Zoltán Horváth

Feldspar: A domain specific language for digital signal processing algorithms

A new language, Feldspar, is presented, enabling high-level and platform-independent description of digital signal processing (DSP) algorithms. Feldspar is a pure functional language embedded in Haskell. It offers a high-level dataflow style of programming, as well as a more mathematical style based on vector indices. The key to generating efficient code from such descriptions is a high-level optimization technique called vector fusion. Feldspar is based on a low-level, functional core language which has a relatively small semantic gap to machine-oriented languages like C. The core language serves as the interface to the back-end code generator, which produces C. For very small examples, the generated code performs comparably to hand-written C code when run on a DSP target. While initial results are promising, to achieve good performance on larger examples, issues related to memory access patterns and array copying will have to be addressed.

Small molecule inhibition of ERK dimerization prevents tumorigenesis by RAS-ERK pathway oncogenes

Nearly 50% of human malignancies exhibit unregulated RAS-ERK signaling; inhibiting it is a valid strategy for antineoplastic intervention. Upon activation, ERK dimerize, which is essential for ERK extranuclear, but not for nuclear, signaling. Here, we describe a small molecule inhibitor for ERK dimerization that, without affecting ERK phosphorylation, forestalls tumorigenesis driven by RAS-ERK pathway oncogenes. This compound is unaffected by resistance mechanisms that hamper classical RAS-ERK pathway inhibitors. Thus, ERK dimerization inhibitors provide the proof of principle for two understudied concepts in cancer therapy: (1) the blockade of sub-localization-specific sub-signals, rather than total signals, as a means of impeding oncogenic RAS-ERK signaling and (2) targeting regulatory protein-protein interactions, rather than catalytic activities, as an approach for producing effective antitumor agents.

Central European Functional Programming School

Domain-specific languages are a popular application area for functional programming; and conversely, functional programming is a popular implementation vehicle for domain-specific languages—at least, for embedded ones. Why is this? The appeal of embedded domain-specific languages is greatly enhanced by the presence of convenient lightweight tools for defining, implementing, and optimising new languages; such tools represent one of functional programming’s strengths. In these lectures we discuss functional programming techniques for embedded domainspecific languages; we focus especially on algebraic datatypes and higherorder functions, and their influence on deep and shallow embeddings.

Signalling Inhibitors Against Mycobacterium tuberculosis – Early Days of a New Therapeutic Concept in Tuberculosis

Tuberculosis causes nearly two million deaths per year world-wide. In addition multidrug-resistant mycobacterial strains rapidly emerge so novel therapeutic approaches are needed. Recently, several promising mycobacterial target molecules were identified, which are involved in bacterial or host cell signalling e.g. the serine/threonine protein kinases, PknB and PknG, NAD kinase and the NAD synthetase. Here we describe some early efforts in the development of novel signal transduction inhibitory anti-mycobacterial drugs using a multiple target approach, with special emphasis on the kinase inhibitory field. Initially, we are using the Nested Chemical Library (NCL) technology and pharmacophore modelling. A hit-finding library, consisting of approximately 19000 small molecules with a bias for prototypic kinase inhibitors from our NCL library and commercial sources was virtually screened against these validated target molecules. Protein structures for the virtual screening were taken from the published three dimensional crystal structures of the enzymes. The hits from the virtual screening were subsequently tested in enzymatic assay systems. Potent hits were then tested for biological activity in macrophages, infected with mycobacteria. The final goal of this exercise is not only to identify potent anti-mycobacterial substances, but also a common pharmacophore for the mycobacterial target PknG in combination with PknB, NAD kinase and/or NAD synthetase. This common pharmacophore still needs to be a unique pharmacophore for the mycobacterial target proteins over human off-targets. Such a pharmacophore might then drive the optimization of a completely new profile of an antibiotic agent with activity against latent mycobacteria and resistance mycobacterial strains.

Discovering parallel pattern candidates in Erlang

The ParaPhrase Refactoring Tool for Erlang PaRTE provides automatic, comprehensive and reliable pattern candidate discovery to locate parallelisable components in Erlang programs. It uses semi-automatic and semantics-preserving program transformations to reshape source code and to introduce high level parallel patterns that can be mapped adaptively to the available hardware resources. This paper describes the main PaRTE tools and demonstrates that significant parallel speedups can be obtained.

Parallel elementwise processable functions in concurrent clean

The behaviour of concurrent and parallel programs can be specified in a functional style. Functional programming style has some inherent concurrent features. However, for a higher degree of expressing parallelism there is a need for new language constructs. In this paper, we introduce Concurrent Clean modules for evaluation strategies in order to control the evaluation degree, the dynamic behaviour, and the parallelism. The usage of the strategies will be illustrated by the parallel elementwise processing method. The implementation of the method in the lazy functional programming language Concurrent Clean operates with a two arguments two values elementwise processable function. In order to obtain abstract type specification for the generalised manipulation of the linear data structures like lists, arrays, and strict arrays, a linear data structure class module is defined. The programming style is skeleton based. Skeletons in functional languages are higher-order functions. The skeleton given in this paper represents a generalisation of the map function. It is triply parameterized: by an elementwise processable function, by type specification, and by the strategy parameter that defines the dynamic behaviour of the program.

