Mutations in the gene encoding IFT dynein complex component WDR34 cause jeune asphyxiating thoracic dystrophy

Bidirectional (anterograde and retrograde) motor-based intraflagellar transport (IFT) governs cargo transport and delivery processes that are essential for primary cilia growth and maintenance and for hedgehog signaling functions. The IFT dynein-2 motor complex that regulates ciliary retrograde protein transport contains a heavy chain dynein ATPase/motor subunit, DYNC2H1, along with other less well functionally defined subunits. Deficiency of IFT proteins, including DYNC2H1, underlies a spectrum of skeletal ciliopathies. Here, by using exome sequencing and a targeted next-generation sequencing panel, we identified a total of 11 mutations in WDR34 in 9 families with the clinical diagnosis of Jeune syndrome (asphyxiating thoracic dystrophy). WDR34 encodes a WD40 repeat-containing protein orthologous to Chlamydomonas FAP133, a dynein intermediate chain associated with the retrograde intraflagellar transport motor. Three-dimensional protein modeling suggests that the identified mutations all affect residues critical for WDR34 protein-protein interactions. We find that WDR34 concentrates around the centrioles and basal bodies in mammalian cells, also showing axonemal staining. WDR34 coimmunoprecipitates with the dynein-1 light chain DYNLL1 in vitro, and mining of proteomics data suggests that WDR34 could represent a previously unrecognized link between the cytoplasmic dynein-1 and IFT dynein-2 motors. Together, these data show that WDR34 is critical for ciliary functions essential to normal development and survival, most probably as a previously unrecognized component of the mammalian dynein-IFT machinery.

Delay tolerant routing protocols for energy-neutral animal tracking

This paper investigates communication protocols for relaying sensor data from animal tracking applications back to base stations. While Delay Tolerant Networks (DTNs) are well suited to such challenging environments, most existing protocols do not consider the available energy that is particularly important when tracking devices can harvest energy. This limits both the network lifetime and delivery probability in energy-constrained applications to the point when routing performance becomes worse than using no routing at all. Our work shows that substantial improvement in data yields can be achieved through simple yet efficient energy-aware strategies. Conceptually, there is need for balancing the energy spent on sensing, data mulling, and delivery of direct packets to destination. We use empirical traces collected in a flying fox (fruit bat) tracking project and show that simple threshold-based energy-aware strategies yield up to 20% higher delivery rates. Furthermore, these results generalize well for a wide range of operating conditions.

Flow evaluation and hemolysis analysis of BVAD centrifugal blood pump by computational fluids dynamics

Computational fluid dynamics (CFD) and particle image velocimetry (PIV) are commonly used techniques to evaluate the flow characteristics in the development stage of blood pumps. CFD technique allows rapid change to pump parameters to optimize the pump performance without having to construct a costly prototype model. These techniques are used in the construction of a bi-ventricular assist device (BVAD) which combines the functions of LVAD and RVAD in a compact unit. The BVAD construction consists of two separate chambers with similar impellers, volutes, inlet and output sections. To achieve the required flow characteristics of an average flow rate of 5 l/min and different pressure heads (left – 100mmHg and right – 20mmHg), the impellers were set at different rotating speeds. From the CFD results, a six-blade impeller design was adopted for the development of the BVAD. It was also observed that the fluid can flow smoothly through the pump with minimum shear stress and area of stagnation which are related to haemolysis and thrombosis. Based on the compatible Reynolds number the flow through the model was calculated for the left and the right pumps. As it was not possible to have both the left and right chambers in the experimental model, the left and right pumps were tested separately.

Document timespan normalisation and understanding temporality for clinical records search

Previous qualitative research has highlighted that temporality plays an important role in relevance for clinical records search. In this study, an investigation is undertaken to determine the effect that the timespan of events within a patient record has on relevance in a retrieval scenario. In addition, based on the standard practise of document length normalisation, a document timespan normalisation model that specifically accounts for timespans is proposed. Initial analysis revealed that in general relevant patient records tended to cover a longer timespan of events than non-relevant patient records. However, an empirical evaluation using the TREC Medical Records track supports the opposite view that shorter documents (in terms of timespan) are better for retrieval. These findings highlight that the role of temporality in relevance is complex and how to effectively deal with temporality within a retrieval scenario remains an open question.

