Thirty Years of Turnstiles and Transport

To characterize transport in a deterministic dynamical system is to compute exit time distributions from regions or transition time distributions between regions in phase space. This paper surveys the considerable progress on this problem over the past thirty years. Primary measures of transport for volume-preserving maps include the exiting and incoming fluxes to a region. For area-preserving maps, transport is impeded by curves formed from invariant manifolds that form partial barriers, e.g., stable and unstable manifolds bounding a resonance zone or cantori, the remnants of destroyed invariant tori. When the map is exact volume preserving, a Lagrangian differential form can be used to reduce the computation of fluxes to finding a difference between the action of certain key orbits, such as homoclinic orbits to a saddle or to a cantorus. Given a partition of phase space into regions bounded by partial barriers, a Markov tree model of transport explains key observations, such as the algebraic decay of exit and recurrence distributions.Comment: Updated and corrected versio

Cellular mRNAs access second ORFs using a novel amino acid sequence-dependent coupled translation termination-reinitiation mechanism

Polycistronic transcripts are considered rare in the human genome. Initiation of translation of internal ORFs of eukaryotic genes has been shown to use either leaky scanning or highly structured IRES regions to access initiation codons. Studies on mammalian viruses identified a mechanism of coupled translation termination-reinitiation that allows translation of an additional ORF. Here, the ribosome terminating translation of ORF-1 translocates upstream to reinitiate translation of ORF-2. We have devised an algorithm to identify mRNAs in the human transcriptome in which the major ORF-1 overlaps a second ORF capable of encoding a product of at least 50 aa in length. This identified 4368 transcripts representing 2214 genes. We investigated 24 transcripts, 22 of which were shown to express a protein from ORF-2 highlighting that 3' UTRs contain protein-coding potential more frequently than previously suspected. Five transcripts accessed ORF-2 using a process of coupled translation termination-reinitiation. Analysis of one transcript, encoding the CASQ2 protein, showed that the mechanism by which the coupling process of the cellular mRNAs was achieved was novel. This process was not directed by the mRNA sequence but required an aspartate-rich repeat region at the carboxyl terminus of the terminating ORF-1 protein. Introduction of wobble mutations for the aspartate codon had no effect, whereas replacing aspartate for glutamate repeats eliminated translational coupling. This is the first description of a coordinated expression of two proteins from cellular mRNAs using a coupled translation termination-reinitiation process and is the first example of such a process being determined at the amino acid level

Cloned defective interfering influenza virus protects ferrets from pandemic 2009 influenza A virus and allows protective immunity to be established

Influenza A viruses are a major cause of morbidity and mortality in the human population, causing epidemics in the winter, and occasional worldwide pandemics. In addition there are periodic outbreaks in domestic poultry, horses, pigs, dogs, and cats. Infections of domestic birds can be fatal for the birds and their human contacts. Control in man operates through vaccines and antivirals, but both have their limitations. In the search for an alternative treatment we have focussed on defective interfering (DI) influenza A virus. Such a DI virus is superficially indistinguishable from a normal virus but has a large deletion in one of the eight RNAs that make up the viral genome. Antiviral activity resides in the deleted RNA. We have cloned one such highly active DI RNA derived from segment 1 (244 DI virus) and shown earlier that intranasal administration protects mice from lethal disease caused by a number of different influenza A viruses. A more cogent model of human influenza is the ferret. Here we found that intranasal treatment with a single dose of 2 or 0.2 µg 244 RNA delivered as A/PR/8/34 virus particles protected ferrets from disease caused by pandemic virus A/California/04/09 (A/Cal; H1N1). Specifically, 244 DI virus significantly reduced fever, weight loss, respiratory symptoms, and infectious load. 244 DI RNA, the active principle, was amplified in nasal washes following infection with A/Cal, consistent with its amelioration of clinical disease. Animals that were treated with 244 DI RNA cleared infectious and DI viruses without delay. Despite the attenuation of infection and disease by DI virus, ferrets formed high levels of A/Cal-specific serum haemagglutination-inhibiting antibodies and were solidly immune to rechallenge with A/Cal. Together with earlier data from mouse studies, we conclude that 244 DI virus is a highly effective antiviral with activity potentially against all influenza A subtypes

Heteroclinic intersections between Invariant Circles of Volume-Preserving Maps

We develop a Melnikov method for volume-preserving maps with codimension one invariant manifolds. The Melnikov function is shown to be related to the flux of the perturbation through the unperturbed invariant surface. As an example, we compute the Melnikov function for a perturbation of a three-dimensional map that has a heteroclinic connection between a pair of invariant circles. The intersection curves of the manifolds are shown to undergo bifurcations in homologyComment: LaTex with 10 eps figure

Cancer mortality in the first degree relatives of young breast cancer patients.

In a retrospective cohort study, the mothers and sisters of 740 breast cancer patients aged under 36 at diagnosis have been studied for mortality and cancer incidence. Significantly increased breast cancer mortality was observed below age 60 (30 deaths; SMR = 3.4), but not at older ages (four deaths; SMR = 0.9). The cumulative breast cancer incidence in the relatives was 3.6% by age 50, 7.6% by age 60 and 11.6% by age 70. They also suffered excess mortality below age 60 for cancers of reproductive sites (cervix, ovary and endometrium; 15 deaths; SMR = 2.6) and lung (11 deaths; SMR = 3.2), but not for other sites (12 deaths; SMR = 0.9). This large population-based cohort study provides further confirmation of genetic susceptibility to breast cancer at young ages

