Patterns and Stability of Coupled Multi-Stable Nonlinear Oscillators.

Nonlinear isolated and coupled oscillators are extensively studied as prototypical nonlinear dynamics models. Much attention has been devoted to oscillator synchronization or the lack thereof. Here, we study the synchronization and stability of coupled driven-damped Helmholtz-Duffing oscillators in bi-stability regimes. We find that despite the fact that the system parameters and the driving force are identical, the stability of the two states to spatially non-uniform perturbations is very different. Moreover, the final stable states, resulting from these spatial perturbations, are not solely dictated by the wavelength of the perturbing mode and take different spatial configurations in terms of the coupled oscillator phases.

Bubble lifetimes in DNA gene promoters and their mutations affecting transcription.

Relative lifetimes of inherent double stranded DNA openings with lengths up to ten base pairs are presented for different gene promoters and corresponding mutants that either increase or decrease transcriptional activity in the framework of the Peyrard-Bishop-Dauxois model. Extensive microcanonical simulations are used with energies corresponding to physiological temperature. The bubble lifetime profiles along the DNA sequences demonstrate a significant reduction of the average lifetime at the mutation sites when the mutated promoter decreases transcription, while a corresponding enhancement of the bubble lifetime is observed in the case of mutations leading to increased transcription. The relative difference in bubble lifetimes between the mutated and wild type promoters at the position of mutation varies from 20% to more than 30% as the bubble length decreases.

Simple Wave-Optical Superpositions as Prime Number Sieves.

We encode the sequence of prime numbers into simple superpositions of identical waves, mimicking the archetypal prime number sieve of Eratosthenes. The primes are identified as zeros accompanied by phase singularities in a physically generated wave field for integer valued momenta. Similarly, primes are encoded in the diffraction pattern from a simple single aperture and in the harmonics of a single vibrating resonator. Further, diffraction physics connections to number theory reveal how to encode all Gaussian primes, twin primes, and how to construct wave fields with amplitudes equal to the divisor function at integer spatial frequencies. Remarkably, all of these basic diffraction phenomena reveal that the naturally irregular sequence of primes can arise from trivially ordered wave superpositions.

Core outcome sets for prevention and treatment of postpartum haemorrhage: an international Delphi consensus study.

OBJECTIVE: To develop core outcome sets (COS) for studies evaluating interventions for (1) prevention and (2) treatment of postpartum haemorrhage (PPH), and recommendations on how to report the COS. DESIGN: A two-round Delphi survey and face-to-face meeting. POPULATION: Healthcare professionals and women's representatives. METHODS: Outcomes were identified from systematic reviews of PPH studies and stakeholder consultation. Participants scored each outcome in the Delphi on a Likert scale between 1 (not important) and 9 (critically important). Results were discussed at the face-to-face meeting to agree the final COS. Consensus at the meeting was defined as ≥ 70% of participants scoring the outcome as critically important (7-9). Lectures, discussion and voting were used to agree how to report COS outcomes. MAIN OUTCOME MEASURES: Outcomes from systematic reviews and consultations. RESULTS: Both Delphi rounds were completed by 152/205 (74%) participants for prevention and 143/197 (73%) for treatment. For prevention of PPH, nine core outcomes were selected: blood loss, shock, maternal death, use of additional uterotonics, blood transfusion, transfer for higher level of care, women's sense of wellbeing, acceptability and satisfaction with the intervention, breastfeeding, and adverse effects. For treatment of PPH, 12 core outcomes were selected: blood loss, shock, coagulopathy, hysterectomy, organ dysfunction, maternal death, blood transfusion, use of additional haemostatic intervention, transfer for higher level of care, women's sense of wellbeing, acceptability and satisfaction with the intervention, breastfeeding, and adverse effects. Recommendations were developed on how to report these outcomes where possible. CONCLUSIONS: These COS will help standardise outcome reporting in PPH trials. TWEETABLE ABSTRACT: Core outcome sets for PPH: nine core outcomes for PPH prevention and 12 core outcomes for PPH treatment.

A disclosure gel for visual detection of live Bacillus anthracis spores.

