Prefetching and Cache Management using Task Lifetimes

Task-based dataflow programming models and runtimes emerge as promising candidates for programming multicore and manycore architectures. These programming models analyze dynamically task dependencies at runtime and schedule independent tasks concurrently to the processing elements. In such models, cache locality, which is critical for performance, becomes more challenging in the presence of fine-grain tasks, and in architectures with many simple cores.

This paper presents a combined hardware-software approach to improve cache locality and offer better performance is terms of execution time and energy in the memory system. We propose the explicit bulk prefetcher (EBP) and epoch-based cache management (ECM) to help runtimes prefetch task data and guide the replacement decisions in caches. The runtimem software can use this hardware support to expose its internal knowledge about the tasks to the architecture and achieve more efficient task-based execution. Our combined scheme outperforms HW-only prefetchers and state-of-the-art replacement policies, improves performance by an average of 17%, generates on average 26% fewer L2 misses, and consumes on average 28% less energy in the components of the memory system.

AßPP over-expressing transgenic rat model of Alzheimer's disease utilizing the Tg2576 mouse protocol.

The current study examined behavioral and histological effects of amyloid-ß (Aß) protein precursor (AßPP) overexpression in transgenic (Tg) rats created using the same gene, mutation, and promoter as the Tg2576 mouse model of Alzheimer's disease (AD). Male Tg+ rats were bred with female wild-type rats to generate litters of hemizygous Tg+ and Tg- offspring. Tg+ rats and Tg- littermates were tested for memory deficits at 4, 8, and 12 months old using a water-maze procedure. There were no significant behavioral differences between Tg+ rats and Tg- littermates at 4 months old but there were significant differences at 8 and 12 months old, and in probe trials at 8 and 12 months old, the Tg+ rats spent significantly less time and covered less distance in the platform zone. Under acquisition of a fixed-consecutive number schedule at 3 months old, Tg- littermates demonstrated a longer latency to learning the response rule than Tg+ rats; while this might seem paradoxical, it is consistent with the role of overexpression of AßPP in learning. Histological analyses revealed activated astrocytes in brains of Tg+ rats but not Tg- littermates at 6 months old, and thioflavin-S positive staining in the hippocampus and cortex of 17-month old Tg+ rats but not Tg- littermates. Quantification of Aß load in the brain at 22 months indicated high levels of Aß38, Aß40, and Aß42 in the Tg+ rats. These data suggest this model might provide a valuable resource for AD research.

Discovery of a Potent Boronic Acid Derived Inhibitor of the HCV RNA-Dependent RNA Polymerase

A boronic acid moiety was found to be a critical pharmacophore for enhanced in vitro potency against wild type hepatitis C replicons and known clinical polymorphic and resistant HCV mutant replicons. The synthesis, optimization, and structure-activity relationships associated with inhibition of HCV replication in a sub-genomic replication system for a series of non-nucleoside boron-containing HCV RNA-Dependent RNA Polymerase (NS5B) inhibitors are described. A summary of the discovery of GSK5852 (3), a molecule which entered clinical trials in subjects infected with HCV in 2011, is included.

Tudor staphylococcal nuclease is an evolutionarily conserved component of the programmed cell death degradome

Programmed cell death (PCD) is executed by proteases, which cleave diverse proteins thus modulating their biochemical and cellular functions. Proteases of the caspase family and hundreds of caspase substrates constitute a major part of the PCD degradome in animals(1,2). Plants lack close homologues of caspases, but instead possess an ancestral family of cysteine proteases, metacaspases(3,4). Although metacaspases are essential for PCD(5-7), their natural substrates remain unknown(4,8). Here we show that metacaspase mcII-Pa cleaves a phylogenetically conserved protein, TSN (Tudor staphylococcal nuclease), during both developmental and stress-induced PCD. TSN knockdown leads to activation of ectopic cell death during reproduction, impairing plant fertility. Surprisingly, human TSN (also known as p100 or SND1), a multifunctional regulator of gene expression(9-15), is cleaved by caspase-3 during apoptosis. This cleavage impairs the ability of TSN to activate mRNA splicing, inhibits its ribonuclease activity and is important for the execution of apoptosis. Our results establish TSN as the first biological substrate of metacaspase and demonstrate that despite the divergence of plants and animals from a common ancestor about one billion years ago and their use of distinct PCD pathways, both have retained a common mechanism to compromise cell viability through the cleavage of the same substrate, TSN.

The Caspase-Related Protease Separase (EXTRA SPINDLE POLES) Regulates Cell Polarity and Cytokinesis in Arabidopsis

Vesicle trafficking plays an important role in cell division, establishment of cell polarity, and translation of environmental cues to developmental responses. However, the molecular mechanisms regulating vesicle trafficking remain poorly understood. Here, we report that the evolutionarily conserved caspase-related protease separase (EXTRA SPINDLE POLES [ESP]) is required for the establishment of cell polarity and cytokinesis in Arabidopsis thaliana. At the cellular level, separase colocalizes with microtubules and RabA2a (for RAS GENES FROM RAT BRAINA2a) GTPase-positive structures. Separase facilitates polar targeting of the auxin efflux carrier PIN-FORMED2 (PIN2) to the rootward side of the root cortex cells. Plants with the radially swollen4 (rsw4) allele with compromised separase activity, in addition to mitotic failure, display isotropic cell growth, perturbation of auxin gradient formation, slower gravitropic response in roots, and cytokinetic failure. Measurements of the dynamics of vesicle markers on the cell plate revealed an overall reduction of the delivery rates of KNOLLE and RabA2a GTPase in separase-deficient roots. Furthermore, dissociation of the clathrin light chain, a protein that plays major role in the formation of coated vesicles, was slower in rsw4 than in the control. Our results demonstrate that separase is a key regulator of vesicle trafficking, which is indispensable for cytokinesis and the establishment of cell polarity.

