Mutations in the ligand-binding domain of the kit receptor: an uncommon site in human piebaldism

Heterozygous mutations in the gene for the Kit transmembrane receptor have been identified recently in human piebaldism and mouse "dominant spotting." Interestingly, all of the 14 known missense mutations that cause depigmentation in these species map to the tyrosine kinase domain of the receptor, whereas none have involved the extracellular ligand-binding domain. In an attempt to detect these uncommon mutations, we screened the nine exons encoding the extracellular portion of Kit for single-strand conformation polymorphisms (SSCP) in eight piebald subjects previously reported to be negative for kinase mutations. Four of these eight kindreds proved to carry novel mutations. The first mutation, found in two apparently unrelated probands with mild piebaldism and English ancestry, substitutes an arginine for a highly conserved cysteine at codon 136. This substitution disrupts a putative disulfide bond required for formation of the second Ig-like (D2) loop of the Kit ligand-binding domain. The second mutation, detected in a piebald kindred characterized by unusually limited depigmentation, substitutes a threonine for an alanine at codon 178, a site just proximal to conserved cysteines at codons 183 and 186. The third mutation, occurring in a kindred with more extensive depigmentation, is a novel four-base insertion in exon 2 that results in a proximal frameshift and premature termination. The data strongly suggest that piebaldism can result from missense mutations in the Kit ligand-binding domain, although the resulting phenotype may be milder than that observed for null or kinase mutations. The apparent clustering of these uncommon mutations at or near the conserved cysteines for the D2 Ig-like loop further suggests a critical role for this region in Kit receptor function.     

Proteomics in chronic kidney disease: The issues clinical nephrologists need an answer for

A growing number of patients are recognised to have chronic kidney disease (CKD). However, only a minority will progress to end-stage renal disease requiring dialysis or transplantation. Currently available diagnostic and staging tools frequently fail to identify those at higher risk of progression or death. Furthermore within specific disease entities there are shortcomings in the prediction of the need for therapeutic interventions or the response to different forms of therapy. Kidney and urine proteomic biomarkers are considered as promising diagnostic tools to predict CKD progression early in diabetic nephropathy, facilitating timely and selective intervention that may reduce the related health-care expenditures. However, independent groups have not validated these findings and the technique is not currently available for routine clinical care. Furthermore, there are gaps in our understanding of predictors of progression or need for therapy in non-diabetic CKD. Presumably, a combination of tissue and urine biomarkers will be more informative than individual markers. This review identifies clinical questions in need of an answer, summarises current information on proteomic biomarkers and CKD, and describes the European Kidney and Urine Proteomics initiative that has been launched to carry out a clinical study aimed at identifying urinary proteomic biomarkers distinguishing between fast and slow progressors among patients with biopsy-proven primary glomerulopathies.     

On the 2-tuples based genetic tuning performance for fuzzy rule based classification systems in imbalanced data-sets

When performing a classification task, we may find some data-sets with a different class distribution among their patterns. This problem is known as classification with imbalanced data-sets and it appears in many real application areas. For this reason, it has recently become a relevant topic in the area of Machine Learning.The aim of this work is to improve the behaviour of fuzzy rule based classification systems (FRBCSs) in the framework of imbalanced data-sets by means of a tuning step. Specifically, we adapt the 2-tuples based genetic tuning approach to classification problems showing the good synergy between this method and some FRBCSs.Our empirical results show that the 2-tuples based genetic tuning increases the performance of FRBCSs in all types of imbalanced data. Furthermore, when the initial Rule Base, built by a fuzzy rule learning methodology, obtains a good behaviour in terms of accuracy, we achieve a higher improvement in performance for the whole model when applying the genetic 2-tuples post-processing step. This enhancement is also obtained in the case of cooperation with a preprocessing stage, proving the necessity of rebalancing the training set before the learning phase when dealing with imbalanced data.     

Shortcut fusion rules for the derivation of circular and higher-order programs

Functional programs often combine separate parts using intermediate data structures for communicating results. Programs so defined are modular, easier to understand and maintain, but suffer from inefficiencies due to the generation of those gluing data structures. To eliminate such redundant data structures, some program transformation techniques have been proposed. One such technique is shortcut fusion, and has been studied in the context of both pure and monadic functional programs. In this paper, we study several shortcut fusion extensions, so that, alternatively, circular or higher-order programs are derived. These extensions are also provided for effect-free programs and monadic ones. Our work results in a set of generic calculation rules, that are widely applicable, and whose correctness is formally established.     

Performance of Scheduling Policies in Adversarial Networks with Non-synchronized Clocks

In this paper we generalize the Continuous Adversarial Queuing Theory (CAQT) model (Blesa et al. in MFCS, Lecture Notes in Computer Science, vol. 3618, pp. 144–155, 2005) by considering the possibility that the router clocks in the network are not synchronized. We name the new model Non Synchronized CAQT (NSCAQT). Clearly, this new extension to the model only affects those scheduling policies that use some form of timing. In a first approach we consider the case in which although not synchronized, all clocks run at the same speed, maintaining constant differences. In this case we show that all universally stable policies in CAQT that use the injection time and the remaining path to schedule packets remain universally stable. These policies include, for instance, Shortest in System (SIS) and Longest in System (LIS). Then, we study the case in which clock differences can vary over time, but the maximum difference is bounded. In this model we show the universal stability of two families of policies related to SIS and LIS respectively (the priority of a packet in these policies depends on the arrival time and a function of the path traversed). The bounds we obtain in this case depend on the maximum difference between clocks. This is a necessary requirement, since we also show that LIS is not universally stable in systems without bounded clock difference. We then present a new policy that we call Longest in Queues (LIQ), which gives priority to the packet that has been waiting the longest in edge queues. This policy is universally stable and, if clocks maintain constant differences, the bounds we prove do not depend on them. To finish, we provide with simulation results that compare the behavior of some of these policies in a network with stochastic injection of packets.     