AIMS: To develop a gel formulation to trigger a visual signal for rapid disclosure of the location and extent of surface contamination with viable Bacillus anthracis spores. METHODS AND RESULTS: Methylumbelliferyl-α-d-glucopyranoside was combined with hyaluronic acid to produce a gel that could be applied to a surface as a coating. It remained hydrated for a sufficient time for α-glucosidase activity present in intact B. anthracis spores to cleave the substrate and release the fluorescent product, methylumbelliferone. The presence of B. anthracis spores could be disclosed at 5 × 104 CFU per reaction test well (0·32 cm2 ) both visually and using fluorescence detection equipment. CONCLUSIONS: The disclosure gel provides a rapid, visual response to the presence of B. anthracis spores on a surface. SIGNIFICANCE AND IMPACT OF THE STUDY: The disclosure gel demonstrates the first steps towards the development of a formulation that can provide nonspecialist users with a visual alert to the presence of B. anthracis spores on a surface. It is envisioned that such a formulation would be beneficial in scenarios where exposure to spore release is a risk, and could be used in the initial assessment of equipment to aid prioritization and localized execution of a decontamination strategy.

Transcutaneous electrical nerve stimulation improves fatigue performance of the treated and contralateral knee extensors.

PURPOSE: Transcutaneous electrical nerve stimulation (TENS) can reduce acute and chronic pain. Unilateral fatigue can produce discomfort in the affected limb and force and activation deficits in contralateral non-exercised muscles. TENS-induced local pain analgesia effects on non-local fatigue performance are unknown. Hence, the aim of the study was to determine if TENS-induced pain suppression would augment force output during a fatiguing protocol in the treated and contralateral muscles. METHODS: Three experiments were integrated for this article. Following pre-tests, each experiment involved 20 min of TENS, sham, or a control condition on the dominant quadriceps. Then either the TENS-treated quadriceps (TENS_Treated) or the contralateral quadriceps (TENS_Contra) was tested. In a third experiment, the TENS and sham conditions involved two\; 100-s isometric maximal voluntary contractions (MVC) (30-s recovery) followed by testing of the contralateral quadriceps (TENS_Contra-Fatigue). Testing involved single knee extensors (KE) MVCs (pre- and post-test) and a post-test 30% MVC to task failure. RESULTS: The TENS-treated study induced greater (p = 0.03; 11.0%) time to KE (treated leg) failure versus control. The TENS_Contra-Fatigue induced significant (p = 0.04; 11.7%) and near-significant (p = 0.1; 7.1%) greater time to contralateral KE failure versus sham and control, respectively. There was a 14.5% (p = 0.02) higher fatigue index with the TENS (36.2 ± 10.1%) versus sham (31.6 ± 10.6%) conditions in the second fatigue intervention set (treated leg). There was no significant post-fatigue KE fatigue interaction with the TENS_Contra. CONCLUSIONS: Unilateral TENS application to the dominant KE prolonged time to failure in the treated and contralateral KE suggesting a global pain modulatory response.

Re-aerosolization of Bacillus thuringiensis spores from concrete and turf.

Spores of Bacillus anthracis deposited on surfaces can become airborne again as a result of air currents and mechanical forces. As such, they are a potential source of infection by inhalation. Spores of Bacillus thuringiensis were used to quantify this phenomenon in a simulation of outdoor conditions. Concrete and turf surfaces were inoculated by aerosol to produce high spore densities (greater than 1 × 109  CFU per m2 ) which were then subjected to the passage of air at 10 ms-1 with and without simulated walking. Re-aerosolized spores were sampled by wetted wall cyclone air samplers. The mean total re-aerosolization rate from concrete (m-2  min-1 ) was 1·16 × 10-3 for wind alone and 3·2 × 10-3 for wind and simulated walking while for turf the respective values were 2·7 × 10-4 and 6·7 × 10-4 . SIGNIFICANCE AND IMPACT OF THE STUDY: Following the malicious and/or accidental release of an aerosol of Bacillus anthracis spores, the immediate risk of human inhalation would decrease as the spores were deposited on surfaces or diluted by wind flow. There is, however, a concern that the deposited spores could become re-aerosolized and so present an ongoing hazard. Using an accurate simulant for B. anthracis spores a method is reported here that allowed the enumeration of re-aerosolized spores from concrete and turf by wind flow and footfall. Under the conditions used, the rates of re-aerosolization were low. These findings will need to be verified under real outdoor conditions before the true significance in terms of secondary exposure to pathogenic spores can be assessed.

