Mechanisms of Ligand–Protein Interaction in Sec-14-like Transporters Investigated by Computer Simulations

We review our recent work on protein-ligand interactions in vitamin transporters of the Sec-14-like protein. Our studies focused on the cellular-retinaldehyde binding protein (CRALBP) and the alpha-tocopherol transfer protein (alpha-TTP). CRALBP is responsible for mobilisation and photo-protection of short-chain cis-retinoids in the dim-light visual cycle or rod photoreceptors. alpha-TTP is a key protein responsible for selection and retention of RRR-alpha-tocopherol, the most active isoform of vitamin E in superior animals. Our simulation studies evidence how subtle chemical variations in the substrate can lead to significant distortion in the structure of the complex, and how these changes can either lead to new protein function, or be used to model engineered protein variants with tailored properties. Finally, we show how integration of computational and experimental results can contribute in synergy to the understanding of fundamental processes at the biomolecular scale.

Computer assisted planning and navigation of periacetabular osteotomy with range of motion optimization

Femoroacetabular impingement (FAI) before or after Periacetabular Osteotomy (PAO) is surprisingly frequent and surgeons need to be aware of the risk preoperatively and be able to avoid it intraoperatively. In this paper we present a novel computer assisted planning and navigation system for PAO with impingement analysis and range of motion (ROM) optimization. Our system starts with a fully automatic detection of the acetabular rim, which allows for quantifying the acetabular morphology with parameters such as acetabular version, inclination and femoral head coverage ratio for a computer assisted diagnosis and planning. The planned situation was optimized with impingement simulation by balancing acetabuar coverage with ROM. Intra-operatively navigation was conducted until the optimized planning situation was achieved. Our experimental results demonstrated: 1) The fully automated acetabular rim detection was validated with accuracy 1.1 ± 0.7mm; 2) The optimized PAO planning improved ROM significantly compared to that without ROM optimization; 3) By comparing the pre-operatively planned situation and the intra-operatively achieved situation, sub-degree accuracy was achieved for all directions.

Predicting dependencies using domain-based coupling

Software dependencies play a vital role in programme comprehension, change impact analysis and other software maintenance activities. Traditionally, these activities are supported by source code analysis; however, the source code is sometimes inaccessible or difficult to analyse, as in hybrid systems composed of source code in multiple languages using various paradigms (e.g. object-oriented programming and relational databases). Moreover, not all stakeholders have adequate knowledge to perform such analyses. For example, non-technical domain experts and consultants raise most maintenance requests; however, they cannot predict the cost and impact of the requested changes without the support of the developers. We propose a novel approach to predicting software dependencies by exploiting the coupling present in domain-level information. Our approach is independent of the software implementation; hence, it can be used to approximate architectural dependencies without access to the source code or the database. As such, it can be applied to hybrid systems with heterogeneous source code or legacy systems with missing source code. In addition, this approach is based solely on information visible and understandable to domain users; therefore, it can be efficiently used by domain experts without the support of software developers. We evaluate our approach with a case study on a large-scale enterprise system, in which we demonstrate how up to 65 of the source code dependencies and 77% of the database dependencies are predicted solely based on domain information.

Top-Down Parsing with Parsing Contexts

The domain of context-free languages has been extensively explored and there exist numerous techniques for parsing (all or a subset of) context-free languages. Unfortunately, some programming languages are not context-free. Using standard context-free parsing techniques to parse a context-sensitive programming language poses a considerable challenge. Im- plementors of programming language parsers have adopted various techniques, such as hand-written parsers, special lex- ers, or post-processing of an ambiguous parser output to deal with that challenge. In this paper we suggest a simple extension of a top-down parser with contextual information. Contrary to the tradi- tional approach that uses only the input stream as an input to a parsing function, we use a parsing context that provides ac- cess to a stream and possibly to other context-sensitive infor- mation. At a same time we keep the context-free formalism so a grammar definition stays simple without mind-blowing context-sensitive rules. We show that our approach can be used for various purposes such as indent-sensitive parsing, a high-precision island parsing or XML (with arbitrary el- ement names) parsing. We demonstrate our solution with PetitParser, a parsing-expression grammar based, top-down, parser combinator framework written in Smalltalk.

