State cycles, initialization and the Trivium stream cipher

Trivium is a keystream generator for a binary additive synchronous stream cipher. It was selected in the final portfolio for the Profile 2 category of the eSTREAM project. The keystream generator is constructed using bit- based shift registers. In this paper we present an alternate representation of Trivium using word-based shift registers, with a word size of three bits. This representation is useful for determining cycles of internal state values. Under this representation it is clear that the state space can be partitioned into subspaces and that over some of these subspaces the state update function is effectively linear. The role of the initialization process is critical in ensuring the states used for generating keystream are updated nonlinearly at some point, as the state update function alone does not provide this.

Sensitivity to the MEK inhibitor E6201 in melanoma cells is associated with mutant BRAF and wildtype PTEN status

BACKGROUND: Melanoma is the most lethal form of skin cancer, but recent advances in molecularly targeted agents against the Ras/Raf/MAPK pathway demonstrate promise as effective therapies. Despite these advances, resistance remains an issue, as illustrated recently by the clinical experience with vemurafenib. Such acquired resistance appears to be the result of parallel pathway activation, such as PI3K, to overcome single-agent inhibition. In this report, we describe the cytotoxicity and anti-tumour activity of the novel MEK inhibitor, E6201, in a broad panel of melanoma cell lines (n = 31) of known mutational profile in vitro and in vivo. We further test the effectiveness of combining E6201 with an inhibitor of PI3K (LY294002) in overcoming resistance in these cell lines. RESULTS: The majority of melanoma cell lines were either sensitive (IC50 < 500 nM, 24/31) or hypersensitive (IC50 < 100 nM, 18/31) to E6201. This sensitivity correlated with wildtype PTEN and mutant BRAF status, whereas mutant RAS and PI3K pathway activation were associated with resistance. Although MEK inhibitors predominantly exert a cytostatic effect, E6201 elicited a potent cytocidal effect on most of the sensitive lines studied, as evidenced by Annexin positivity and cell death ELISA. Conversely, E6201 did not induce cell death in the two resistant melanoma cell lines tested. E6201 inhibited xenograft tumour growth in all four melanoma cell lines studied to varying degrees, but a more pronounced anti-tumour effect was observed for cell lines that previously demonstrated a cytocidal response in vitro. In vitro combination studies of E6201 and LY294002 showed synergism in all six melanoma cell lines tested, as defined by a mean combination index < 1. CONCLUSIONS: Our data demonstrate that E6201 elicits a predominantly cytocidal effect in vitro and in vivo in melanoma cells of diverse mutational background. Resistance to E6201 was associated with disruption of PTEN and activation of downstream PI3K signalling. In keeping with these data we demonstrate that co-inhibition of MAPK and PI3K is effective in overcoming resistance inherent in melanoma.

Hormone-dependent bacterial growth persistence and biofilm formation - A pilot study investigating human follicular fluid collected during IVF cycles

Human follicular fluid, considered sterile, is aspirated as part of an in vitro fertilization (IVF) cycle. However, it is easily contaminated by the trans-vaginal collection route and little information exists in its potential to support the growth of microorganisms. The objectives of this study were to determine whether human follicular fluid can support bacterial growth over time, whether the steroid hormones estradiol and progesterone (present at high levels within follicular fluid) contribute to the in vitro growth of bacterial species, and whether species isolated from follicular fluid form biofilms. We found that bacteria in follicular fluid could persist for at least 28 weeks in vitro and that the steroid hormones stimulated the growth of some bacterial species, specifically Lactobacillus spp., Bifidobacterium spp. Streptococcus spp. and E. coli. Several species, Lactobacillus spp., Propionibacterium spp., and Streptococcus spp., formed biofilms when incubated in native follicular fluids in vitro (18/24, 75%). We conclude that bacteria aspirated along with follicular fluid during IVF cycles demonstrate a persistent pattern of growth. This discovery is important since it can offer a new avenue for investigation in infertile couples.

Modification of advanced programmatic risk analysis and management model for the whole project life cycle’s risks

The advanced programmatic risk analysis and management model (APRAM) is one of the recently developed methods that can be used for risk analysis and management purposes considering schedule, cost, and quality risks simultaneously. However, this model considers those failure risks that occur only over the design and construction phases of a project’s life cycle. While it can be sufficient for some projects for which the required cost during the operating life is much less than the budget required over the construction period, it should be modified in relation to infrastructure projects because the associated costs during the operating life cycle are significant. In this paper, a modified APRAM is proposed, which can consider potential risks that might occur over the entire life cycle of the project, including technical and managerial failure risks. Therefore, the modified model can be used as an efficient decision-support tool for construction managers in the housing industry in which various alternatives might be technically available. The modified method is demonstrated by using a real building project, and this demonstration shows that it can be employed efficiently by construction managers. The Delphi method was applied in order to figure out the failure events and their associated probabilities. The results show that although the initial cost of a cold-formed steel structural system is higher than a conventional construction system, the former’s failure cost is much lower than the latter’s

Countercyclical markups and news-driven business cycles

The standard one-sector real business cycle model is unable to generate expectations-driven fluctuations. The addition of countercyclical mark-ups and modest investment adjustment costs offers an easy fix to this conundrum. The simulated model replicates the regular features of U.S. aggregate fluctuations.

