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Treatment relapse due to clonal evolution was shown to be an independent factor for poor prognosis in advanced stages of chronic myeloid leukemia. Overcoming secondary resistance arising due to clonal evolution is still an unmet need and lack of adequate pre-clinical models hampers the identification of underlying mechanisms and testing of alternate treatment strategies. The current study thus aimed to create cellular models to study molecular mechanisms underlying clonal evolution and identify strategies to overcome the secondary drug resistance. Analysis of cell lines derived from three independent cell-based screens revealed the co-evolution specifically of imatinib and HSP90 inhibitor (HSP90i) resistances despite their exposure to a single inhibitor alone. Molecular and biochemical characterization of these cell lines revealed additional cytogenetic abnormalities, differential activation of pro-survival signaling molecules and over expression of ABL kinase and HSP90 genes. Importantly, all the imatinib-HSP90i dual resistant cell lines remained sensitive to sorafenib and vorinostat suggesting their utility in treating patients who relapse upon imatinib treatment due to clonal evolution. In addition, we cite similar examples of dual resistance towards various kinase inhibitors and HSP90i in some cell lines that represent solid cancers suggesting co-evolution leading to secondary drug resistance as a pan-cancer phenomenon. Taken together, our results suggest the efficacy of HSP90i in overcoming drug resistance caused by point mutations in the target kinase but not in cases of clonal evolution.

Nowadays, network security plays a major role in the field of wireless communications. Wired networks propagate electrical signals or pulses through cables. Whereas wireless signals propagate through the air. If wireless networks are left open and exposed to the outside world, there are high chances of being misused by others. The intruders take advantage of this, to intercept the wireless signals. This is the reason why an extra level of security is required for wireless networks. The physical layer is one of the important layers of the Open System Interconnection (OSI) model which plays an important role in the network’s physical connections like wireless transmission, cabling, connections etc. The physical layer supports the bit-level transmission between various devices by connecting to the physical medium for synchronized communication.In this thesis, a method is studied for exchanging secret key [1] bits using a pseudo-random sequence generator based on Frequency Division Duplex (FDD) systems. The principle of this method is to generate a secret key in a manner that produces low correlation at the intruder. By uniquely relating the secret key bits to the channel in a private version of the universal codebook, a robust key exchange between the transmitter and the receiver is then performed.

The genus Andrographis, belonging to the family Acanthaceae, contains several species of medicinal importance. Species, such as Andrographis alata, Andrographis echioides, Andrographis glandulosa, Andrographis lineata, Andrographis nallamalayana and Andrographis paniculata, with several bio-active compounds are being extensively used in folk medicine. However, difference of opinion exists with regard to inclusion of the species echioides into the genus Andrographis. The present study, using rbcL and matK sequences, for the first time established DNA barcodes for these six species. The nucleotide sequence of rbcL provided species-specific haplotypes for A. alata, A. lineata, and A. paniculata. Despite the differences with regard to nucleotide sequence, all the six species showed conserved amino acid sequence. However, all the six species showed distinct haplotypes in nucleotide sequence of matK and facilitated the identification and discrimination of these species. The phylogenetic tree generated with combined sequence of rbcL and matK revealed grouping of all the six species into a single clade confirming the positioning of the species echioides into the genus Andrographis.

We revisit the problem of a spatially developing turbulent boundary layer over a concave surface. Unlike previous investigations, we simulate the combined effects of streamline curvature as well as curvature-induced pressure gradients on the turbulence. Our focus is on investigating the response of the turbulent boundary layer to the sudden onset of curvature and the destabilising influence of concave surface in the presence of pressure gradients. This is of interest for evaluating the turbulence closure models. At the beginning of the curve, the momentum thickness Reynolds number is 1520 and the ratio of the boundary layer thickness to the radius of curvature is δ0/R = 0.055. The radial profiles of the mean velocity and turbulence statistics at different locations along the concave surface are presented. Our recently proposed curvature-corrected Reynolds Averaged Navier-Stokes (RANS) model is assessed in an a posteriori sense and the improvements obtained over the base model are reported. From the large ...