Residual stress generation in tungsten-copper brazed joint using brazing alloy

Understanding the residual stress state in brazed joints is crucial for operational design and life time performance of the part in service. High magnitudes residual stresses are expected in the joined materials following cooling from brazing temperatures (≈950°C) due to large mismatches in material properties such as coefficient of thermal expansion and Young’s modulus. This study aims at further understanding of the generation and distribution of residual stresses when brazing tungsten to copper using a eutectic gold-copper brazing alloy. This configuration is potentially useful for future divertor designs. Finite Element Analysis (FEM) has been used to predict the brazing induced stresses and residual stress measurements were carried out on the brazed joint by X-ray diffraction (XRD) to validate the prediction model. Large residual stresses are predicted and measured in the tungsten; however there is disagreement in the sign of the stress. Predicted stresses are highly tensile in nature close to the brazing interface, whereas the measured stresses are highly compressive. The disagreement is believed to be caused by the model not accurately simulating the complex brazing process. Residual stress measurements on the copper were not possible due to texturing during brazing, grain growth and significant inelastic strains and deformations. Misalignment of parent materials was also observed to significantly affect residual stresses

Residual stress generations in brazed tungsten dissimilar joints

Understanding the residual stress state in brazed joints is crucial for the operational design and lifetime performance of the part in service. High-magnitude residual stresses are expected in the joined materials following cooling from brazing temperatures (≈950 °C) due to large mismatches in the thermal and mechanical properties. This paper aims at further understanding of the residual stresses caused when brazing tungsten to copper and tungsten to 316L austenitic steel using a eutectic gold-copper brazing alloy. These configurations are potentially useful for future diverter designs. Finite element analysis has been used to predict the brazing-induced stresses and residual stress measurements were carried out on the brazed joint by X-ray diffraction to validate the prediction model. Large residual stresses are predicted and measured in the tungsten; however, there is disagreement in the nature of the stress in the tungsten-copper configuration. Predicted stresses are highly tensile in nature close to the brazing interface, whereas the measured stresses are highly compressive. The disagreement is believed to be caused by the model not accurately simulating the complex brazing process. Residual stress measurements on the copper were not possible due to texturing during brazing, grain growth, and significant inelastic strains. There is excellent correlation between the measured and predicted stresses in the tungsten-316L configuration. High-tensile stresses were predicted in the tungsten (magnitude approximately 1000 MPa close to the braze interface) and high tensile stresses were measured (magnitude approximately 800 MPa in the same region). Joint misalignment of parent materials was also observed to significantly affect the residual stresses

Grain refinement of stainless steel in ultrasound-assisted additive manufacturing

Metals and alloys fabricated by fusion-based additive manufacturing (AM), or 3D printing, undergo complex dynamics of melting and solidification, presenting challenges to the effective control of grain structure. Herein, we report on the use of high-intensity ultrasound that controls the process of solidification during AM of 316L stainless steel. We find that the use of ultrasound favours the columnar-to-equiaxed transition, promoting the formation of fine equiaxed grains with random crystallographic texture. Moreover, the use of ultrasound increases the number density of grains from 305 mm-2 to 2748 mm-2 despite an associated decrease in cooling rate and temperature gradient in the melt pool during AM. Our assessment of the relationship between grain size and cooling rate indicates that the formation of crystallites during AM is enhanced by ultrasound. Furthermore, the use of ultrasound increases the amount of constitutional supercooling during solidification by lowering the temperature gradient in the bulk of the melt pool, thus creating an environment that favours nucleation, growth, and survival of grains. This new understanding provides opportunities to better exploit ultrasound to control grain structure in AM-fabricated metal products.Comment: Paper published in Additive Manufacturin

Design of a hydrophobic tripeptide that self-assembles into amphiphilic superstructures forming a hydrogel biomaterial

We report the rational design of a heterochiral hydrophobic tripeptide self-assembling into amphiphilic D-superstructures that yield a self-supportive hydrogel at physiological pH. The material endures cell culture conditions and sustains fibroblast proliferation. Tripeptide superstructures are thoroughly analysed by several techniques

Qualitative exploration of the potential for adverse events when using an online peer support network for mental health: Cross-sectional survey

Background: Online peer support networks are a growing area of mental health support for offering social connection, identity, and support. However, it has been reported that not all individuals have a positive experience on such networks. The potential for adverse events within a moderated online peer support network is a new area of research exploration. Objective: The objective of the study was to determine if use of an online moderated peer networks leads to adverse events for users. Methods: Four biannual online surveys (October 2014 to March 2016) were conducted by a large national UK mental health charity, with users of their online peer support network exploring personal safety, moderation, experiences on the site, and how the site could be improved. Data were analyzed using thematic analysis by 2 independent researchers using a priori themes: negative experiences of moderation, social exclusion, contagion, negative interactions with other users, online relationships, co-rumination and collusion, and other. Results: In total, 2353 survey responses were logged with 197 (8.37%) documenting an adverse event of negative experience. A dominant theme of negative experiences of moderation emerged (73/197, 37.1%) with evidence of social exclusion (50/197, 25.4%). Reading user posts was shown to be a cause of worry and distress for a few users, and analysis highlighted several instances of depressogenic and emotional contagion as well as some limited evidence of behavioral contagion (46/197, 23.4%). Very limited evidence of co-rumination (1/197, 0.5%) and no evidence of collusion were identified. Conclusions: Evidence of adverse events was identified at low levels in the sample of respondents, although we have no comparison data to indicate if levels are low compared with comparable platforms. Not all users of online peer support networks find them wholly beneficial. Research must explore what works for whom. The next stage of service development should consider which users may be likely to receive no benefit, or even deteriorate, as a result of using the service