Bis-guanylhydrazone diimidazo[1,2-a:1,2-c]pyrimidine as a novel and specific G-quadruplex binding motif

A bis-guanylhydrazone derivative of diimidazo[1,2-a:1,2-c]pyrimidine has unexpectedly been found to be a potent stabiliser of several quadruplex DNAs, whereas there is no significant interaction with duplex DNA. Molecular modeling suggests that the guanylhydrazone groups play an active role in quadruplex binding.

Detection of aberrant behaviour in home environments from video sequence

We introduce an application for the detection of aberrant behaviour within home based environments, with a focus on repetitive actions, which may be present in instance of persons suffering from dementia. Video based analysis has been used to detect the motion of a person within a given scene in addition to tracking them over the time. Detection of repetitive actions has been based on the analysis of a person's trajectory using the principles of signal correlation. Along with the ability to detect repetitive motion the developed approach also has the ability to measure the amount of activity/inactivity within the scene during a given period of time. Our results showed that the developed approach had the ability to detect all patterns in the data set examined with an average accuracy of 96.67%. This work has therefore validated the proposed concept of video based analysis for the detection of repetitive activities.

The Costs of Taking It Slowly Fast and Slow Movement Timing in Older Age

We investigated adult age differences in timing control of fast vs slow repetitive movements using a dual task approach Twenty two young (M = 24 23 yr) and 22 older adults (M = 66 64 yr) performed three cognitive tasks differing in working memory load and response production demands and they tapped series of 550 ms or 2100 ms target Intervals Single task timing was comparable in both groups Dual task timing was characterized by shortening of produced intervals and increases in drift and variability Dual task costs for both cognitive and timing performances were pronounced at slower tapping tempos an effect exacerbated in older adults Our findings implicate attention and working memory processes as critical components of slow movement timing and sources of specific challenges thereof for older adults

Interval timing and trajectory in unequal amplitude movements

The Wing-Kristofferson (WK) model of movement timing emphasises the separation of central timer and motor processes. Several studies of repetitive timing have shown that increase in variability at longer intervals is attributable to timer processes; however, relatively little is known about the way motor aspects of timing are affected by task movement constraints. In the present study, we examined timing variability in finger tapping with differences in interval to assess central timer effects, and with differences in movement amplitude to assess motor implementation effects. Then, we investigated whether effects of motor timing observed at the point of response (flexion offset/tap) are also evident in extension, which would suggest that both phases are subject to timing control. Eleven participants performed bimanual simultaneous tapping, at two target intervals (400, 600 ms) with the index finger of each hand performing movements of equal (3 or 6 cm) or unequal amplitude (left hand 3, right hand 6 cm and vice versa). As expected, timer variability increased with the mean interval but showed only small, non-systematic effects with changes in movement amplitude. Motor implementation variability was greater in unequal amplitude conditions. The same pattern of motor variability was observed both at flexion and extension phases of movement. These results suggest that intervals are generated by a central timer, triggering a series of events at the motor output level including flexion and the following extension, which are explicitly represented in the timing system.

Low frequency rTMS effects on sensorimotor synchronization

Previous studies using low frequency (1 Hz) rTMS over the motor and premotor cortex have examined repetitive movements, but focused either on motor aspects of performance such as movement speed, or on variability of the produced intervals. A novel question is whether TMS affects the synchronization of repetitive movements with an external cue (sensorimotor synchronization). In the present study participants synchronized finger taps with the tones of an auditory metronome. The aim of the study was to examine whether motor and premotor cortical inhibition induced by rTMS affects timing aspects of synchronization performance such as the coupling between the tap and the tone and error correction after a metronome perturbation. Metronome sequences included perturbations corresponding to a change in the duration of a single interval (phase shifts) that were either small and below the threshold for conscious perception (10 ms) or large and perceivable (50 ms). Both premotor and motor cortex stimulation induced inhibition, as reflected in a lengthening of the silent period. Neither motor nor premotor cortex rTMS altered error correction after a phase shift. However, motor cortex stimulation made participants tap closer to the tone, yielding a decrease in tap-tone asynchrony. This provides the first neurophysiological demonstration of a dissociation between error correction and tap-tone asynchrony in sensorimotor synchronization. We discuss the results in terms of current theories of timing and error correction.

Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodelling genes

Gastric cancer is a major cause of global cancer mortality. We surveyed the spectrum of somatic alterations in gastric cancer by sequencing the exomes of 15 gastric adenocarcinomas and their matched normal DNAs. Frequently mutated genes in the adenocarcinomas included TP53 (11/15 tumors), PIK3CA (3/15) and ARID1A (3/15). Cell adhesion was the most enriched biological pathway among the frequently mutated genes. A prevalence screening confirmed mutations in FAT4, a cadherin family gene, in 5% of gastric cancers (6/110) and FAT4 genomic deletions in 4% (3/83) of gastric tumors. Frequent mutations in chromatin remodeling genes (ARID1A, MLL3 and MLL) also occurred in 47% of the gastric cancers. We detected ARID1A mutations in 8% of tumors (9/110), which were associated with concurrent PIK3CA mutations and microsatellite instability. In functional assays, we observed both FAT4 and ARID1A to exert tumor-suppressor activity. Somatic inactivation of FAT4 and ARID1A may thus be key tumorigenic events in a subset of gastric cancers.

Primary motor cortex involvement in initial learning during visuomotor adaptation

Human motor behaviour is continually modified on the basis of errors between desired and actual movement outcomes. It is emerging that the role played by the primary motor cortex (M1) in this process is contingent upon a variety of factors, including the nature of the task being performed, and the stage of learning. Here we used repetitive TMS to test the hypothesis that M1 is intimately involved in the initial phase of sensorimotor adaptation. Inhibitory theta burst stimulation was applied to M1 prior to a task requiring modification of torques generated about the elbow/forearm complex in response to rotations of a visual feedback display. Participants were first exposed to a 30° clockwise (CW) rotation (Block A), then a 60° counterclockwise rotation (Block B), followed immediately by a second block of 30° CW rotation (A2). In the STIM condition, participants received 20s of continuous theta burst stimulation (cTBS) prior to the initial A Block. In the conventional (CON) condition, no stimulation was applied. The overt characteristics of performance in the two conditions were essentially equivalent with respect to the errors exhibited upon exposure to a new variant of the task. There were however, profound differences between the conditions in the latency of response preparation, and the excitability of corticospinal projections from M1, which accompanied phases of de-adaptation and re-adaptation (during Blocks B and A2). Upon subsequent exposure to the A rotation 24h later, the rate of re-adaptation was lower in the stimulation condition than that present in the conventional condition. These results support the assertion that primary motor cortex assumes a key role in a network that mediates adaptation to visuomotor perturbation, and emphasise that it is engaged functionally during the early phase of learning.

A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor-negative and -positive breast cancers

BRCA1 encodes a tumour suppressor protein that plays pivotal roles in homologous recombination (HR) DNA repair, cell-cycle checkpoints, and transcriptional regulation. BRCA1 germline mutations confer a high risk of early-onset breast and ovarian cancer. In more than 80% of cases, tumours arising in BRCA1 germline mutation carriers are oestrogen receptor (ER)-negative; however, up to 15% are ER-positive. It has been suggested that BRCA1 ER-positive breast cancers constitute sporadic cancers arising in the context of a BRCA1 germline mutation rather than being causally related to BRCA1 loss-of-function. Whole-genome massively parallel sequencing of ER-positive and ER-negative BRCA1 breast cancers, and their respective germline DNAs, was used to characterize the genetic landscape of BRCA1 cancers at base-pair resolution. Only BRCA1 germline mutations, somatic loss of the wild-type allele, and TP53 somatic mutations were recurrently found in the index cases. BRCA1 breast cancers displayed a mutational signature consistent with that caused by lack of HR DNA repair in both ER-positive and ER-negative cases. Sequencing analysis of independent cohorts of hereditary BRCA1 and sporadic non-BRCA1 breast cancers for the presence of recurrent pathogenic mutations and/or homozygous deletions found in the index cases revealed that DAPK3, TMEM135, KIAA1797, PDE4D, and GATA4 are potential additional drivers of breast cancers. This study demonstrates that BRCA1 pathogenic germline mutations coupled with somatic loss of the wild-type allele are not sufficient for hereditary breast cancers to display an ER-negative phenotype, and has led to the identification of three potential novel breast cancer genes (ie DAPK3, TMEM135, and GATA4).