An intermittency model that is formulated in local variables is proposed for representing bypass transition in Reynolds-Averaged Navier-Stokes (RANS) computations. No external data correlation is used to fix transition. Transition is initiated by diffusion, and a source term carries it to completion. A sink term is created to predict the laminar region before transition, then it vanishes in the turbulent region. Both the source and sink are functions of a wall-distance Reynolds number and turbulence scale. A modification is introduced to predict transition in separated boundary layers. The transition model is incorporated with the k−ω RANS model. The present model is implemented into a general purpose, computational fluid dynamics (CFD) code. The model is validated with several test cases. Decent agreement with the available data is observed in a range of flows.

Two approaches to incorporate the effects of rotation and curvature in scalar eddy viscosity models are explored. One is the “Modified coefficients approach” – to parameterize the model coefficients such that the growth rate of turbulent kinetic energy is suppressed or enhanced. The other is the “Bifurcation approach” – to parameterize the eddy viscosity coefficient such that the equilibrium solution bifurcates from healthy to decaying solution branches. Simple, yet, predictive models in each of these two approaches are proposed and validated on some benchmark test cases characterized by profound effects of system rotation and/or streamline curvature. The results obtained with both the models are encouraging.

Numerical simulations of spatially developing turbulent boundary layers require specification of realistic, coherent series of time-varying velocity components at the inflow. In this work, a variant of the widely used recycling and rescaling method of generating inflow turbulence has been explored for the large eddy simulation of turbomachinery flows. To avoid the spurious linking of spanwise structures and error accumulation, a mirroring method proposed in the literature has been adopted. A computational framework is developed within an existing LES module in OpenFOAM and preliminary validation is carried out. This framework can potentially be used for eddy simulations of spatially developing boundary layers as well as turbomachinery internal flows with a specific boundary layer thickness at the inflow boundary.

A simple variant of recycling and rescaling method to generate inflow turbulence using unstructured grid CFD codes is presented. The method has been validated on large eddy simulation of spatially developing flat plate turbulent boundary layer. The proposed rescaling algorithm is based on the momentum thickness which is more robust and essentially obviates the need of finding the edge of the turbulent boundary layer in unstructured grid codes. Extension of this algorithm to hybrid RANS/LES type of approaches and for wall-bounded turbomachinery flows is also discussed. Results from annular diffuser with different inflow boundary layer characteristics is presented as an example application to show the utility of such an algorithm., Comment: arXiv admin note: text overlap with arXiv:1408.1060

Scalar eddy viscosity models are the workhorses of industrial CFD. But they are insensitive to the effects of frame rotation and streamline curvature. To enhance the utility of these models in the design process, it is necessary to sensitise them with a rotation/curvature correction. In this paper, we present a unified model for rotation/curvature effects and discuss its applicability for two practically relevant flow configurations. Mean flow characteristics obtained through RANS computations are compared with LES data or experiments. The improvements obtained in using the rotation/curvature correction are highlighted.

International audience; Software applications often depend on external libraries and must be updated when one of those libraries releases a new version. To make this process easier, library developers try to reduce the negative effect of breaking changes by deprecating the API elements before removing them and suggesting replacements to the clients. Modern programming languages and IDEs provide powerful tools for deprecations that can reference the replacement or incorporate the rules written by library developers and use them to automatically update the client code. However, in practice library developers often miss the deprecation opportunities and fail to document the deprecations. In this work, we propose to help library developers support their clients with better deprecations. We rely on the transforming deprecations offered by Pharo and use data mining to detect the missing deprecation opportunities and generate the transformation rules. We implemented our approach for Pharo in a prototype tool called DepMiner. We have applied our tool to five open-source projects and proposed the generated deprecations to core developers of those projects. 63 recommended deprecations were accepted as pull requests.