Inter-rater reliability and validity of two ataxia rating scales in children with brain tumours.

OBJECTIVES: This study aimed to investigate the inter-rater reliability and construct validity of the Scale for the Assessment and Rating of Ataxia (SARA) and Brief Ataxia Rating Scale (BARS) in children with posterior fossa tumours. These scales have been developed for adults with genetic ataxias, and the performance of these scales in children with brain tumours has not previously been described. METHODS: The participants, who had undergone surgical resection for a posterior fossa tumour (inclusion criteria age 4-18 years), were recruited from the neuro-oncology service at a tertiary children's hospital. Children were assessed using the SARA, BARS and Paediatric Evaluation of Disability Index (PEDI) mobility domain, a measure of function. Children were independently rated by two therapists to determine the inter-rater reliability of the SARA and BARS. The construct validity was determined by assessing the correlation between the two scales with the PEDI. RESULTS: Forty-four children were recruited. Inter-rater reliability was good for both scales, demonstrating the strong correlations (SARA, r = 0.94; BARS, r = 0.91) and the good consistency (93 % of SARA and 90 % of BARS paired scores differing by less than 2 points) between two raters. Both ataxia scales demonstrated a strong negative correlation with the mobility domain of the PEDI (SARA, r = -0.77; BARS, r = -0.76), indicating that more severe ataxia was associated with worse mobility. The mean time for completion of the SARA was 4.5 and 2.7 min for the BARS. CONCLUSIONS: The SARA and BARS are reliable and valid measures and appear to be of equal value in determining the severity of ataxia in children with posterior fossa tumours.

Attractive inverse square potential, U(1) gauge, and winding transitions.

The inverse square potential arises in a variety of different quantum phenomena, yet notoriously it must be handled with care: it suffers from pathologies rooted in the mathematical foundations of quantum mechanics. We show that its recently studied conformality breaking corresponds to an infinitely smooth winding-unwinding topological transition for the classical statistical mechanics of a one-dimensional system: this describes the tangling or untangling of floppy polymers under a biasing torque. When the ratio between torque and temperature exceeds a critical value the polymer undergoes tangled oscillations, with an extensive winding number. At lower torque or higher temperature the winding number per unit length is zero. Approaching criticality, the correlation length of the order parameter-the extensive winding number-follows a Kosterlitz-Thouless-type law. The model is described by the Wilson line of a (0+1) U(1) gauge theory, and applies to the tangling or untangling of floppy polymers and to the winding or diffusing kinetics in diffusion-convection reactions.

Germination and persistence of Bacillus anthracis and Bacillus thuringiensis in soil microcosms.

AIMS: Decontaminating large, outdoor spaces of Bacillus anthracis spores presents significant problems, particularly in soil. Proof was sought that the addition of germinant chemicals could cause spores of B. anthracis and Bacillus thuringiensis, a commonly used simulant of the threat agent, to convert to the less resistant vegetative form in a microcosm. METHODS AND RESULTS: Nonsterile plant/soil microcosms were inoculated with spores of B. thuringiensis and two nonpathogenic strains of B. anthracis. A combination of L-alanine (100 mmol l(-1)) and inosine (10 mmol l(-1)) resulted in a 6 log decrease in spore numbers in both strains of B. anthracis over 2 weeks at 22°C; a 3 log decrease in B. anthracis Sterne spore numbers was observed after incubation for 2 weeks at 10°C. Negligible germination nor a decrease in viable count occurred in either strain when the concentration of L-alanine was decreased to 5 mmol l(-1). Germinated spores of B. thuringiensis were able to persist in vegetative form in the microcosms, whereas those of B. anthracis rapidly disappeared. The pleiotropic regulator PlcR, which B. anthracis lacks, does not contribute to the persistence of B. thuringiensis in vegetative form in soil. CONCLUSIONS: The principle of adding germinants to soil to trigger the conversion of spores to vegetative form has been demonstrated. Bacillus anthracis failed to persist in vegetative form or resporulate in the microcosms after it had been induced to germinate. SIGNIFICANCE AND IMPACT OF THE STUDY: The large scale, outdoor decontamination of B. anthracis spores may be facilitated by the application of simple, defined combinations of germinants.

