The Origin of the Universe as Revealed Through the Polarization of the Cosmic Microwave Background

Modern cosmology has sharpened questions posed for millennia about the origin of our cosmic habitat. The age-old questions have been transformed into two pressing issues primed for attack in the coming decade: How did the Universe begin? and What physical laws govern the Universe at the highest energies? The clearest window onto these questions is the pattern of polarization in the Cosmic Microwave Background (CMB), which is uniquely sensitive to primordial gravity waves. A detection of the special pattern produced by gravity waves would be not only an unprecedented discovery, but also a direct probe of physics at the earliest observable instants of our Universe. Experiments which map CMB polarization over the coming decade will lead us on our first steps towards answering these age-old questions.Comment: Science White Paper submitted to the US Astro2010 Decadal Survey. Full list of 212 author available at http://cmbpol.uchicago.ed

Asymmetric Migration of Human Keratinocytes under Mechanical Stretch and Cocultured Fibroblasts in a Wound Repair Model

Keratinocyte migration during re-epithelization is crucial in wound healing under biochemical and biomechanical microenvironment. However, little is known about the underlying mechanisms whereby mechanical tension and cocultured fibroblasts or keratinocytes modulate the migration of keratinocytes or fibroblasts. Here we applied a tensile device together with a modified transwell assay to determine the lateral and transmembrane migration dynamics of human HaCaT keratinocytes or HF fibroblasts. A novel pattern of asymmetric migration was observed for keratinocytes when they were cocultured with non-contact fibroblasts, i.e., the accumulative distance of HaCaT cells was significantly higher when moving away from HF cells or migrating from down to up cross the membrane than that when moving close to HF cells or when migrating from up to down, whereas HF migration was symmetric. This asymmetric migration was mainly regulated by EGF derived from fibroblasts, but not transforming growth factor alpha or beta_1 production. Mechanical stretch subjected to fibroblasts fostered keratinocyte asymmetric migration by increasing EGF secretion, while no role of mechanical stretch was found for EGF secretion by keratinocytes. These results provided a new insight into understanding the regulating mechanisms of two or three-dimensional migration of keratinocytes or fibroblasts along or across dermis and epidermis under biomechanical microenvironment

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

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

More than smell - COVID-19 is associated with severe impairment of smell, taste, and chemesthesis

Recent anecdotal and scientific reports have provided evidence of a link between COVID-19 and chemosensory impairments, such as anosmia. However, these reports have downplayed or failed to distinguish potential effects on taste, ignored chemesthesis, and generally lacked quantitative measurements. Here, we report the development, implementation, and initial results of a multilingual, international questionnaire to assess self-reported quantity and quality of perception in 3 distinct chemosensory modalities (smell, taste, and chemesthesis) before and during COVID-19. In the first 11 days after questionnaire launch, 4039 participants (2913 women, 1118 men, and 8 others, aged 19-79) reported a COVID-19 diagnosis either via laboratory tests or clinical assessment. Importantly, smell, taste, and chemesthetic function were each significantly reduced compared to their status before the disease. Difference scores (maximum possible change ±100) revealed a mean reduction of smell (-79.7 ± 28.7, mean ± standard deviation), taste (-69.0 ± 32.6), and chemesthetic (-37.3 ± 36.2) function during COVID-19. Qualitative changes in olfactory ability (parosmia and phantosmia) were relatively rare and correlated with smell loss. Importantly, perceived nasal obstruction did not account for smell loss. Furthermore, chemosensory impairments were similar between participants in the laboratory test and clinical assessment groups. These results show that COVID-19-associated chemosensory impairment is not limited to smell but also affects taste and chemesthesis. The multimodal impact of COVID-19 and the lack of perceived nasal obstruction suggest that severe acute respiratory syndrome coronavirus strain 2 (SARS-CoV-2) infection may disrupt sensory-neural mechanisms. © 2020 The Author(s) 2020. Published by Oxford University Press. All rights reserved