Performance characterization of VGCF/epoxy nanocomposite sensors under static load cycles and in static structural health monitoring

Compared to conventional metal-foil strain gauges, nanocomposite piezoresistive strain sensors have demonstrated high strain sensitivity and have been attracting increasing attention in recent years. To fulfil their ultimate success, the performance of vapor growth carbon fiber (VGCF)/epoxy nanocomposite strain sensors subjected to static cyclic loads was evaluated in this work. A strain-equivalent quantity (resistance change ratio) in cantilever beams with intentionally induced notches in bending was evaluated using the conventional metal-foil strain gauges and the VGCF/epoxy nanocomposite sensors. Compared to the metal-foil strain gauges, the nanocomposite sensors are much more sensitive to even slight structural damage. Therefore, it was confirmed that the signal stability, reproducibility, and durability of these nanocomposite sensors are very promising, leading to the present endeavor to apply them for static structural health monitoring.

Long summer days : grounded learning of words for the uneven cycles of real world events

Time and space are fundamental to human language and embodied cognition. In our early work we investigated how Lingodroids, robots with the ability to build their own maps, could evolve their own geopersonal spatial language. In subsequent studies we extended the framework developed for learning spatial concepts and words to learning temporal intervals. This paper considers a new aspect of time, the naming of concepts like morning, afternoon, dawn, and dusk, which are events that are part of day-night cycles, but are not defined by specific time points on a clock. Grounding of such terms refers to events and features of the diurnal cycle, such as light levels. We studied event-based time in which robots experienced day-night cycles that varied with the seasons throughout a year. Then we used meet-at tasks to demonstrate that the words learned were grounded, where the times to meet were morning and afternoon, rather than specific clock times. The studies show how words and concepts for a novel aspect of cyclic time can be grounded through experience with events rather than by times as measured by clocks or calendars

A tumour-derived mutant allele of XRCC2 preferentially suppresses homologous recombination at DNA replication forks

Homologous recombination repair (HRR) is required for both the repair of DNA double strand breaks (DSBs) and the maintenance of the integrity of DNA replication forks. To determine the effect of a mutant allele of the RAD51 paralog XRCC2 (342delT) found in an HRR-defective tumour cell line, 342delT was introduced into HRR proficient cells containing a recombination reporter substrate. In one set of transfectants, expression of 342delT conferred sensitivity to thymidine and mitomycin C and suppressed HRR induced at the recombination reporter by thymidine but not by DSBs. In a second set of transfectants, the expression of 342delT was accompanied by a decreased level of the full-length XRCC2. These cells were defective in the induction of HRR by either thymidine or DSBs. Thus 342delT suppresses recombination induced by thymidine in a dominant negative manner while recombination induced by DSBs appears to depend upon the level of XRCC2 as well as the expression of the mutant XRCC2 allele. These results suggest that HRR pathways responding to stalled replication forks or DSBs are genetically distinguishable. They further suggest a critical role for XRCC2 in HRR at replication forks, possibly in the loading of RAD51 onto gapped DNA.

TUNEL analysis of DNA fragmentation in mouse unfertilized oocytes : the effect of microorganisms within human follicular fluid collected during IVF cycles

Recently we reported the presence of bacteria within follicular fluid. Previous studies have reported that DNA fragmentation in human spermatozoa after in vivo or in vitro incubation with bacteria results in early embryo demise and a reduced rate of ongoing pregnancy, but the effect of bacteria on oocytes is unknown. This study examined the DNA within mouse oocytes after 12 hours’ incubation within human follicular fluids (n = 5), which were collected from women undergoing in vitro fertilization (IVF) treatment. Each follicular fluid sample was cultured to detect the presence of bacteria. Terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL) was used to label DNA fragmentation in ovulated, non-fertilized mouse oocytes following in vitro incubation in human follicular fluid. The bacteria Streptococcus anginosus and Peptoniphilus spp., Lactobacillus gasseri (low-dose), L. gasseri (high-dose), Enterococcus faecalis, or Propionibacterium acnes were detected within the follicular fluids. The most severe DNA fragmentation was observed in oocytes incubated in the follicular fluids containing P. acnes or L. gasseri (high-dose). No DNA fragmentation was observed in the mouse oocytes incubated in the follicular fluid containing low-dose L. gasseri or E. faecalis. Low human oocyte fertilization rates (<29%) were associated with extensive fragmentation in mouse oocytes (80–100%). Bacteria colonizing human follicular fluid in vivo may cause DNA fragmentation in mouse oocytes following 12 h of in vitro incubation. Follicular fluid bacteria may result in poor quality oocytes and/or embryos, leading to poor IVF outcomes.