Bacillus thuringiensis HD-1 Cry- : development of a safe, non-insecticidal simulant for Bacillus anthracis.

AIMS: A representative simulant for spores of Bacillus anthracis is needed for field testing. Bacillus thuringiensis is gaining recognition as a suitable organism. A strain that does not form the insecticidal, parasporal crystals that are characteristic of this species is a more accurate physical representative of B. anthracis spores. We developed noninsecticidal derivatives of two isolates of B. thuringiensis HD-1. METHODS AND RESULTS: Two plasmid-cured derivatives of B. thuringiensis HD-1, unable to make crystal toxins ('Cry(-) '), were isolated. These isolates and the existing Cry(-) strain, B. thuringiensis Al Hakam, were probed with PCR assays against the known insecticidal genes cry, vip and cyt. Their genomic DNA was sequenced to demonstrate a lack of insecticidal genes. This was confirmed by bioassays against a number of invertebrate species. Real-time PCR assays were developed to identify the B. thuringiensis HD-1 Cry(-) derivatives and an effective differential and selective medium was assessed. CONCLUSIONS: All three Cry(-) isolates are devoid of known insecticidal determinants. The B. thuringiensis HD-1 Cry(-) derivatives can easily be recovered from soil and identified by PCR with some selectivity. SIGNIFICANCE AND IMPACT OF THE STUDY: The B. thuringiensis HD-1 Cry(-) derivatives represent accurate, nongenetically manipulated simulants for B. anthracis with excellent human and environmental safety records.

Thermomechanical stability and mechanochemical response of DNA: a minimal mesoscale model.

We show that a mesoscale model, with a minimal number of parameters, can well describe the thermomechanical and mechanochemical behavior of homogeneous DNA at thermal equilibrium under tension and torque. We predict critical temperatures for denaturation under torque and stretch, phase diagrams for stable DNA, probe/response profiles under mechanical loads, and the density of dsDNA as a function of stretch and twist. We compare our predictions with available single molecule manipulation experiments and find strong agreement. In particular we elucidate the difference between angularly constrained and unconstrained overstretching. We propose that the smoothness of the angularly constrained overstretching transition is a consequence of the molecule being in the vicinity of criticality for a broad range of values of applied tension.

Identification of genes required for soil survival in Burkholderia thailandensis by transposon-directed insertion site sequencing.

Transposon-directed insertion site sequencing was used to identify genes required by Burkholderia thailandensis to survive in plant/soil microcosms. A total of 1,153 genetic loci fulfilled the criteria as being likely to encode survival characteristics. Of these, 203 (17.6 %) were associated with uptake and transport systems; 463 loci (40.1 %) coded for enzymatic properties, 99 of these (21.4 %) had reduction/oxidation functions; 117 (10.1 %) were gene regulation or sensory loci; 61 (5.3 %) encoded structural proteins found in the cell envelope or with enzymatic activities related to it, distinct from these, 46 (4.0 %) were involved in chemotaxis and flagellum, or pilus synthesis; 39 (3.4 %) were transposase enzymes or were bacteriophage-derived; and 30 (2.6 %) were involved in the production of antibiotics or siderophores. Two hundred and twenty genes (19.1 %) encoded hypothetical proteins or those of unknown function. Given the importance of motility and pilus formation in microcosm persistence the nature of the colonization of the rhizosphere was examined by confocal microscopy. Wild type B. thailandensis expressing red fluorescent protein was inoculated into microcosms. Even though the roots had been washed, the bacteria were still present but they were motile with no attachment having taken place, perhaps being retained in a biofilm.

Expression of prtA from Photorhabdus luminescens in Bacillus thuringiensis enhances mortality in lepidopteran larvae by sub-cutaneous but not oral infection.