Automated categorisation of patent claims that reference human genome sequences

Debates on gene patents have necessitated the analysis of patents that disclose and reference human sequences. In this study, we built an automated classifier that assigns sequences to one of nine predefined categories according to their functional roles in patent claims by applying natural language processing and supervised learning techniques. To improve its correctness, we experimented with various feature mappings, resulting in the maximal accuracy of 79%.

Programming: Reading, writing and reversing

In this paper, we look at the concept of reversibility, that is, negating opposites, counterbalances, and actions that can be reversed. Piaget identified reversibility as an indicator of the ability to reason at a concrete operational level. We investigate to what degree novice programmers manifest the ability to work with this concept of reversibility by providing them with a small piece of code and then asking them to write code that undoes the effect of that code. On testing entire cohorts of students in their first year of learning to program, we found an overwhelming majority of them could not cope with such a concept. We then conducted think aloud studies of novices where we observed them working on this task and analyzed their contrasting abilities to deal with it. The results of this study demonstrate the need for better understanding our students' reasoning abilities, and a teaching model aimed at that level of reality.

Medical free-text to concept mapping as an information retrieval problem

Concept mapping involves determining relevant concepts from a free-text input, where concepts are defined in an external reference ontology. This is an important process that underpins many applications for clinical information reporting, derivation of phenotypic descriptions, and a number of state-of-the-art medical information retrieval methods. Concept mapping can be cast into an information retrieval (IR) problem: free-text mentions are treated as queries and concepts from a reference ontology as the documents to be indexed and retrieved. This paper presents an empirical investigation applying general-purpose IR techniques for concept mapping in the medical domain. A dataset used for evaluating medical information extraction is adapted to measure the effectiveness of the considered IR approaches. Standard IR approaches used here are contrasted with the effectiveness of two established benchmark methods specifically developed for medical concept mapping. The empirical findings show that the IR approaches are comparable with one benchmark method but well below the best benchmark.

A data mining approach for fault diagnosis: An application of anomaly detection algorithm

Rolling-element bearing failures are the most frequent problems in rotating machinery, which can be catastrophic and cause major downtime. Hence, providing advance failure warning and precise fault detection in such components are pivotal and cost-effective. The vast majority of past research has focused on signal processing and spectral analysis for fault diagnostics in rotating components. In this study, a data mining approach using a machine learning technique called anomaly detection (AD) is presented. This method employs classification techniques to discriminate between defect examples. Two features, kurtosis and Non-Gaussianity Score (NGS), are extracted to develop anomaly detection algorithms. The performance of the developed algorithms was examined through real data from a test to failure bearing. Finally, the application of anomaly detection is compared with one of the popular methods called Support Vector Machine (SVM) to investigate the sensitivity and accuracy of this approach and its ability to detect the anomalies in early stages.

Situated interfaces for engaging citizens on the go

Insights Live screening and playfulness of the interactive space can be effective strategies for attracting the attention of passers-by and turn them into active participants. While urban screen interfaces increase participation by encouraging group interaction, privately-oriented tangible user interfaces give people a longer time to reflect upon their answers.

Target acquired: Progress and promise of targeted therapeutics in the treatment of prostate cancer

Cancer is fundamentally a genomic disease caused by mutations or rearrangements in the DNA or epigenetic machinery of a patient. An emerging field in cancer treatment targets key aberrations arising from the mutational landscape of an individual patient’s disease rather than employing a cancer-wide cytotoxic therapy approach. In prostate cancer in particular, where there is an observed variation in response to standard treatments between patients with disease of a similar pathological stage and grade, mutationdirected treatment may grow to be a viable tool for clinicians to tailor more effective treatments. This review will describe a number of mutations across multiple forms of cancer that have been successfully antagonised by targeted therapeutics including their identification, the development of targeted compounds to combat them and the development of resistance to these therapies. This review will continue to examine these same mutations in the treatment and management of prostate cancer; the prevalence of targetable mutations in prostate cancer, recent clinical trials of targeted-agents and the potential or limitations for their use.