64-point Fourier transform chip for digital television applications

A 64-point Fourier transform chip is described that performs a forward or inverse, 64-point Fourier transform on complex two's complement data supplied at a rate of 13.5MHz and can operate at clock rates of up to 40MHz, under worst-case conditions. It uses a 0.6µm double-level metal CMOS technology, contains 535k transistors and uses an internal 3.3V power supply. It has an area of 7.8×8mm, dissipates 0.9W, has 48 pins and is housed in a 84 pin PLCC plastic package. The chip is based on a FFT architecture developed from first principles through a detailed investigation of the structure of the relevant DFT matrix and through mapping repetitive blocks within this matrix onto a regular silicon structure.

Exploring the Transcriptome of Atlantic Salmon (Salmo salar) Skin, a Major Defense Organ

The skin of fish is the first line of defense against pathogens and parasites. The skin transcriptome of the Atlantic salmon is poorly characterized, and currently only 2,089 expressed sequence tags (ESTs) out of a total of half a million sequences are generated from skin-derived cDNA libraries. The primary aim of this study was to enhance the transcriptomic knowledge of salmon skin by using next-generation sequencing (NGS) technology, namely the Roche-454 platform. An equimolar mixture of high-quality RNA from skin and epidermal samples of salmon reared in either freshwater or seawater was used for 454-sequencing. This technique yielded over 600,000 reads, which were assembled into 34,696 isotigs using Newbler. Of these isotigs, 12 % had not been sequenced in Atlantic salmon, hence representing previously unreported salmon mRNAs that can potentially be skin-specific. Many full-length genes have been acquired, representing numerous biological processes. Mucin proteins are the main structural component of mucus and we examined in greater detail the sequences we obtained for these genes. Several isotigs exhibited homology to mammalian mucins (MUC2, MUC5AC and MUC5B). Mucin mRNAs are generally > 10 kbp and contain large repetitive units, which pose a challenge towards full-length sequence discovery. To date, we have not unearthed any full-length salmon mucin genes with this dataset, but have both N- and C-terminal regions of a mucin type 5. This highlights the fact that, while NGS is indeed a formidable tool for sequence data mining of non-model species, it must be complemented with additional experimental and bioinformatic work to characterize some mRNA sequences with complex features.

Neonatal pain in relation to postnatal growth in infants born very preterm

Procedural pain is associated with poorer neurodevelopment in infants born very preterm (= 32 weeks gestational age), however, the etiology is unclear. Animal studies have demonstrated that early environmental stress leads to slower postnatal growth; however, it is unknown whether neonatal pain-related stress affects postnatal growth in infants born very preterm. The aim of this study was to examine whether greater neonatal pain (number of skin-breaking procedures adjusted for medical confounders) is related to decreased postnatal growth (weight and head circumference [HC] percentiles) early in life and at term-equivalent age in infants born very preterm. Participants were n=78 preterm infants born = 32 weeks gestational age, followed prospectively since birth. Infants were weighed and HC measured at birth, early in life (median: 32 weeks [interquartile range 30.7-33.6]) and at term-equivalent age (40 weeks [interquartile range 38.6-42.6]). Weight and HC percentiles were computed from sex-specific British Columbia population-based data. Greater neonatal pain predicted lower body weight (Wald ?(2)=7.36, P=0.01) and HC (Wald ?(2)=4.36, P=0.04) percentiles at 32 weeks postconceptional age, after adjusting for birth weight percentile and postnatal risk factors of illness severity, duration of mechanical ventilation, infection, and morphine and corticosteroid exposure. However, later neonatal infection predicted lower weight percentile at term (Wald ?(2)=5.09, P=0.02). Infants born very preterm undergo repetitive procedural pain during a period of physiological immaturity that appears to impact postnatal growth, and may activate a downstream cascade of stress signaling that affects later growth in the neonatal intensive care unit.

The role of areas MT+/V5 and SPOC in spatial and temporal control of manual interception: an rTMS study

Manual interception, such as catching or hitting an approaching ball, requires the hand to contact a moving object at the right location and at the right time. Many studies have examined the neural mechanisms underlying the spatial aspects of goal-directed reaching, but the neural basis of the spatial and temporal aspects of manual interception are largely unknown. Here, we used repetitive transcranial magnetic stimulation (rTMS) to investigate the role of the human middle temporal visual motion area (MT+/V5) and superior parieto-occipital cortex (SPOC) in the spatial and temporal control of manual interception. Participants were required to reach-to-intercept a downward moving visual target that followed an unpredictably curved trajectory, presented on a screen in the vertical plane. We found that rTMS to MT+/V5 influenced interceptive timing and positioning, whereas rTMS to SPOC only tended to increase the spatial variance in reach end points for selected target trajectories. These findings are consistent with theories arguing that distinct neural mechanisms contribute to spatial, temporal, and spatiotemporal control of manual interception.