Mining the Ecosystem to Improve Type Inference For Dynamically Typed Languages

Dynamically typed languages lack information about the types of variables in the source code. Developers care about this information as it supports program comprehension. Ba- sic type inference techniques are helpful, but may yield many false positives or negatives. We propose to mine information from the software ecosys- tem on how frequently given types are inferred unambigu- ously to improve the quality of type inference for a single system. This paper presents an approach to augment existing type inference techniques by supplementing the informa- tion available in the source code of a project with data from other projects written in the same language. For all available projects, we track how often messages are sent to instance variables throughout the source code. Predictions for the type of a variable are made based on the messages sent to it. The evaluation of a proof-of-concept prototype shows that this approach works well for types that are sufficiently popular, like those from the standard librarie, and tends to create false positives for unpopular or domain specific types. The false positives are, in most cases, fairly easily identifiable. Also, the evaluation data shows a substantial increase in the number of correctly inferred types when compared to the non-augmented type inference.

Fully Automatic CT Segmentation for Computer-Assisted Pre-operative Planning of Hip Arthroscopy

Extraction of both pelvic and femoral surface models of a hip joint from CT data for computer-assisted pre-operative planning of hip arthroscopy is addressed. We present a method for a fully automatic image segmentation of a hip joint. Our method works by combining fast random forest (RF) regression based landmark detection, atlas-based segmentation, with articulated statistical shape model (aSSM) based hip joint reconstruction. The two fundamental contributions of our method are: (1) An improved fast Gaussian transform (IFGT) is used within the RF regression framework for a fast and accurate landmark detection, which then allows for a fully automatic initialization of the atlas-based segmentation; and (2) aSSM based fitting is used to preserve hip joint structure and to avoid penetration between the pelvic and femoral models. Validation on 30 hip CT images show that our method achieves high performance in segmenting pelvis, left proximal femur, and right proximal femur surfaces with an average accuracy of 0.59 mm, 0.62 mm, and 0.58 mm, respectively.

Service level agreements-driven management of distributed applications in cloud computing environments

Advancements in cloud computing have enabled the proliferation of distributed applications, which require management and control of multiple services. However, without an efficient mechanism for scaling services in response to changing workload conditions, such as number of connected users, application performance might suffer, leading to violations of Service Level Agreements (SLA) and possible inefficient use of hardware resources. Combining dynamic application requirements with the increased use of virtualised computing resources creates a challenging resource Management context for application and cloud-infrastructure owners. In such complex environments, business entities use SLAs as a means for specifying quantitative and qualitative requirements of services. There are several challenges in running distributed enterprise applications in cloud environments, ranging from the instantiation of service VMs in the correct order using an adequate quantity of computing resources, to adapting the number of running services in response to varying external loads, such as number of users. The application owner is interested in finding the optimum amount of computing and network resources to use for ensuring that the performance requirements of all her/his applications are met. She/he is also interested in appropriately scaling the distributed services so that application performance guarantees are maintained even under dynamic workload conditions. Similarly, the infrastructure Providers are interested in optimally provisioning the virtual resources onto the available physical infrastructure so that her/his operational costs are minimized, while maximizing the performance of tenants’ applications. Motivated by the complexities associated with the management and scaling of distributed applications, while satisfying multiple objectives (related to both consumers and providers of cloud resources), this thesis proposes a cloud resource management platform able to dynamically provision and coordinate the various lifecycle actions on both virtual and physical cloud resources using semantically enriched SLAs. The system focuses on dynamic sizing (scaling) of virtual infrastructures composed of virtual machines (VM) bounded application services. We describe several algorithms for adapting the number of VMs allocated to the distributed application in response to changing workload conditions, based on SLA-defined performance guarantees. We also present a framework for dynamic composition of scaling rules for distributed service, which used benchmark-generated application Monitoring traces. We show how these scaling rules can be combined and included into semantic SLAs for controlling allocation of services. We also provide a detailed description of the multi-objective infrastructure resource allocation problem and various approaches to satisfying this problem. We present a resource management system based on a genetic algorithm, which performs allocation of virtual resources, while considering the optimization of multiple criteria. We prove that our approach significantly outperforms reactive VM-scaling algorithms as well as heuristic-based VM-allocation approaches.