Effect of overload cycles on thin steel roof claddings during cyclonic winds

During an investigation on thin steel roof claddings under simulated cyclonic wind loading, it was found that trapezoidal roof claddings behaved quite differently to corrugated (arc and tangent type) roof claddings due to the presence of overload cycles. The overload cycles caused a reduction in fatigue life for corrugated roofing whereas the reverse occurred for trapezoidal roofing. This contrasting behavior of the two crest-fixed roof claddings was investigated using small scale roofing models instead of the commonly used large scale two-span roof claddings. It was found that overload cycles formed a weaker locally dimpled mechanism around the fastener holes of corrugated roofing and thus accelerated the fatigue-caused pull-through failure. In contrast, a stronger deformed shape was formed in trapezoidal roofing which delayed the pull-through failure. Both laboratory testing and finite element analysis of small scale models were used to study the contrasting behavior of roof claddings.

Learner-focused evaluation cycles : facilitating learning using feedforward, concurrent and feedback evaluation

There is a growing trend to offer students learning opportunities that are flexible, innovative and engaging. As educators embrace student-centred agile teaching and learning methodologies, which require continuous reflection and adaptation, the need to evaluate students’ learning in a timely manner has become more pressing. Conventional evaluation surveys currently dominate the evaluation landscape internationally, despite recognition that they are insufficient to effectively evaluate curriculum and teaching quality. Surveys often: (1) fail to address the issues for which educators need feedback, (2) constrain student voice, (3) have low response rates and (4) occur too late to benefit current students. Consequently, this paper explores principles of effective feedback to propose a framework for learner-focused evaluation. We apply a three-stage control model, involving feedforward, concurrent and feedback evaluation, to investigate the intersection of assessment and evaluation in agile learning environments. We conclude that learner-focused evaluation cycles can be used to guide action so that evaluation is not undertaken simply for the benefit of future offerings, but rather to benefit current students by allowing ‘real-time’ learning activities to be adapted in the moment. As a result, students become co-producers of learning and evaluation becomes a meaningful, responsive dialogue between students and their instructors.

Facile mutant identification via a single parental backcross method and application of whole genome sequencing based mapping pipelines

Forward genetic screens have identified numerous genes involved in development and metabolism, and remain a cornerstone of biological research. However, to locate a causal mutation, the practice of crossing to a polymorphic background to generate a mapping population can be problematic if the mutant phenotype is difficult to recognize in the hybrid F2 progeny, or dependent on parental specific traits. Here in a screen for leaf hyponasty mutants, we have performed a single backcross of an Ethane Methyl Sulphonate (EMS) generated hyponastic mutant to its parent. Whole genome deep sequencing of a bulked homozygous F2 population and analysis via the Next Generation EMS mutation mapping pipeline (NGM) unambiguously determined the causal mutation to be a single nucleotide polymorphisim (SNP) residing in HASTY, a previously characterized gene involved in microRNA biogenesis. We have evaluated the feasibility of this backcross approach using three additional SNP mapping pipelines; SHOREmap, the GATK pipeline, and the samtools pipeline. Although there was variance in the identification of EMS SNPs, all returned the same outcome in clearly identifying the causal mutation in HASTY. The simplicity of performing a single parental backcross and genome sequencing a small pool of segregating mutants has great promise for identifying mutations that may be difficult to map using conventional approaches.

Posttranscriptional gene silencing is not compromised in the Arabidopsis CARPEL FACTORY (DICER-LIKE1) mutant, a homolog of dicer-1 from Drosophila

Posttranscriptional silencing (PTGS) in plants, nematodes, Drosophila, and perhaps all eukaryotes operates by sequence-specific degradation or translational inhibition of the target mRNA. These processes are mediated by duplexed RNA. In Drosophila and nematodes, double-stranded (ds)RNA or self-complementary RNA is processed into fragments of approximately 21 nt by Dicer-1 [1, 2]. These small interfering RNAs (siRNAs) serve as guides to target degradation of homologous single-stranded (ss)RNA [1, 3]. In some cases, the approximately 21 nt guide fragments derived from endogenous, imperfectly self-complementary RNAs cause translational inhibition of their target mRNAs, with which they have substantial, but not perfect sequence complementarity [4-6]. These small temporal RNAs (stRNAs) belong to a class of noncoding microRNAs (miRNAs), 20-24 nt in length, that are found in flies, plants, nematodes, and mammals [4, 6-12]. In nematodes, the Dicer-1 enzyme catalyzes the production of both siRNA and stRNA [2, 13-15]. Mutation of the Arabidopsis Dicer-1 homolog, CARPEL FACTORY (CAF), blocks miRNA production [1, 4, 16-18]. Here, we report that the same caf mutant does not block either PTGS or siRNA production induced by self-complementary hairpin RNA. This suggests either that this mutation only impairs miRNA formation or, more interestingly, that plants have two distinct dicer-like enzymes, one for miRNA and another for siRNAi production.