Role of TATATAA element in the regulation of tRNA(1)(Gly) gene expression in Bombyx mori is position dependent

Transcription of tRNA genes by RNA polymerase III is controlled by the internal conserved sequences within the coding region and the immediate upstream flanking sequences. A highly transcribed copy of glycyl tRNA gene tRNA1(Gly)-1 from Bombyx mori is down regulated by sequences located much farther upstream in the region -150 to -300 nucleotides (nt), with respect to the +1 nt of tRNA. The negative regulatory effect has been narrowed down to a sequence motif 'TATATAA', a perfect consensus recognised by the TATA binding protein, TBP. This sequence element, when brought closer to the transcription start point, on the other hand, exerts a positive effect by promoting transcription of the gene devoid of other cis regulatory elements. The identity of the nuclear protein interacting with this 'TATATAA' element to TBP has been established by antibody and mutagenesis studies. The 'TATATAA' element thus influences the transcription of tRNA genes positively or negatively in a position-dependent manner either by recruitment or sequestration of TBP from the transcription machinery.

Identification of putative regulatory motifs in the upstream regions of co-expressed functional groups of genes in Plasmodium falciparum

Background: Regulation of gene expression in Plasmodium falciparum (Pf) remains poorly understood. While over half the genes are estimated to be regulated at the transcriptional level, few regulatory motifs and transcription regulators have been found. Results: The study seeks to identify putative regulatory motifs in the upstream regions of 13 functional groups of genes expressed in the intraerythrocytic developmental cycle of Pf. Three motif-discovery programs were used for the purpose, and motifs were searched for only on the gene coding strand. Four motifs – the 'G-rich', the 'C-rich', the 'TGTG' and the 'CACA' motifs – were identified, and zero to all four of these occur in the 13 sets of upstream regions. The 'CACA motif' was absent in functional groups expressed during the ring to early trophozoite transition. For functional groups expressed in each transition, the motifs tended to be similar. Upstream motifs in some functional groups showed 'positional conservation' by occurring at similar positions relative to the translational start site (TLS); this increases their significance as regulatory motifs. In the ribonucleotide synthesis, mitochondrial, proteasome and organellar translation machinery genes, G-rich, C-rich, CACA and TGTG motifs, respectively, occur with striking positional conservation. In the organellar translation machinery group, G-rich motifs occur close to the TLS. The same motifs were sometimes identified for multiple functional groups; differences in location and abundance of the motifs appear to ensure different modes of action. Conclusion: The identification of positionally conserved over-represented upstream motifs throws light on putative regulatory elements for transcription in Pf.

Unsteady Free-Convection Flow on a Rotating flat-Plate Under Nonuniform Gravity

The free convection problem with nonuniform gravity finds applications in several fields. For example, centrifugal gravity fieldsarisein many rotating machinery applications. A gravity field is also created artificially in an orbital space station by rotation. The effect of nonuniform gravity due to the rotation of isothermal or nonisothermal plates has been studied by several authors [l-5] using various mathematical techniques.

Impedance tube technology for flow acoustics

Acoustic impedance of a termination, or of a passive subsystem, needs to be measured not only for acoustic lining materials but also in the exhaust systems of flow machinery, where mean flow introduces peculiar problems. Out of the various methods of measurement of acoustic impedance, the discrete frequency, steady state, impedance tube method [1] is most reliable, though time consuming, and requires no special instrumentation.

Focused Prefetching: Performance Oriented Prefetching Based On Commit Stalls

Loads that miss in L1 or L2 caches and waiting for their data at the head of the ROB cause significant slow down in the form of commit stalls. We identify that most of these commit stalls are caused by a small set of loads, referred to as LIMCOS (Loads Incurring Majority of COmmit Stalls). We propose simple history-based classifiers that track commit stalls suffered by loads to help us identify this small set of loads. We study an application of these classifiers to prefetching. The classifiers are used to train the prefetcher to focus on the misses suffered by LIMCOS. This, referred to as focused prefetching, results in a 9.8% gain in IPC over naive GHB based delta correlation prefetcher along with a 20.3% reduction in memory traffic for a set of 17 memory-intensive SPEC2000 benchmarks. Another important impact of focused prefetching is a 61% improvement in the accuracy of prefetches. We demonstrate that the proposed classification criterion performs better than other existing criteria like criticality and delinquent loads. Also we show that the criterion of focusing on commit stalls is robust enough across cache levels and can be applied to any prefetcher without any modifications to the prefetcher.