Skolemization for Substructural Logics

The usual Skolemization procedure, which removes strong quantifiers by introducing new function symbols, is in general unsound for first-order substructural logics defined based on classes of complete residuated lattices. However, it is shown here (following similar ideas of Baaz and Iemhoff for first-order intermediate logics in [1]) that first-order substructural logics with a semantics satisfying certain witnessing conditions admit a “parallel” Skolemization procedure where a strong quantifier is removed by introducing a finite disjunction or conjunction (as appropriate) of formulas with multiple new function symbols. These logics typically lack equivalent prenex forms. Also, semantic consequence does not in general reduce to satisfiability. The Skolemization theorems presented here therefore take various forms, applying to the left or right of the consequence relation, and to all formulas or only prenex formulas.

Decision Support Models for Composing and Navigating through e-Learning Objects

Libraries of learning objects may serve as basis for deriving course offerings that are customized to the needs of different learning communities or even individuals. Several ways of organizing this course composition process are discussed. Course composition needs a clear understanding of the dependencies between the learning objects. Therefore we discuss the metadata for object relationships proposed in different standardization projects and especially those suggested in the Dublin Core Metadata Initiative. Based on these metadata we construct adjacency matrices and graphs. We show how Gozinto-type computations can be used to determine direct and indirect prerequisites for certain learning objects. The metadata may also be used to define integer programming models which can be applied to support the instructor in formulating his specifications for selecting objects or which allow a computer agent to automatically select learning objects. Such decision models could also be helpful for a learner navigating through a library of learning objects. We also sketch a graph-based procedure for manual or automatic sequencing of the learning objects.

The sequence comparison index: A novel method for comparing proteins and proteomes

Historically morphological features were used as the primary means to classify organisms. However, the age of molecular genetics has allowed us to approach this field from the perspective of the organism's genetic code. Early work used highly conserved sequences, such as ribosomal RNA. The increasing number of complete genomes in the public data repositories provides the opportunity to look not only at a single gene, but at organisms' entire parts list. ^ Here the Sequence Comparison Index (SCI) and the Organism Comparison Index (OCI), algorithms and methods to compare proteins and proteomes, are presented. The complete proteomes of 104 sequenced organisms were compared. Over 280 million full Smith-Waterman alignments were performed on sequence pairs which had a reasonable expectation of being related. From these alignments a whole proteome phylogenetic tree was constructed. This method was also used to compare the small subunit (SSU) rRNA from each organism and a tree constructed from these results. The SSU rRNA tree by the SCI/OCI method looks very much like accepted SSU rRNA trees from sources such as the Ribosomal Database Project, thus validating the method. The SCI/OCI proteome tree showed a number of small but significant differences when compared to the SSU rRNA tree and proteome trees constructed by other methods. Horizontal gene transfer does not appear to affect the SCI/OCI trees until the transferred genes make up a large portion of the proteome. ^ As part of this work, the Database of Related Local Alignments (DaRLA) was created and contains over 81 million rows of sequence alignment information. DaRLA, while primarily used to build the whole proteome trees, can also be applied shared gene content analysis, gene order analysis, and creating individual protein trees. ^ Finally, the standard BLAST method for analyzing shared gene content was compared to the SCI method using 4 spirochetes. The SCI system performed flawlessly, finding all proteins from one organism against itself and finding all the ribosomal proteins between organisms. The BLAST system missed some proteins from its respective organism and failed to detect small ribosomal proteins between organisms. ^