Novel 5-aryloxypyrimidine SEN1576 as a candidate for the treatment of Alzheimer's disease

Prefibrillar assembly of amyloid-ß (Aß) is a major event underlying the development of neuropathology and dementia in Alzheimer's disease (AD). This study determined the neuroprotective properties of an orally bioavailable Aß synaptotoxicity inhibitor, SEN1576. Binding of SEN1576 to monomeric Aß 1–42 was measured using surface plasmon resonance. Thioflavin-T and MTT assays determined the ability of SEN1576 to block Aß 1–42-induced aggregation and reduction in cell viability, respectively. In vivo long-term potentiation (LTP) determined effects on synaptic toxicity induced by intracerebroventricular (i.c.v.) injection of cell-derived Aß oligomers. An operant behavioural schedule measured effects of oral administration following i.c.v. injection of Aß oligomers in normal rats. SEN1576 bound to monomeric Aß 1–42, protected neuronal cells exposed to Aß 1–42, reduced deficits in in vivo LTP and behaviour. SEN1576 exhibits the necessary features of a drug candidate for further development as a disease modifying treatment for the early stages of AD-like dementia.

A New Irish? Problems of communication in modern Irish media and new speakers.

While the Gaeltacht (Irish speaking) areas of Ireland are geographically isolated from each other and relatively small in area, it is expected that the number of second language Irish speakers throughout the country should ensure the future of the language. Nevertheless, while the official standard grammar has been established for many decades, there is still a tendency in the spoken language to give precedence to regional dialectal variants in schools and the broadcast media which often raises barriers between native speakers themselves and between learners and native speakers.
All pupils in school in the Republic and many in Northern Ireland learn Irish and there has been a great increase in the number of pupils attending immersion Irish language Gaelscoileanna. But concern has been expressed about the phonetic and structural accuracy achieved in schools, all of which contributes to communication breakdown.
This paper discusses how a greater awareness of the link between phoneme and grapheme in Irish and the proposals for the Lárchanúint (Central Dialect) in the 1980s and current discussions on Caighdeán Leathan agus Caighdeán Cúng (Broad and Narrow Standard) would mitigate these concerns.

Language Teacher Education in Ireland, North and South

The European Union considers modern languages among the basic skills or key competencies required by all its citizens and is concerned to promote excellence in the teaching and learning of languages as well as greater diversity in the range of languages available to learners in the Member States, as witnessed by the recent European Commission Action Plan, Promoting Language Learning and Linguistic Diversity: An Action Plan 2004-2006. This consideration, the changing socio-cultural demography of Ireland, the need for more joined-up thinking in the context of language teaching in schools, and in the context of language teacher education in particular, form the back-drop to the paper. Among the challenges facing modern/world languages’ education in Ireland identified in the paper are, lack of a languages’ policy, lack of a languages’ strategy, and lack of an integrated language curriculum and by implication, a whole school approach to language teaching and learning. The paper refers to positive signs that are occurring in this context as well, e.g. official recognition to Irish as a working language in the European Union and in the Official Languages Act in Ireland (2003). The paper reports on the recent first ever all Ireland cross-border conference in the context of language teacher education. It outlines the background, aims, and content of the conference that includes findings from a study about the impact of autonomous language teaching and learning supported by the European Language Portfolio in the context of post-primary language teacher education in Ireland. The paper shows data from the first ever survey on language teacher education provision, policy and practice across colleges in Ireland, North and South. Initial teacher education is on the cusp of change. This paper highlights several key issues facing language teacher education. This paper has implications for Irish as well as international readers, and is aimed at supporting all those who want to bring about improvement in this important area.

A spectroscopically normal type Ic supernova from a very massive progenitor

We present observations of the Type Ic supernova (SN Ic) 2011bm spanning a period of about one year. The data establish that SN 2011bm is a spectroscopically normal SN Ic with moderately low ejecta velocities and with a very slow spectroscopic and photometric evolution (more than twice as slow as SN 1998bw). The Pan-STARRS1 retrospective detection shows that the rise time from explosion to peak was 40 days in the R band. Through an analysis of the light curve and the spectral sequence, we estimate a kinetic energy of 7-17 foe and a total ejected mass of 7-17 Mo, 5-10 Mo of which is oxygen and 0.6-0.7 Mo is 56Ni. The physical parameters obtained for SN 2011bm suggest that its progenitor was a massive star of initial mass 30-50 Mo. The profile of the forbidden oxygen lines in the nebular spectra show no evidence of a bi-polar geometry in the ejected material.