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

A Koiter-Newton arclength method for buckling-sensitive structures

Thin-walled structures, when properly designed, possess a high strength-to-weight and stiffness-to-weight ratio, and therefore are used as the primary components in some weight critical structural applications, such as aerospace and marine engineering. These structures are prone to be limited in their load carrying capability by buckling, while staying in the linear elastic range of the material. Buckling of thinwalled structures is an inherently nonlinear phenomena. When the material stays within its linear elastic range, the source of the nonlinearity is purely geometric. Thus, the analysis of nonlinear response of structures, especially thin-walled structures which are buckling sensitive, is important for determining their load carrying capability. For this reason, structural geometric nonlinearities are increasingly taken into account in engineering design. Nowadays, with the expanding computational power of modern computers nonlinear finite element analysis using commercial software is becoming the standard technique used to obtain the nonlinear response of complex structures, however, the repeated analyses that are needed in the design phase are still computationally intensive, in terms of the computation time required to run large models, even for modern computers. For this reason, reduced order techniques that reduce the problem size are attractive whenever repetitive analyses are required, such as in design optimization. Research on reduced order modeling of the nonlinear response of structures has attracted much attention from researchers. Some analytic techniques constitute very powerful tools for reducing the number of degrees of freedom (DOFs) in a nonlinear system, such as the Rayleigh-Ritz techniques and perturbation techniques. These two reduced basis techniques can be implemented in both analytical and numerical contexts, and due to the modeling versatility of the finite element method (FEM), most researchers prefer to reconstruct them within the FEM context, referred to as reduction methods. There are two families of reduction methods which can be recognized. The first family consists the path-following reduction methods which are based on some analytic techniques to reduce the number of DOFs in the full model and are able to trace the entire nonlinear equilibrium path of structures automatically, while they may find difficulties in the presence of buckling. Koiter reduction methods belong to the second family, and they are very good at handling the buckling sensitive cases due to the use of Koiter’s classical initial postbuckling theory, but the Koiter perturbation approach also limits the validity of these methods to a small range around the bifurcation point. The focus of the research reported in this thesis therefore is to find ways to synthesize the advantages of current reduction methods and obtain a new reduced basis path-following approach. In this thesis, a new approach called the Koiter-Newton (K-N) is presented for the numerical solution of a class of elastic nonlinear structural analysis problems. The method combines ideas from Koiter’s initial post-buckling analysis and Newton arclength methods to obtain an algorithm that is accurate over the entire equilibrium path of structures and efficient in the presence of buckling and/or imperfection sensitivity. The proposed approach is performed in a step by step manner to trace the entire equilibrium path, as is commonly used in the classical Newton arc-length method. In every expansion step, the approach works by combining a prediction step using a nonlinear reduced order model (ROM) based on Koiter’s initial postbuckling expansion with a Newton arc-length correction procedure. This nonlinear prediction provided by the reduced order model is much better compared to linear predictors used by the classical Newton-Raphson method, thus allowing the algorithm to use fairly large step sizes. The basic premise behind the proposed approach is the use of Koiter’s asymptotic expansion from the beginning rather than using it only at the bifurcation point in contrast to the traditional Koiter approaches. In each asymptotic expansion, the force space is reduced by the span of a set of perturbation loads that are chosen to excite the possible buckling branches. According to the stability of the equilibrium point, at which the asymptotic expansion is applied, different ways for selecting the perturbation loads are proposed. The proposed selection rules guarantee that the expansion step of the proposed approach can be applied at any point along the equilibrium path. The proposed technique requires derivatives of the element load vectors with respect to the degrees of freedom up to the third order. This is two orders more than what is traditionally needed for Newton’s method. To facilitate differentiation, nonlinear elements based on the element independent co-rotational frame are applied in the Koiter-Newton analysis. Automatic differentiation is used to find the derivatives of the co-rotational frame with respect to element degrees of freedom. In this way, full nonlinear kinematics are taken into account when constructing the reduced order model. In some cases, the nonlinear in-plane rotations of structures can be neglected, although the rotations of the normals to the mid-surface are finite. In such cases, Von Karman kinematics, which ignore some nonlinear items in the Green’s staindisplacement relations, possess an acceptable accuracy compared with the full nonlinear kinematics. Hence, the Koiter-Newton approach is also implemented based on Von Karman kinematics to achieve a better computational efficiency. Various numerical examples of beam and shell models are presented and used to evaluate the performance of the method. The Koiter-Newton analyses using the corotational kinematics and the Von K´arm´an kinematics are accurate and more computational efficient, compared with the results obtained using ABAQUS which adopts a full nonlinear analysis. The improved efficiency demonstrated by the Koiter-Newton technique will open the door to the direct use of detailed nonlinear finite element models in the design optimization of next generation flight and launch vehicles.Aerospace Structures and Computational MechanicsAerospace Engineerin