Optimization of biochemical systems through mathematical programming: Methods and applications

In this work we present a general (mono and multiobjective) optimization framework for the technological improvement of biochemical systems. The starting point of the method is a mathematical model in ordinary differential equations (ODEs) of the investigated system, based on qualitative biological knowledge and quantitative experimental data. In the method we take advantage of the special structural features of a family of ODEs called power-law models to reduce the computational complexity of the optimization program. In this way, the genetic manipulation of a biochemical system to meet a certain biotechnological goal can be expressed as an optimization program with some desired properties such as linearity or convexity.The general method of optimization is presented and discussed in its linear and geometric programming versions. We furthermore illustrate the use of the method by several real case studies. We conclude that the technological improvement of microorganisms can be afforded using the combination of mathematical modelling and optimization. The systematic nature of this approach facilitates the redesign of biochemical systems and makes this a predictive exercise rather than a trial-and-error procedure.     

A methodology to specify three-dimensional interaction using Petri Nets

This work presents a methodology to formally model and to build three-dimensional interaction tasks in virtual environments using three different tools: Petri Nets, the Interaction Technique Decomposition taxonomy, and Object-Oriented techniques. User operations in the virtual environment are represented as Petri Net nodes; these nodes, when linked, represent the interaction process stages. In our methodology, places represent all the states an application can reach, transitions define the conditions to start an action, and tokens embody the data manipulated by the application. As a result of this modeling process we automatically generate the core of the application's source code. We also use a Petri Net execution library to run the application code. In order to facilitate the application modeling, we have adapted Dia, a well-known graphical diagram editor, to support Petri Nets creation and code generation. The integration of these approaches results in a modular application, based on Petri Nets formalism that allows for the specification of an interaction task and for the reuse of developed blocks in new virtual environment projects.     

Network interfaces for programmable NICs and multicore platforms

The availability of multicore processors and programmable NICs, such as TOEs (TCP/IP Offloading Engines), provides new opportunities for designing efficient network interfaces to cope with the gap between the improvement rates of link bandwidths and microprocessor performance. This gap poses important challenges related with the high computational requirements associated to the traffic volumes and wider functionality that the network interface has to support. This way, taking into account the rate of link bandwidth improvement and the ever changing and increasing application demands, efficient network interface architectures require scalability and flexibility. An opportunity to reach these goals comes from the exploitation of the parallelism in the communication path by distributing the protocol processing work across processors which are available in the computer, i.e. multicore microprocessors and programmable NICs.Thus, after a brief review of the different solutions that have been previously proposed for speeding up network interfaces, this paper analyzes the onloading and offloading alternatives. Both strategies try to release host CPU cycles by taking advantage of the communication workload execution in other processors present in the node. Nevertheless, whereas onloading uses another general-purpose processor, either included in a chip multiprocessor (CMP) or in a symmetric multiprocessor (SMP), offloading takes advantage of processors in programmable network interface cards (NICs). From our experiments, implemented by using a full-system simulator, we provide a fair and more complete comparison between onloading and offloading. Thus, it is shown that the relative improvement on peak throughput offered by offloading and onloading depends on the rate of application workload to communication overhead, the message sizes, and on the characteristics of the system architecture, more specifically the bandwidth of the buses and the way the NIC is connected to the system processor and memory. In our implementations, offloading provides lower latencies than onloading, although the CPU utilization and interrupts are lower for onloading. Taking into account the conclusions of our experimental results, we propose a hybrid network interface that can take advantage of both, programmable NICs and multicore processors.     

A scalable organization for distributed directories

Although directory-based cache-coherence protocols are the best choice when designing chip multiprocessors with tens of cores on-chip, the memory overhead introduced by the directory structure may not scale gracefully with the number of cores. Many approaches aimed at improving the scalability of directories have been proposed. However, they do not bring perfect scalability and usually reduce the directory memory overhead by compressing coherence information, which in turn results in extra unnecessary coherence messages and, therefore, wasted energy and some performance degradation. In this work, we present a distributed directory organization based on duplicate tags for tiled CMP architectures whose size is independent on the number of tiles of the system up to a certain number of tiles. We demonstrate that this number of tiles corresponds to the number of sets in the private caches. Additionally, we show that the area overhead of the proposed directory structure is 0.56% with respect to the on-chip data caches. Moreover, the proposed directory structure keeps the same information than a non-scalable full-map directory. Finally, we propose a mechanism that takes advantage of this directory organization to remove the network traffic caused by replacements. This mechanism reduces total traffic by 15% for a 16-core configuration compared to a traditional directory-based protocol.