Comprehensive Investigation of the Caveolin 2 Gene: Resequencing and Association for Kidney Transplant Outcomes

Caveolae are plasma membrane structures formed from a complex of the proteins caveolin-1 and caveolin-2. Caveolae interact with pro-inflammatory cytokines and are dysregulated in fibrotic disease. Although caveolae are present infrequently in healthy kidneys, they are abundant during kidney injury. An association has been identified between a CAV1 gene variant and long term kidney transplant survival. Chronic, gradual decline in transplant function is a persistent problem in kidney transplantation. The aetiology of this is diverse but fibrosis within the transplanted organ is the common end point. This study is the first to investigate the association of CAV2 gene variants with kidney transplant outcomes. Genomic DNA from donors and recipients of 575 kidney transplants performed in Belfast was investigated for common variation in CAV2 using a tag SNP approach. The CAV2 SNP rs13221869 was nominally significant for kidney transplant failure. Validation was sought in an independent group of kidney transplant donors and recipients from Dublin, Ireland using a second genotyping technology. Due to the unexpected absence of rs13221869 from this cohort, the CAV2 gene was resequenced. One novel SNP and a novel insertion/deletion in CAV2 were identified; rs13221869 is located in a repetitive region and was not a true variant in resequenced populations. CAV2 is a plausible candidate gene for association with kidney transplant outcomes given its proximity to CAV1 and its role in attenuating fibrosis. This study does not support an association between CAV2 variation and kidney transplant survival. Further analysis of CAV2 should be undertaken with an awareness of the sequence complexities and genetic variants highlighted by this study. 

Avoidance Techniques: State Related Defences in International Antitrust Cases

Despite its economic significance, competition law still remains fragmented, lacking an international framework allowing for dispute settlement. This, together with the growing importance of non-free-market economies in world trade require us to re-consider and re-evaluate the possibilities of bringing an antitrust suit against a foreign state. If the level playing field on the global marketplace is to be achieved, the possibility of hiding behind the bulwark of state sovereignty should be minimised. States should not be free to act in an anti-competitive way, but at present the legal framework seems ill-equipped to handle such challenges.

This paper deals with the defences available in litigation concerning transnational anti-competitive agreements involving or implicating foreign states. Four important legal doctrines are analysed: non-justiciability (political question doctrine), state immunity, act of state doctrine and foreign state compulsion. The paper addresses also the general problem of applicability of competition laws to a foreign state as such. This is a tale about repetitive unsuccessful efforts to sue OPEC and recent attempts in the US to deal with export cartels of Chinese state-owned enterprises

Neutral Genomic Microevolution of a Recently Emerged Pathogen, Salmonella enterica Serovar Agona

Salmonella enterica serovar Agona has caused multiple food-borne outbreaks of gastroenteritis since it was first isolated in 1952. We analyzed the genomes of 73 isolates from global sources, comparing five distinct outbreaks with sporadic infections as well as food contamination and the environment. Agona consists of three lineages with minimal mutational diversity: only 846 single nucleotide polymorphisms (SNPs) have accumulated in the non-repetitive, core genome since Agona evolved in 1932 and subsequently underwent a major population expansion in the 1960s. Homologous recombination with other serovars of S. enterica imported 42 recombinational tracts (360 kb) in 5/143 nodes within the genealogy, which resulted in 3,164 additional SNPs. In contrast to this paucity of genetic diversity, Agona is highly diverse according to pulsed-field gel electrophoresis (PFGE), which is used to assign isolates to outbreaks. PFGE diversity reflects a highly dynamic accessory genome associated with the gain or loss (indels) of 51 bacteriophages, 10 plasmids, and 6 integrative conjugational elements (ICE/IMEs), but did not correlate uniquely with outbreaks. Unlike the core genome, indels occurred repeatedly in independent nodes (homoplasies), resulting in inaccurate PFGE genealogies. The accessory genome contained only few cargo genes relevant to infection, other than antibiotic resistance. Thus, most of the genetic diversity within this recently emerged pathogen reflects changes in the accessory genome, or is due to recombination, but these changes seemed to reflect neutral processes rather than Darwinian selection. Each outbreak was caused by an independent clade, without universal, outbreak-associated genomic features, and none of the variable genes in the pan-genome seemed to be associated with an ability to cause outbreaks. © 2013 Achtman et al