Stable isotope geochemistry of calcrete nodules and septarian concretions in a Quaternary ‘red clay’ paleovertisol from Hungary

Calcrete nodules and concretions in unusually large amounts are embedded in the Quaternary clay-rich (Vertisol-type) ‘red clay’ soil-sedimentary complex at the pediment of the Mátra Mountains (Hungary). Stable isotope signatures were studied in nodules and septarian concretions, uncommon due to their several millimeter sized calcite crystals filling voids and fractures, to reveal their origin. The isotope composition of calcrete covers a wide range: δ18O=−5.9 to−10.4 ‰ and δ13C=−8.9 to−12.3 ‰ (vs. V-PDB). Isotope compositions support pedogenic (sensu stricto) and/or shallow groundwater origin for the calcrete nodules and concretions, the role of ‘evolved’ (isotopically modified) groundwaters in the formation of secondary carbonate was possibly subordinate. Late-stage, large, Mn-rich euhedral calcite crystals in concretions have the lowest δ13C values, which are interpreted as a result of larger contribution of isotopically light organic carbon due to decomposition of organic matter under reducing conditions. Precipitation of late calcite crystals in concretions occurred in early diagenetic environment after shallow burial of the ‘red clay’ paleovertisol. †Revised version of a paper presented at the VIII Isotope Workshop of the European Society for Isotope Research (ESIR), June 25 to 30, 2005, Leipzig-Halle, Germany

Impact analysis of erlang programs using behaviour dependency graphs

During the lifetime of a software product certain changes could be performed on its source code. After those changes a regression test should be performed, which is the most expensive part of the software development cycle. This paper focuses on programs written in a dynamic functional programming language Erlang, and discusses a mechanism that could select those test cases, which are affected by a change, i.e. altering the program on some point may have impact on the result/behaviour of those test cases. In the result of that analysis it is possible to reduce the number of necessary test cases, and after modifying the source code, just a subset of the test cases should be retested. The discussed approach introduces a behaviour dependency graph for Erlang programs to represent the dependencies in the source code. The impact of a change can be calculated by traversing the graph.

Developing FGFR4 Inhibitors As Potential Anti-Cancer Agents Via In Silico Design, Supported by In Vitro and Cell-Based Testing

Fibroblast growth factor receptor-4 (FGFR4) is a tyrosine kinase with a range of important physiological functions. However, it is also frequently mutated in various cancers and is now generating significant interest as a potential therapeutic target. Unfortunately, biochemical characterization of its role in disease, and further evaluation as a drug target is hampered by lack of a specific inhibitor. We aimed to discover new inhibitors for FGFR4 ab initio using a strategy combining in silico, in vitro and cell-based assays. We used the homologous FGFR1 to calculate docking scores of a chemically-diverse library of approximately 2000 potential kinase inhibitors. Nineteen potential inhibitors and ten randomly- selected negative controls were taken forward for in vitro FGFR4 kinase assays. All compounds with good docking scores significantly inhibited FGFR4 kinase activity, some with sub-micromolar (most potent being V4-015 with an IC(50) of 0.04 μM). Four of these compounds also demonstrated substantial activity in cellular assays using the FGFR4- overexpressing breast carcinoma cell line, MDA-MB453. Through immunoblot assays, these compounds were shown to block the phosphorylation of the FGFR4 adaptor protein, FGFR substrate protein-2α (FRS2α). The most potent compound to date, V4-015, suppressed proliferation of MDA-MB453 cells at sub-micromolar concentrations, activated the pro-apoptotic caspases 3/7 and inhibited cellular migration. While achieving complete selectivity of this compound for FGFR4 will require further lead optimization, this study has successfully identified new chemical scaffolds with unprecedented FGFR4 inhibition capacities that will support mechanism of action studies and future anti-cancer drug design.

Introducing records by refactoring

This paper focuses on introducing a new transformation to our existing model for refactoring Erlang programs. The goal of the transformation is to introduce a new abstraction level in data representation by substituting a group ofrelated data with a record. Using records enhances the legibility of the source code, makes further development easier, and makes programming less error-prone by providing better possibilities for both compilation time and runtime checks. There is a strong industrial demand for such a transformation in refactoring legacy code. Erlang is a dynamically typed language, and many of its semantical rules are also dynamic. Therefore the main challenge in this research is to ensure the safety of statically performed refactoring steps.