Two cycles of voluminous pyroclastic volcanism and sedimentation related to episodic granite emplacement during the late Archean : Eastern Yilgarn Craton, Western Australia

The thick piles of late-Archean volcaniclastic sedimentary successions that overlie the voluminous greenstone units of the eastern Yilgarn Craton, Western Australia, record the important transition from the cessation in mafic-ultramafic volcanism to cratonisation between about 2690 and 2655 Ma. Unfortunately, an inability to clearly subdivide the superficially similar sedimentary successions and correlate them between the various geological terranes and domains of the eastern Yilgarn Craton has led to uncertainty about the timing and nature of the region's palaeogeographic and palaeotectonic evolution. Here, we present the results of some 2025 U–Pb laser-ablation-ICP-MS analyses and 323 Sensitive High-Resolution Ion Microprobe (SHRIMP) analyses of detrital zircons from 14 late-Archean felsic clastic successions of the eastern Yilgarn Craton, which have enabled correlation of clastic successions. The results of our data, together with those compiled from previous studies, show that the post-greenstone sedimentary successions include two major cycles that both commenced with voluminous pyroclastic volcanism and ended with widespread exhumation and erosion associated with granite emplacement. Cycle One commences with an influx of rapidly reworked feldspar-rich pyroclastic debris. These units, here-named the Early Black Flag Group, are dominated by a single population of detrital zircons with an average age of 2690–2680 Ma. Thick (up to 2 km) dolerite bodies, such as the Golden Mile Dolerite, intrude the upper parts of the Early Black Flag Group at about 2680 Ma. Incipient development of large granite domes during Cycle One created extensional basins predominantly near their southeastern and northwestern margins (e.g., St Ives, Wallaby, Kanowna Belle and Agnew), into which the Early Black Flag Group and overlying coarse mafic conglomerate facies of the Late Black Flag Group were deposited. The clast compositions and detrital-zircon ages of the late Black Flag Group detritus match closely the nearby and/or stratigraphically underlying successions, thus suggesting relatively local provenance. Cycle Two involved a similar progression to that observed in Cycle One, but the age and composition of the detritus were notably different. Deposition of rapidly reworked quartz-rich pyroclastic deposits dominated by a single detrital-zircon age population of 2670–2660 Ma heralded the beginning of Cycle Two. These coarse-grained quartz-rich units, are name here the Early Merougil Group. The mean ages of the detrital zircons from the Early Merougil Group match closely the age of the peak in high-Ca (quartz-rich) granite magmatism in the Yilgarn Craton and thus probably represent the surface expression of the same event. Successions of the Late Merougil Group are dominated by coarse felsic conglomerate with abundant volcanic quartz. Although the detrital zircons in these successions have a broad spread of age, the principal sub-populations have ages of about 2665 Ma and thus match closely those of the Early Merougil Group. These successions occur most commonly at the northwestern and southeastern margins of the granite batholiths and thus are interpreted to represent resedimented units dominted by the stratigraphically underlying packages of the Early Merougil Group. The Kurrawang Group is the youngest sedimentary units identified in this study and is dominated by polymictic conglomerate with clasts of banded iron formation (BIF), granite and quartzite near the base and quartz-rich sandstone units containing detrital zircons aged up to 3500 Ma near the top. These units record provenance from deeper and/or more-distal sources. We suggest here that the principal driver for the major episodes of volcanism, sedimentation and deformation associated with basin development was the progressive emplacement of large granite batholiths. This interpretation has important implication for palaeogeographic and palaeotectonic evolution of all late-Archean terranes around the world.

Distribution state estimation based on particle swarm and doubly loop mutant optimization (DLM-PSO)

This paper presents a novel algorithm based on particle swarm optimization (PSO) to estimate the states of electric distribution networks. In order to improve the performance, accuracy, convergence speed, and eliminate the stagnation effect of original PSO, a secondary PSO loop and mutation algorithm as well as stretching function is proposed. For accounting uncertainties of loads in distribution networks, pseudo-measurements is modeled as loads with the realistic errors. Simulation results on 6-bus radial and 34-bus IEEE test distribution networks show that the distribution state estimation based on proposed DLM-PSO presents lower estimation error and standard deviation in comparison with algorithms such as WLS, GA, HBMO, and original PSO.