion of the von Karman wake and corresponding vortex roll-up and shedding process. The power spectral density of flow fluctuations as well as the acoustic spectra, however, did not indicate any second mode of shedding. The Strouhal numbers of the vortex shedding for various Gurney flaps were close to that of a bluff body in a flow. Stereoscopic PIV measurements showed the periodic vortex shedding to be highly correlated in the spanwise direction (correlation length of 4cm). The large spanwise correlation length indicates the use of serrations can be useful in breaking-down such coherent structures. The tonal peaks were clearly audible and correspond to the vortex shedding frequency. Causality correlation between pressure fluctuations generated in the far-eld and the near-field fluctuations indicate a high correlation with unsteady vertical velocity in the wake (associated with unsteady lift). It was found that the dynamics in the upstream recirculation region (cavity) was not responsible in the production of noise. Further, the results indicate the location of the actual source of noise to be the flap. The high values of correlation further downstream are due to the presence of an upstream source (the flap) and are not sources of sound themselves. Thus, TR-PIV in a way clears the ambiguity expressed by other researchers in the past in interpreting the high values of correlation to be sources of sound.AerodynamicsAerodynamics and Wind EnergyAerospace Engineerin

Investigation of aeroacoustics and flow dynamics of a NACA 0015 airfoil with a Gurney flap using TR-PIV

The present study employs simultaneous planar TR-PIV and microphone measurements to obtain the flow dynamics and aeroacoustic causality correlation associated with a Gurney flap of various sizes in case of low Mach and high Reynolds number flows. The objectives are to investigate the secondary shedding mode for the case of a turbulent boundary layer and to understand the mechanism of noise generation by identifying structures that are highly correlated with far field pressure fluctuations. The instantaneous velocity and vorticity fields show the flapping motion of the wake and the coherent vortex shedding process. The tonal peaks are clearly audible and correspond to the vortex shedding frequency. The PSD of the flow fluctuations and acoustic spectra did not indicate a secondary mode of shedding in case of turbulent boundary layer. The Strouhal numbers of the vortex shedding are found to be close to that of a bluff body in a flow. Causality correlation between pressure fluctuations in the far-field and the near field fluctuations indicates that the vertical velocity in the wake of the model is highly correlated with the far-field pressure fluctuations. This study provides an example of the potential of the causality correlation technique in identifying flow structures/regions highly correlated with noise in case of complex high-lift devices, making it possible to design flaps with lower acoustic emissions.AerodynamicsWind Energ

Copper Nanoparticle Sintering Enabled Hermetic Packaging With Fine Sealing Ring for MEMS Application

Driving by the increased demand for hermetic packaging in the more than Moore (MtM) roadmap, a Cu nanoparticle sintering-enabled hermetic sealing solution was developed with a small-size sealing ring. The developed technology simplifies microfabrication and requires less surface roughness using a sinterable Cu nanoparticle paste. A 50μm size Cu paste sealing ring was achieved using a lithography patterned photoresist as a stencil mask. A groove-structured chip was used to amplify localized stress. The Cu nanoparticle paste was fully sintered at 300 °C under pressure ranging from 10 to 40 MPa resulting in a robust bonding with a maximum shear strength of 280 MPa and implementing hermetic packaging. The deflection of the Si diaphragms estimated a vacuum level of 7 kPa. Vacuum sealing was maintained for over six months, and the lowest leak rate was calculated as 8.4× 10 -13Pa·m 3/s. The developed technology that comprises small-size patterning and pressure-assisted sintering offers the potential for a simple, cost-effective, but robust solution for hermetic packaging.Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Electronic Components, Technology and MaterialsElectrical Engineering, Mathematics and Computer Scienc

Effect of silicon, manganese and heating rate on the ferrite recrystallization kinetics

This study presents the effects of silicon (Si) and manganese (Mn) concentration and of heating rate on the ferrite recrystallization kinetics in seven model alloys with different Si and Mn concentrations, which are of relevance for the development of Advanced High Strength Steels (AHSS). The recrystallization kinetics were studied with in-situ 2D X-ray Diffraction (2D-XRD) and ex-situ microstructure observations using Scanning Electron Microscopy (SEM). The experimentally observed differences in the recrystallization start temperature (Ts), dependent on the Si and Mn concentrations and the heating rate, can be described by combining the non-isothermal JMAK-model with a modified version of Cahn's solute drag model. The modified Cahn model takes into account - in an approximate manner - that the interaction energy of the solute atoms with the grain boundary depends on the Si and Mn concentrations in the boundary and the Wagner interaction parameters. The collective contribution of the Si and Mn atoms to the increase in the Ts with respect to the reference alloy (without Si and with very little Mn) is higher than would be expected from the simple addition of the effects of the Si and Mn concentrations alone. This means that the interaction between Si and Mn atoms leads to an additional increase in Ts, i.e. a coupled solute drag effect. For the later stages of recrystallization, we have studied the change in the number density and the growth rates of the recrystallizing grains using SEM. The observations show non-random nucleation, early impingement of the grains in the normal-direction and non-constant growth rates of recrystallizing grains. (OLD) MSE-1Materials Science and Engineering(OLD) MSE-

Large-deformation crystal plasticity simulation of microstructure and microtexture evolution through adaptive remeshing