The prtA gene from Photorhabdus luminescens encodes the virulence factor Protease A. When P. luminescens is injected into the hemocoel of insects by entomopathogenic nematodes, PrtA is a key component of pathogenicity thought to help degrade the immune system. The prtA gene was cloned and introduced on a plasmid into Bacillus thuringiensis. PrtA was shown to be actively expressed in vitro by cleavage of a specific Dabcyl-Edans heptapeptide substrate. There was no difference in the speed or level of mortality when spores and δ-endotoxins crystals of the transformed strain were fed to larvae of Pieris brassicae, as compared to the wild-type strain. When vegetative cells were injected into the hemocoel of larvae of Galleriamellonella, however, there was a significant increase in the rate and level of mortality over the wild type. The yield of B. thuringiensis per cadaver was a hundred-fold greater in the PrtA-secreting strain. The increased pathogenicity from intrahemocoelic infection may have been due to a greater ability to overcome the immune response of G. mellonella while other factors such as resident gut bacteria may have negated this advantage after oral dosage.

Comparative studies to assess bacterial communities on the clover phylloplane using MLST, DGGE and T-RFLP.

Denaturing gradient gel electrophoresis (DGGE) and terminal restriction fragment length polymorphism (T-RFLP) were used to characterise the changes that occurred in Bacillus cereus group strains present in the phylloplane of clover Trifolium hybridum over 4 months. These strains had previously been analysed by multiple locus sequence typing (MLST). DGGE displayed many equally intense bands which indicated many equally abundant ribotypes. The bacterial community composition was variable and the leaves sampled as little as a week apart were found to have some temporal variability, indicating that diverse phylloplane bacterial communities follow sequential patterns from time to time. The B. cereus group community clearly clustered into early, mid and late branches, possibly due to multiple successional sequences occurring during growing seasons. The functionally and phylogenetically diverse microbial communities appeared to exhibit predictable successional patterns over shorter time scales. DGGE analysis with the molecular marker rpoB gave better resolution than 16S rRNA amplicons. There were no strong similarities between the dendrograms produced by DGGE, MLST and T-RFLP and the clustering produced by the automated T-RFLP method was variable even between the three restriction enzymes used. The DGGE-MLST method emerged as a superior method to T-RFLP-MLST for rapid typing of bacterial communities.

RKKY interaction and intrinsic frustration in non-Fermi-liquid metals.

We study the RKKY interaction in non-Fermi-liquid metals. We find that the RKKY interaction mediated by some non-Fermi-liquid metals can be of much longer range than for a Fermi liquid. The oscillatory nature of the RKKY interaction thus becomes more important in such non-Fermi liquids, and gives rise to enhanced frustration when the spins form a lattice. Frustration suppresses the magnetic ordering temperature of the lattice spin system. Furthermore, we find that the spin system with a longer range RKKY interaction can be described by the Brazovskii model, where the ordering wave vector lies on a higher dimensional manifold. Strong fluctuations in such a model lead to a first-order phase transition and/or glassy phase. This may explain some recent experiments where glassy behavior was observed in stoichiometric heavy fermion material close to a ferromagnetic quantum critical point.

Inelastic electron tunneling spectroscopy for topological insulators.

Inelastic electron tunneling spectroscopy is a powerful spectroscopy that allows one to investigate the nature of local excitations and energy transfer in the system of interest. We study inelastic electron tunneling spectroscopy for topological insulators and investigate the role of inelastic scattering on the Dirac node states on the surface of topological insulators. Local inelastic scattering is shown to significantly modify the Dirac node spectrum. In the weak coupling limit, peaks and steps are induced in second derivative d2I/dV2. In the strong coupling limit, the local negative-U centers are formed at impurity sites, and the Dirac cone structure is fully destroyed locally. At intermediate coupling, resonance peaks emerge. We map out the evolution of the resonance peaks from weak to strong coupling, which interpolate nicely between the two limits. There is a sudden qualitative change of behavior at intermediate coupling, indicating the possible existence of a local quantum phase transition. We also find that, even for a simple local phonon mode, the inherent coupling of spin and orbital degrees in topological insulators leads to the spin-polarized texture in inelastic Friedel oscillations induced by the local mode.

Promoter polymorphisms in two overlapping 6p25 genes implicate mitochondrial proteins in cognitive deficit in schizophrenia.