Interest Rate Derivative Pricing with Stochastic Volatility

One purpose of exotic derivative pricing models is to enable financial institutions to quantify and manage their financial risk, arising from large books of portfolios. These portfolios consist of many non-standard exotic financial products. Risk is managed by means of the evaluation of sensitivity parameters, i.e. the so-called Greeks, the deltas, vegas, gammas and also volgas, vannas, and others. In practice, practitioners do not expect an exotic derivative pricing model to be a high precision predictive model. What is important is a high precision replication of the hedging instruments, as well as efficient computation with the model. Plain vanilla interest rate options like swaptions and caps are liquidly traded instruments, serving as fundamental building blocks of hedging portfolios for exotic products. In the early twenty-first century, the so-called implied volatility skew and smile in the market became pronounced in the interest rate plain vanilla market. The stochastic alpha beta rho (SABR) model then became widely accepted as the market standard to model this implied volatility skew/smile. The model's popularity is due to the existence of an accurate analytic approximation for the implied volatilities, presented by Hagan et al.. This approximation formula is often used by practitioners to inter- and extrapolate the implied volatility surface. The application of the SABR model is so prevalent that one can even observe SABR-type implied volatility curves in the market nowadays (which means that the SABR model can perfectly resemble one set of market implied volatilities with different strike prices). This PhD thesis considers the SABR model as its basis for further extension, and focuses on the various problems arising from the application of the SABR model in both plain vanilla and exotic option pricing, from a modelling as well as numerical point of view. In Chapter 2, we present an analytic approximation to the convexity correction of Constant Maturity Swap (CMS) products under a two-factor SABR model by means of small time asymptotic expansion technique. In Chapter 3, we apply the small time asymptotic expansion differently, to a problem of approximating the first and second moments of the integrated variance of the log-normal volatility process in the context of defining a low-bias discretization scheme for the SABR model. With the approximated moment information, we can approximate the density of the integrated variance by means of a log-normal distribution with the first two moments matched to that information. The conditional SABR process turns out to be a squared Bessel process, given the terminal volatility level and the integrated variance. Based on the idea of mixing conditional distributions and a direct inversion of the noncentral chi-square distributions, we propose the low-bias SABR Monte Carlo scheme. The low-bias scheme can handle the asset price process in the vicinity of the zero boundary well. The scheme is stable and exhibits a superior convergence behaviour compared to the truncated Euler scheme. In Chapter 4, we extend the discretization scheme proposed in Chapter 3 towards a SABR model with stochastic interest rate in the form of a Hull-White short rate model, the SABR-HW model. The hybrid model is meant for pricing long-dated equity-interest-rate linked exotic options with exposure to both the interest rate and the equity price risk. To facilitate the calibration of the SABRHW model, we propose a projection formula, mapping the SABR-HW model parameters onto the parameters of the nearest SABR model. The numerical inversion of the projection formula can be used to calibrate the model. In Chapter 5, we focus on a version of the stochastic volatility LIBOR Market Model with time-dependent skew and volatility parameters. As a result of choosing time-dependent parameters, the model has the flexibility to match to the market quotes of an entire swaption cube (in terms of various combinations of expiry, tenor and strike), as observed in the current interest rate market. Thus, this model is in principle well-suited for managing the risk of a complete exotic option trading book in a financial institution, consisting of both exotic options and its plain vanilla hedge instruments. The calibration of the model to the swaption quotes relies on a model mapping procedure, which relates the model parameters (most often time-dependent) in a high-dimensional LMM model to swaption prices. The model mapping procedure maps the high-dimensional swap rate dynamics implied by the model onto a one-dimensional displaced diffusion process with time-dependent coefficient. Those time-dependent parameters are subsequently averaged to obtain the effective constant parameters of the projected model. Two known projection methods that are available in the literature, the freezing projection and the more involved Markov projection, have been compared within the calibration process. The basic freezing projection achieves a good accuracy at significantly less computational cost in our tests, and it is thus applied within the calibration purpose. A second advantage of the freezing projection formula is that it enables us to formulate the time-dependent skew calibration problem as a convex optimization problem. Our contribution in this chapter is the convex optimization formulation of the skew calibration problem. Based on the convex formulation, we are able to translate the calibration of a large number of free variables into a well-known quadratic programming problem formulation, for which efficient algorithms are available. The convexity of the formulated optimization problem guarantees the obtained solution to be a global optimum. The stability of the procedure can be beneficial for application in the day-to-day derivative trading practice, i.e. the daily re-calibration and hedging.Applied mathematicsElectrical Engineering, Mathematics and Computer Scienc