The capability of high-resolution modeling of crystals subjected to large plastic strain is essential in predicting many important phenomena occurring in polycrystalline materials, such as microstructure, deformation localization and in-grain texture evolution. However, due to the heterogeneity of the plastic deformation in polycrystals, the simulation mesh gets distorted during the deformation. This mesh distortion deteriorates the accuracy of the results, and after reaching high local strain levels, it is no longer possible to continue the simulation. In this work, two different adaptive remeshing approaches are introduced for simulating large deformation of 3D polycrystals with high resolution under periodic boundary conditions. In the first approach, a new geometry with a new mesh is created, and then the simulation is restarted as a new simulation in which the initial state is set based on the last deformation state that had been reached. In the second approach, the mesh is smoothened by removing the distortion part of the deformation, and then the simulation is continued after finding a new equilibrium state for the smoothed mesh and geometry. The first method is highly efficient for conducting high-resolution large-deformation simulations. On the other hand, the second method's primary advantage is that it can overcome periodicity issues related to shear loading, and it can be used in conjunction with complex loading conditions. The merits of the methodologies are demonstrated using full-field simulations performed using a dislocation-density-based crystal plasticity model for Interstitial free (IF-) steel. Particular emphasis is put on studying the effect of resolution and adaptive meshing. The algorithms presented have been implemented into the free and open-source software package, DAMASK (Düsseldorf Advanced Material Simulation Kit).Team Jilt Sietsm

Data Compression Versus Signal Fidelity Tradeoff in Wired-OR Analog-to-Digital Compressive Arrays for Neural Recording

Future high-density and high channel count neural interfaces that enable simultaneous recording of tens of thousands of neurons will provide a gateway to study, restore and augment neural functions. However, building such technology within the bit-rate limit and power budget of a fully implantable device is challenging. The wired-OR compressive readout architecture addresses the data deluge challenge of a high channel count neural interface using lossy compression at the analog-to-digital interface. In this article, we assess the suitability of wired-OR for several steps that are important for neuroengineering, including spike detection, spike assignment and waveform estimation. For various wiring configurations of wired-OR and assumptions about the quality of the underlying signal, we characterize the trade-off between compression ratio and task-specific signal fidelity metrics. Using data from 18 large-scale microelectrode array recordings in macaque retina ex vivo, we find that for an event SNR of 7-10, wired-OR correctly detects and assigns at least 80% of the spikes with at least 50× compression. The wired-OR approach also robustly encodes action potential waveform information, enabling downstream processing such as cell-type classification. Finally, we show that by applying an LZ77-based lossless compressor (gzip) to the output of the wired-OR architecture, 1000× compression can be achieved over the baseline recordings.Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Bio-Electronic

Real-Time MRI-Guided Catheter Tracking Using Hyperpolarized Silicon Particles

Visualizing the movement of angiocatheters during endovascular interventions is typically accomplished using x-ray fluoroscopy. There are many potential advantages to developing magnetic resonance imaging-based approaches that will allow three-dimensional imaging of the tissue/vasculature interface while monitoring other physiologically-relevant criteria, without exposing the patient or clinician team to ionizing radiation. Here we introduce a proof-of-concept development of a magnetic resonance imaging-guided catheter tracking method that utilizes hyperpolarized silicon particles. The increased signal of the silicon particles is generated via low-temperature, solid-state dynamic nuclear polarization, and the particles retain their enhanced signal for ?40?minutes—allowing imaging experiments over extended time durations. The particles are affixed to the tip of standard medical-grade catheters and are used to track passage under set distal and temporal points in phantoms and live mouse models. With continued development, this method has the potential to supplement x-ray fluoroscopy and other MRI-guided catheter tracking methods as a zero-background, positive contrast agent that does not require ionizing radiation.QN/Quantum NanoscienceApplied Science

High mobility group box-1 induces pro-inflammatory signaling in human Nucleus Pulposus cells via Toll-like receptor 4-dependent pathway.

Intervertebral disc (IVD) degeneration (DD) is associated with low back pain, the leading cause of disability worldwide. Damage-associated molecular patterns (DAMPs) that contribute to inflammation and trigger DD have not been well characterized. Extracellular high mobility group box-1 (HMGB1) protein has been implicated as a potent DAMP and pro-inflammatory stimulus in the immune system. In this study, we show that HMGB1 and IL-6 levels increase in patients with advanced DD in comparison to early DD. This study further tested the hypothesis that HMGB1 promotes inflammatory signaling driving DD in human nucleus pulposus (NP) cells and tissue. Immunofluorescence and western blot analysis confirmed the expression of HMGB1 and its extracellular release by NP cells under cell stress. Gene expression and protein quantification indicate that HMGB1 stimulates the expression IL-6 and MMP-1 in a dose-dependent manner. The contributions of toll-like receptor (TLR) -2, -4 and receptor for advanced glycation end products (RAGE) as receptors mediating HMGB1 signaling was examined using small molecule inhibitors. Inhibition of TLR-4 signaling, with TAK-242, completely abrogated HMGB1 induced IL-6 and MMP-1 expression, whereas inhibition of TLR-2, with O-vanillin, or RAGE, with FPS-ZM1, had mild inhibitory effects. HMGB1 stimulation activated NF-kB signaling while TAK-242 co-treatment abrogated it. Lastly, effects of HMGB1 on matrix deposition was evaluated in a 3D culture system of human NP cells. These results implicate HMGB1 as a potent DAMP that promotes inflammation in NP cells and degradation of NP tissues. TLR4-HMGB1 axis is a potential major pathway to alleviate disc inflammation and mitigate DD. This article is protected by copyright. All rights reserved