On Understanding How Developers Use the Spotter Search Tool

Analyzing how software engineers use the Integrated Development Environment (IDE) is essential to better understanding how engineers carry out their daily tasks. Spotter is a code search engine for the Pharo programming language. Since its inception, Spotter has been rapidly and broadly adopted within the Pharo community. However, little is known about how practitioners employ Spotter to search and navigate within the Pharo code base. This paper evaluates how software engineers use Spotter in practice. To achieve this, we remotely gather user actions called events. These events are then visually rendered using an adequate navigation tool chain. Sequences of events are represented using a visual alphabet. We found a number of usage patterns and identified underused Spotter features. Such findings are essential for improving Spotter.

Reusable Knowledge-based Components for Building Software Applications: A Knowledge Modelling Approach

In computer science, different types of reusable components for building software applications were proposed as a direct consequence of the emergence of new software programming paradigms. The success of these components for building applications depends on factors such as the flexibility in their combination or the facility for their selection in centralised or distributed environments such as internet. In this article, we propose a general type of reusable component, called primitive of representation, inspired by a knowledge-based approach that can promote reusability. The proposal can be understood as a generalisation of existing partial solutions that is applicable to both software and knowledge engineering for the development of hybrid applications that integrate conventional and knowledge based techniques. The article presents the structure and use of the component and describes our recent experience in the development of real-world applications based on this approach.

Some issues in analysis and specialization of modular ciao-prolog programs

Separating programs into modules is a well-known technique which has proven very useful in program development and maintenance. Starting by introducing a number of possible scenarios, in this paper we study different issues which appear when developing analysis and specialization techniques for modular logic programming. We discuss a number of design alternatives and their consequences for the different scenarios considered and describe where applicable the decisions made in the Ciao system analyzer and specializer. In our discussion we use the module system of Ciao Prolog. This is both for concreteness and because Ciao Prolog is a second-generation Prolog system which has been designed with global analysis and specialization in mind, and which has a strict module system. The aim of this work is not to provide a theoretical basis on modular analysis and specialization, but rather to discuss some interesting practical issues.

The ciao module system: A new module system for prolog

Ciao Prolog incorporates a module system which allows sepárate compilation and sensible creation of standalone executables. We describe some of the main aspects of the Ciao modular compiler, ciaoc, which takes advantage of the characteristics of the Ciao Prolog module system to automatically perform sepárate and incremental compilation and efficiently build small, standalone executables with competitive run-time performance, ciaoc can also detect statically a larger number of programming errors. We also present a generic code processing library for handling modular programs, which provides an important part of the functionality of ciaoc. This library allows the development of program analysis and transformation tools in a way that is to some extent orthogonal to the details of module system design, and has been used in the implementation of ciaoc and other Ciao system tools. We also describe the different types of executables which can be generated by the Ciao compiler, which offer different tradeoffs between executable size, startup time, and portability, depending, among other factors, on the linking regime used (static, dynamic, lazy, etc.). Finally, we provide experimental data which illustrate these tradeoffs.

The ciao modular, standalone compiler and its generic program processing library

Ciao Prolog incorporates a module system which allows sepárate compilation and sensible creation of standalone executables. We describe some of the main aspects of the Ciao modular compiler, ciaoc, which takes advantage of the characteristics of the Ciao Prolog module system to automatically perform sepárate and incremental compilation and efficiently build small, standalone executables with competitive run-time performance, ciaoc can also detect statically a larger number of programming errors. We also present a generic code processing library for handling modular programs, which provides an important part of the functionality of ciaoc. This library allows the development of program analysis and transformation tools in a way that is to some extent orthogonal to the details of module system design, and has been used in the implementation of ciaoc and other Ciao system tools. We also describe the different types of executables which can be generated by the Ciao compiler, which offer different tradeoffs between executable size, startup time, and portability, depending, among other factors, on the linking regime used (static, dynamic, lazy, etc.). Finally, we provide experimental data which illustrate these tradeoffs.