On the Michael addition of water to C = C bonds

?-Hydroxy carbonyl compounds are an important class of compounds often found as a common structural motif in natural products. Although the molecules themselves look rather simple, their synthesis can be challenging. Water addition to conjugated C = C bonds opens up a straightforward route for the preparation of ?-hydroxy carbonyl compounds. Moreover, water addition to C = C bonds benefits a lot from its simplicity and excellent atom economy. However, the enantioselective addition of water to ?,?-unsaturated carbonyl (Michael) acceptors still represents a chemically very challenging reaction, due to the poor nucleophilicity of water and its small size, which make regio- and stereoinduction difficult. Equally, the often unfavorable equilibrium of water-addition reactions remains to be solved. In contrast, enzymes such as fumarase, malease, citraconase, aconitase, and enoyl-CoA hydratase have been successfully used on industrial scale, and their excellent (enantio-) selectivities are highly valued. Unfortunately, most hydratases are part of the primary metabolism where perfect substrate specificity is required. This very high substrate selectivity severely limits their practical applicability in organic synthesis. Thus, a straightforward approach with broad applicability still had not been described. The aim of the research presented in this thesis was to take up this challenge and dedicated to the search for a Michael hydratase with a more relaxed substrate specificity for the preparation of important ?-hydroxy carbonyl compounds. The stereospecificity of enzyme-catalysed reactions has been a fruitful source of information about the mechanisms of enzyme catalysis and vice versa; the application of stereospecifically labelled substrates allows for studying the course of the reaction. It offers a very promising opportunity to comprehensively understand the precise mechanistic and kinetic details of even the most complex enzymatic reactions. Thus Chapter 1 provides unifying ideas for stereochemistry of the enzymatic water addition to C = C bonds. This enhances our understanding of the chemistry of water addition to C = C bonds, and further allows us to find more hydratases from natural sources or obtained via protein engineering. In Chapter 2, a direct, enantioselective Michael addition of water in water to prepare important ?-hydroxy carbonyl compounds using whole cells of Rhodococcus strains is described. Good yields and excellent enantioselectivities were achieved with this method. This opens up an entirely new approach for the preparation of important ?-hydroxy carbonyl compounds. Deuterium labelling studies demonstrate that a Michael hydratase catalyzes the water addition exclusively with anti-stereochemistry, which belongs to the family members of hydratases: oleate hydratase, fumarase, malease, aconitase and type II dehydroquinase with a preference for the anti-addition; whereas, type I dehydroquinase, enoyl-CoA hydratase and artificial hydratase exclusive prefer for the syn-addition, as discussed in Chapter 1. The biocatalytic reaction system was carefully optimized for gram-scale synthesis, resulting in good conversions and excellent enantioselectivities. Under the optimized conditions, whole cells could be reused for 4 cycles without significant loss of activity while maintaining up to 90% ee. Since whole cells from Rhodococcus strains were used to catalyse the Michael addition of water in water to a series of ?,?-unsaturated carbonyl compounds, and when the work presented in Chapter 2 started, no genomic information of Rhodococcus strains was publically available, we sequenced and annotated the strain R. rhodochrous ATCC 17895. This is described in Chapter 3 together with features of the R. rhodochrous ATCC 17895. It is a Gram-positive aerobic bacterium with a rod-like morphology. The 6,869,887 bp long genome contains 6,609 protein-coding genes and 53 RNA genes. Our study suggests the Michael hydratase has not been described before. In the work presented in Chapter 2, we found that most ?-hydroxy ketones are not commercially available or commercially expensive as we mentioned in the first paragraph, which made the stereoselectivity determination of Michael addition products difficult. Indeed, many seemingly simple molecules have to be prepared via multi-step syntheses, in particular so if they are optically active. Therefore a straightforward approach to enantiomerically enriched (R)- and (S)-3-hydroxycyclopentanone was established by kinetic resolution in Chapter 4. This methodology allows us to prepare more ?-hydroxy carbonyl compounds structurally closely related to 3-hydroxycyclopentanone. The isolated chiral alcohols were used to determine the stereochemistry of the Michael addition of water in Chapter 2, saving us a lot of laboratory work. Moreover, unexpected stereoselective reduction of conjugated C = C bonds was discovered during studies on the enantioselective Michael addition of water. As mentioned in Chapter 2, the whole cells of R. rhodochrous ATCC 17895 reduced ?,?-unsaturated cyclic ketones into the corresponding ketones as initially undesired side reaction for the addition of water to C = C bonds. Therefore, ene-reductase activity was also investigated in Chapter 5. A series of substrates, including activated ketones, aldehydes, amines and nitro-compounds were screened for ene-reductase activity using whole cells of R. rhodochrous ATCC 17895. This showed that R. rhodochrous is a very promising catalyst for the reduction of C = C bonds and harbours ene-reductases. Indeed, looking for the annotated ene reductase from the genome of R. rhodochrous ATCC 17895 as described in Chapter 3, three candidates were observed and were classified as ene-reductases by amino acid sequence alignment with the known Old Yellow Enzymes (OYEs). Thus, the putative ene-reductase genes from R. rhodochrous ATCC 17895 were heterologously overexpressed in Escherichia coli and one of the encoded proteins was purified and characterized for their biocatalytic and biochemical properties. Based on these accomplishments it can be concluded that we have discovered a new Michael hydratase and three new ene reductases from Rhodococcus strains. Genome sequence and annotation of strain R. rhodochrous ATCC 17895 has been done, offering an excellent opportunity for the discovering novel enzymes, for instance, the Michael hydratase and S-selective ene reductase. The important chiral ?-hydroxy carbonyl compounds can be prepared by kinetic resolution of racemic alcohols using lipases or the direct enantioselective Michael addition of water using whole cells of Rhodococcus strains. The isolated products from kinetic resolution were readily used for the stereochemistry determination of Michael addition of water in water, completes the story of water addition to C = C bonds.BiotechnologyApplied Science