In a previous study, we detected a 6p25-p24 region linked to schizophrenia in families with high composite cognitive deficit (CD) scores, a quantitative trait integrating multiple cognitive measures. Association mapping of a 10 Mb interval identified a 260 kb region with a cluster of single-nucleotide polymorphisms (SNPs) significantly associated with CD scores and memory performance. The region contains two colocalising genes, LYRM4 and FARS2, both encoding mitochondrial proteins. The two tagging SNPs with strongest evidence of association were located around the overlapping putative promoters, with rs2224391 predicted to alter a transcription factor binding site (TFBS). Sequencing the promoter region identified 22 SNPs, many predicted to affect TFBSs, in a tight linkage disequilibrium block. Luciferase reporter assays confirmed promoter activity in the predicted promoter region, and demonstrated marked downregulation of expression in the LYRM4 direction under the haplotype comprising the minor alleles of promoter SNPs, which however is not driven by rs2224391. Experimental evidence from LYRM4 expression in lymphoblasts, gel-shift assays and modelling of DNA breathing dynamics pointed to two adjacent promoter SNPs, rs7752203-rs4141761, as the functional variants affecting expression. Their C-G alleles were associated with higher transcriptional activity and preferential binding of nuclear proteins, whereas the G-A combination had opposite effects and was associated with poor memory and high CD scores. LYRM4 is a eukaryote-specific component of the mitochondrial biogenesis of Fe-S clusters, essential cofactors in multiple processes, including oxidative phosphorylation. LYRM4 downregulation may be one of the mechanisms involved in inefficient oxidative phosphorylation and oxidative stress, increasingly recognised as contributors to schizophrenia pathogenesis.

Can retrospectively fusing SPECT to CT images reduce radiation doses in myocardial perfusion imaging?

INTRODUCTION: To establish if the CT dataset acquired during the stress element of myocardial perfusion imaging can be fused to the subsequent rest scan to reduce radiation doses from these procedures. METHODS: 86 rest scans were processed and evaluated using a self-designed project specific tool. Recording processing time, the time between the two data sets selected for fusion and assessing radiographic reports to ensure produced images were of diagnostic quality. RESULTS: 70% of fused scans were acquired 6-7 days apart; the mean (SD) processing time was calculated as 2.03 (0.36) minutes. The Pearson's correlation between these two variables was determined to be 0.22, showing a slight positive correlation although not statistically significant. 100% of the images produced were of diagnostic quality. CONCLUSION: Rest scans can be fused to a previously acquired CT, careful consideration should be given when positioning the patient and to the time interval between acquiring the two data sets, departmental guidelines can assist with this. Staff training may also be beneficial to ensure staff can assess if data sets are fusible prior to completing a scan. IMPLICATIONS FOR PRACTICE: This data provides evidence that retrospective fusion can reduce patient radiation doses in myocardial perfusion imaging without compromising diagnostic outcomes. Dose optimisation is an essential part of the ionising radiation (medical exposure) regulations therefore retrospective fusion should be considered in practice to ensure departmental compliance, although it is noteworthy this study is solely based in a single centred one camera department.

RLSuite: An Integrative R-Loop Bioinformatics Framework.

We recently described the development of a database of 810 R-loop mapping datasets and used this data to conduct a meta-analysis of R-loops. R-loops are three-stranded nucleic acid structures containing RNA:DNA hybrids and we were able to verify that 30% of expressed genes have an associated R-loop in a location conserved manner.. Moreover, intergenic R-loops map to enhancers, super enhancers and with TAD domain boundaries. This work demonstrated that R-loop mapping via high-throughput sequencing can reveal novel insight into R-loop biology, however the analysis and quality control of these data is a non-trivial task for which few bioinformatic tools exist. Herein we describe RLSuite, an integrative R-loop bioinformatics framework for pre-processing, quality control, and downstream analysis of R-loop mapping data. RLSuite enables users to compare their data to hundreds of public datasets and generate a user-friendly analysis report for sharing with non-bioinformatician colleagues. Taken together, RLSuite is a novel analysis framework that should greatly benefit the emerging R-loop bioinformatics community in a rapidly expanding aspect of epigenetic control that is still poorly understood.