A global-local finite element analysis of hybrid composite-to-metal bolted connections used in aerospace engineering

Efficient bolted joint design is an essential part of designing the minimum weight aerospace structures, since structural failures usually occur at connections and interface. A comprehensive numerical study of three-dimensional (3D) stress variations is prohibitively expensive for a large-scale structure where hundreds of bolts can be present. In this work, the hybrid composite-to-metal bolted connections used in the upper stage of European Ariane 5ME rocket are analyzed using the global-local finite element (FE) approach which involves an approximate analysis of the whole structure followed by a detailed analysis of a significantly smaller region of interest. We calculate the Tsai-Wu failure index and the margin of safety using the stresses obtained from ABAQUS. We find that the composite part of a hybrid bolted connection is prone to failure compared to the metal part. We determine the bolt preload based on the clamp-up load calculated using a maximum preload to make the composite part safe. We conclude that the unsuitable bolt preload may cause the failure of the composite part due to the high stress concentration in the vicinity of the bolt. The global-local analysis provides an efficient computational tool for enhancing 3D stress analysis in the highly loaded region.Aerospace Structures & Computational Mechanic

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HPAKE: Honey Password-authenticated Key Exchange for Fast and Safer Online Authentication

Password-only authentication is one of the most popular secure mechanisms for real-world online applications. But it easily suffers from a practical threat - password leakage, incurred by external and internal attackers. The external attacker may compromise the password file stored on the authentication server, and the insider may deliberately steal the passwords or inadvertently leak the passwords. So far, there are two main techniques to address the leakage: Augmented password-authentication key exchange (aPAKE) against insiders and honeyword technique for external attackers. But none of them can resist both attacks. To fill the gap, we propose the notion of <italic>honey PAKE (HPAKE)</italic> that allows the authentication server to detect the password leakage and achieve the security beyond the traditional bound of aPAKE. Further, we build an HPAKE construction on the top of the honeyword mechanism, honey encryption, and OPAQUE which is a standardized aPAKE. We formally analyze the security of our design, achieving the insider resistance and the password breach detection. We implement our design and deploy it in the real environment. The experimental results show that our protocol only costs 71.27 ms for one complete run, within 20.67 ms on computation and 50.6 ms on communication. This means our design is secure and practical for real-world applications.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.Cyber Securit

No-Directional and Backward-Leak Uni-Directional Updatable Encryption Are Equivalent

Updatable encryption (UE) enables the cloud server to update the previously sourced encrypted data to a new key with only an update token received from the client. Two interesting works have been proposed to clarify the relationships among various UE security notions. Jiang (ASIACRYPT 2020) proved the equivalence of every security notion in the bi-directional and uni-directional key update settings and further, the security notion in the no-directional key update setting is strictly stronger than the above two. In contrast, Nishimaki (PKC 2022) proposed a new definition of uni-directional key update that is called the backward-leak uni-directional key update, and showed the equivalence relation by Jiang does not hold in this setting. We present a detailed comparison of every security notion in the four key update settings and prove that the security in the backward-leak uni-directional key update setting is actually equivalent to that in the no-directional key update setting. Our result reduces the hard problem of constructing no-directional key update UE schemes to the construction of those with backward-leak uni-directional key updates.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.Cyber Securit