Application of discrete mathematics in urban transportation system analysis

Editorial.Technology, Policy and Managemen

A Symbolic Approach to Discrete Structural Optimization Using Quantum Annealing

With the advent of novel quantum computing technologies and the new possibilities thereby offered, a prime opportunity has presented itself to investigate the practical application of quantum computing. This work investigates the feasibility of using quantum annealing for structural optimization. The target problem is the discrete truss sizing problem—the goal is to select the best size for each truss member so as to minimize a stress-based objective function. To make the problem compatible with quantum annealing devices, the objective function must be translated into a quadratic unconstrained binary optimization (QUBO) form. This work focuses on exploring the feasibility of making this translation. The practicality of using a quantum annealer for such optimization problems is also assessed. A method is eventually established to translate the objective function into a QUBO form and have it solved by a quantum annealer. However, scaling the method to larger problems faces some challenges that would require further research to addressAerospace Structures & Computational Mechanic

Overcoming the cohesive zone limit in composites delamination: modeling with slender structural elements and higher-order adaptive integration

Cohesive element (CE) is a well-established finite element for fracture, widely used for the modeling of delamination in composites. However, an extremely fine mesh is usually needed to resolve the cohesive zone, making CE-based delamination analysis computationally prohibitive for applications beyond the scale of lab coupons. In this work, a new CE-based method of modeling delamination in composites is proposed to overcome this cohesive zone limit on the mesh density. The proposed method makes use of slender structural elements for the plies, a compatible formulation with adaptive higher-order integration for the CEs, and the corotational formulation for geometrically nonlinear analysis. The proposed method is verified and validated on the classical benchmark problems of Mode I, II, mixed-mode delamination, a buckling-induced delamination problem and a double-delamination problem. The results show that elements much larger than the cohesive zone length can be used while retaining accuracy.Aerospace Structures & Computational Mechanic