International audience; Deprecations are a common way to indicate that a given feature or API will not be available in subsequent versions of a library or framework. While raising deprecation warnings lets developers of libraries evolve their APIs, the developers of client applications often have to manually rewrite their applications to adapt to the deprecation (removal, new APIs.. .). Some may use static analysis tools to support the rewriting. However, dynamically-typed languages or the use of reflective features often produce incorrect rewrite candidates. This is a costly activity that can lead to bug introductions. In this article, we present a method deprecation approach and a tool called DEPREWRITER that can automatically rewrite the callers of deprecated methods during program execution. Clients of a deprecated API execute their program and associated tests, and DEPREWRITER dynamically rewrites the source code of methods that called a deprecated API to use the new API. The implementation of DEPREWRITER is based on dynamic program transformation: when a deprecated method is executed, a program transformation engine rewrites and recompiles the caller's code before continuing the execution. The approach presented in this article has been developed by the Pharo consortium. Since 2016, DEPREWRITER is used in production in multiple distributions of the Pharo programming language: Pharo 6, 7, 8, and 9 alpha. This article presents and validates this approach. The validation is done in two steps: first with an analysis of deprecations available in Pharo 8 and second with an open survey of software developers about DEPREWRITER. We studied 367 Pharo 8 deprecations, among which we analyzed the 218 rewriting deprecations that use transformation rules. We identified the validity conditions and reported defects to the community. We also proposed 33 transformation rules to be added to the non-rewriting deprecations. Both contributions were accepted into Pharo 9 alpha. We classified the rules and identified possible points of improvement. In addition, we performed a user survey and collected information from 46 software developers: some of them used existing DEPREWRITER' rules and executed them on their code, others used DEPREWRITER to create rewriting deprecations, and finally, some were not aware of DEPREWRITER. 28 of 46 developers (60%) reported that the rewriting deprecations helped them, while 10 stated the inverse and 8 were uncertain. After discussing the current implementation, we sketch possible implementations for other languages than Pharo, showing that the approach is general enough to be applied to other languages.

International audience; Programming is a form of communication between the person who is writing code and the one reading it. Nevertheless, very often developers neglect readability, and even well-written code becomes less understandable as software evolves. Together with the growing complexity of software systems, this creates an increasing need for automated tools for improving the readability of source code. In this work, we focus on method names and study how a descriptive name can be automatically generated from a method's body. We experiment with two approaches from the field of text summarization: One based on TF-IDF and the other on deep recurrent neural network. We collect a dataset of methods from 50 real world projects. We evaluate our approaches by comparing the generated names to the actual ones and report the result using Precision and Recall metrics. For TF-IDF, we get results as good as 28% precision and 45% recall; and for deep neural network, 46% precision and 32% recall.

International audience; The evolution of software libraries is a process that requires a joint effort of two groups of developers: the library developers who prepare the release and client developers who need to update their applications to the new versions. To build better tools that support both library and client developers throughout the evolution, we need to understand what problems they face and how they react to those problems. In this paper, we present the result of two surveys: one for library developers and one for client developers. Our surveys involved developers from two industrial companies and an open-source community. We assess (1) how they perceive the impact of library evolution and (2) what is the support that library developers can provide to their clients. By approaching those questions from the perspectives of library and client developers, we try to assess how challenging library update is for each of those groups and how motivated they are to overcome those challenges.

International audience; As many other modern programming languages, Pharo spreads its applications into computationally demanding fields such as machine learning, big data, cryptocurrency, etc. This raises a need for fast numerical computation libraries. In this work, we propose to speed up the low-level computations by calling the routines from highly optimized external libraries, e.g., LAPACK or BLAS through the foreign function interface (FFI). As a proof of concept, we build a prototype implementation of linear regression based on the DGELSD routine of LAPACK. Using three benchmark datasets of different sizes, we compare the execution time of our algorithm agains pure Pharo implementation and scikit-learn - a popular Python library for machine learning. We show that LAPACK & Pharo is up to 2103 times faster than pure Pharo. We also show that scikit-learn is 8-5 times faster than our prototype, depending on the size of the data. Finally, we demonstrate that pure Pharo is up to 15 times faster than the equivalent implementation in pure Python. Those findings can lay the foundation for the future work in building fast numerical libraries for Pharo and further using them in higher-level libraries such as pharo-ai.