Thermal deformation and stress of alkali-activated slag concrete under semi-adiabatic condition: Experiments and simulations

This study investigates the deformation of free and stress of restrained alkali-activated slag concrete (AASC), respectively, under semi-adiabatic condition. The concrete shows first thermal expansion, which is compensated soon by autogenous shrinkage. The subsequent cooling down of the concrete aggravates shrinkage and development of tensile stress, which eventually results in early cracking of the concrete. The results show that semi-adiabatic condition is severer for AASC than isothermal condition in view of cracking tendency. The evolutions of coefficient of thermal expansion (CTE) and elastic modulus are measured by elaborated experimental methods. Simulating the deformation of AASC by summing thermal and autogenous deformations appears feasible. With the consideration of relaxation, the stress evolution in restrained AASC can be predicted pretty well by the model used in this paper. This study provides insights into the thermal deformation and cracking tendency of AASC in practical circumstances.Materials and Environmen

Combining ID’s, Attributes, and Policies in Hyperledger Fabric

This work aims to provide a more secure access control in Hyperledger Fabric blockchain by combining multiple ID’s, attributes, and policies with the components that regulate access control. The access control system currently used by Hyperledger Fabric is first completely analyzed. Next, a new implementation is proposed that builds upon the existing solution but provides users and developers with easier ways to make access control decisions based on combinations of multiple ID’s, attributes, and policies. Our proposed implementation encapsulates the Fabric CA client to facilitate attribute addition and simplify the process of registering and enrolling a newly created certificate (corresponding to a new user). This research, concludes that it is possible to combine multiple ID’s, attributes, and policies with the help of Hyperledger Fabric’s smart contract technology. Furthermore, it could be seen that the performance impact for real-world applications is negligible compared to the insecure case of always providing access to a resource without performing access control.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.Cyber Securit

ID-Based Self-encryption via Hyperledger Fabric Based Smart Contract

This paper offers a prototype of a Hyperledger Fabric-IPFS based network architecture including a smart contract based encryption scheme that meant to improve the security of user’s data that is being uploaded to the distributed ledger. A new extension to the self-encryption scheme was deployed by integrating data owner’s identity into the encryption process. Such integration allows to permanently preserve ownership of the original file and link it to the person/entity who originally uploaded it. Moreover, self-encryption provides strong security guarantees that decryption of a file is computationally not feasible under the condition that the encrypted file and the key are safely stored.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.Cyber Securit

Your Smart Contracts Are Not Secure: Investigating Arbitrageurs and Oracle Manipulators in Ethereum

Smart contracts on Ethereum enable billions of dollars to be transacted in a decentralized, transparent and trustless environment. However, adversaries lie await in the Dark Forest, waiting to exploit any and all smart contract vulnerabilities in order to extract profits from unsuspecting victims in this new financial system. As the blockchain space moves at a breakneck pace, exploits on smart contract vulnerabilities rapidly evolve, and existing research quickly becomes obsolete. It is imperative that smart contract developers stay up to date on the current most damaging vulnerabilities and countermeasures to ensure the security of users' funds, and to collectively ensure the future of Ethereum as a financial settlement layer. This research work focuses on two smart contract vulnerabilities: transaction-ordering dependency and oracle manipulation. Combined, these two vulnerabilities have been exploited to extract hundreds of millions of dollars from smart contracts in the past year (2020-2021). For each of them, this paper presents: (1) a literary survey from recent (as of 2021) formal and informal sources; (2) a reproducible experiment as code demonstrating the vulnerability and, where applicable, countermeasures to mitigate the vulnerability; and (3) analysis and discussion on proposed countermeasures. To conclude, strengths, weaknesses and trade-offs of these countermeasures are summarised, inspiring directions for future research. Cyber Securit