International audience; Studies have shown that more than 50% of software maintenance time is spent reading code to understand it. This puts a strong emphasis on the understandability of source code. Class names constitute one of the first pieces of information developers have access to. Proposal: To assist developers in understanding the logic and regularity of class names, we present a new and simple visualization, called ClassName Distribution. It brings together package and inheritance as structural perspectives on class names. ClassName Distribution allows one to spot naming irregularities in large hierarchies scattered over multiple packages. Validation: We show (1) how this visualization helps capture recurrent patterns relative to concept reference in class names and (2) that this visualization supports the evolution of software systems by monitoring and guiding class renamings over multiple versions. To evaluate our approach we did a consequent assessment with real practitioners and open-source software structured in two different setups: in the first one, we asked domain experts to use the visualization: three groups of engineers applied our tool to the the software they develop or maintain. They proposed and performed respectively 91, 68, and 24 class renamings. In the second setup, as authors of the visualization and the tool (visualization experts), we applied our tool to a new UI framework for Pharo. We sent 34 pull requests for renaming classes and 32 were accepted. Finally, we applied our visualizations to 50 Java projects and identified visual patterns in most of them. Consequently, it shows that the proposed visualization is effective for spotting class name inconsistencies, and this by both developers of the system and external persons. The visualization presented in this article has been designed with colors, therefore the paper should be printed using an adequate medium or be read digitally.

International audience; Context: Literals are constant values (numbers, strings, etc.) used in the source code. Magic literals are such values used without an explicit explanation of their meaning. Such undocumented values may hinder sourcecode comprehension, negatively impacting maintenance. Relatively little literature can be found on the subject beyond the usual (and very old) recommendation of avoiding literals and preferring named constants. Yet, magic literals are still routinely found in source code. Objective: We studied literal values in source code to understand when they should be considered magic or not (i.e., acceptable). Methods: First, we perform a qualitative study of magic literals, to establish why and under which conditions they are considered harmful. We formalize hypotheses about the reasoning behind how literals are considered magic. Second, we perform a quantitative study on seven real systems ranging from small (a few classes) to large (thousands of classes). We report the literals' types (number, string, Boolean,. . .), their grammatical function (e.g., argument in a call, operand in an expression, value assigned,. . .), or the purpose of the code in which they appear (test methods, regular code). Third, we report on another study involving 26 programmers who analyzed about 24,000 literals, to understand which ones they consider magic. Finally, we evaluate the hypotheses defining specific conditions under which literals are acceptable. Results: We show that (1) literals still exist and are relatively frequent (found in close to 50% of the methods considered); (2) they are more frequent in test methods (in 80% of test methods); (3) to a large extent, they were considered acceptable (only 25% considered magic); and (4) the hypotheses concerning acceptable literals are valid to various degrees. Conclusion: We thus pave the way to future research on magic literals, for example, with tools that could help developers deciding if a literal is acceptable.

International audience; In object-oriented programming, classes are the primary abstraction mechanism used by and exposed to developers. Understanding classes is key for the development and evolution of object-oriented applications. The fundamental problem faced by developers is that while classes are intrinsically structured entities, in IDEs they are represented as a blob of text. The idea behind the original CLASS BLUEPRINT visualization was to represent the internal structure of classes in terms of fields, their accesses, and the method call flow. Additional information was depicted using colors. The thus created visualization proved to be an effective means to support program comprehension. However, a number of omissions rendered it only partially useful. We propose CLASS BLUEPRINT V2 (in short BLUEPRINTV2), which in addition to the information depicted by CLASS BLUEPRINT also supports dead code identification, methods under tests, and calling relationships between class and instance level methods. In addition, BLUEPRINTV2 enhances the understanding of fields by showing how fields of super/subclasses are accessed. We present the enhanced visualization and report on a first validation with 26 developers and 18 projects.