Deformation-Driven Diffusion and Plastic Flow in Two-Dimensional Amorphous Granular Pillars

We report a combined experimental and simulation study of deformation-induced diffusion in compacted two-dimensional amorphous granular pillars, in which thermal fluctuations play negligible role. The pillars, consisting of bidisperse cylindrical acetal plastic particles standing upright on a substrate, are deformed uniaxially and quasistatically by a rigid bar moving at a constant speed. The plastic flow and particle rearrangements in the pillars are characterized by computing the best-fit affine transformation strain and non-affine displacement associated with each particle between two stages of deformation. The non-affine displacement exhibits exponential crossover from ballistic to diffusive behavior with respect to the cumulative deviatoric strain, indicating that in athermal granular packings, the cumulative deviatoric strain plays the role of time in thermal systems and drives effective particle diffusion. We further study the size-dependent deformation of the granular pillars by simulation, and find that different-sized pillars follow self-similar shape evolution during deformation. In addition, the yield stress of the pillars increases linearly with pillar size. Formation of transient shear lines in the pillars during deformation becomes more evident as pillar size increases. The width of these elementary shear bands is about twice the diameter of a particle, and does not vary with pillar size.Comment: 14 pages, 11 figure

A Sustained Dietary Change Increases Epigenetic Variation in Isogenic Mice

Epigenetic changes can be induced by adverse environmental exposures, such as nutritional imbalance, but little is known about the nature or extent of these changes. Here we have explored the epigenomic effects of a sustained nutritional change, excess dietary methyl donors, by assessing genomic CpG methylation patterns in isogenic mice exposed for one or six generations. We find stochastic variation in methylation levels at many loci; exposure to methyl donors increases the magnitude of this variation and the number of variable loci. Several gene ontology categories are significantly overrepresented in genes proximal to these methylation-variable loci, suggesting that certain pathways are susceptible to environmental influence on their epigenetic states. Long-term exposure to the diet (six generations) results in a larger number of loci exhibiting epigenetic variability, suggesting that some of the induced changes are heritable. This finding presents the possibility that epigenetic variation within populations can be induced by environmental change, providing a vehicle for disease predisposition and possibly a substrate for natural selection.This work was supported by the Australian Research Council (DP0771859) and the National Health and Medical Research Council (#459412, #635510)

Variations in neonatal mortality, infant mortality, preterm birth and birth weight in England and Wales according to ethnicity and maternal country or region of birth: an analysis of linked national data from 2006 to 2012.

BACKGROUND: Risks of adverse birth outcomes in England and Wales are relatively low but vary across ethnic groups. We aimed to explore the role of mother's country of birth on birth outcomes across ethnic groups using a large population-based linked data set. METHODS: We used a cohort of 4.6 million singleton live births in England and Wales to estimate relative risks of neonatal mortality, infant mortality and preterm birth, and differences in birth weight, comparing infants of UK-born mothers to infants whose mothers were born in their countries or regions of ethnic origin, or elsewhere. RESULTS: The crude neonatal and infant death risks were 2.1 and 3.2 per 1000, respectively, the crude preterm birth risk was 5.6% and the crude mean birth weight was 3.36 kg. Pooling across all ethnic groups, infants of mothers born in their countries or regions of ethnic origin had lower adjusted risks of death and preterm birth, and higher gestational age-adjusted mean birth weights than those of UK-born mothers. White British infants of non-UK-born mothers had slightly lower gestational age-adjusted mean birth weights than White British infants of UK-born mothers (mean difference -3 g, 95% CI -5 g to -0.3 g). Pakistani infants of Pakistan-born mothers had lower adjusted risks of neonatal death (adjusted risk ratio (aRR) 0.84, 95% CI 0.72 to 0.98), infant death (aRR 0.84, 95% CI 0.75 to 0.94) and preterm birth (aRR 0.85, 95% CI 0.82 to 0.88) than Pakistani infants of UK-born Pakistani mothers. Indian infants of India-born mothers had lower adjusted preterm birth risk (aRR 0.91, 95% CI 0.87 to 0.96) than Indian infants of UK-born Indian mothers. There was no evidence of a difference by mother's country of birth in risk of birth outcomes among Black infants, except Black Caribbean infants of mothers born in neither the UK nor their region of origin, who had higher neonatal death risks (aRR 1.71, 95% CI 1.06 to 2.76). CONCLUSION: This study highlights evidence of better birth outcomes among UK-born infants of non-UK-born minority ethnic group mothers, and could inform the design of future interventions to reduce the risks of adverse birth outcomes through improved targeting of at-risk groups

A socio-technical framework to guide implementation and value realisation of distributed ledger technologies (dlt) in the construction sector

Construction is highly resistant to change. Its many challenges have persisted for decades rooted in a lack of trust, reluctance to collaborate and share information. New technologies offer increased transparency, efficiency, and collaboration. Building Information Modelling (BIM), while being the most successful to advance construction to date, has not done enough to combat the challenges. The aim of this research was to investigate the potential of distributed ledger technologies (DLT) and smart contracts (SCs) to provide solutions for the sector. Through empirical investigations (systematic literature review, interviews, focus groups, survey), a framework to guide implementation and value realisation of DLT and SCs in the construction sector was proposed. A socio-technical approach was taken resulting in a framework encompassing four dimensions of technology, process, policy and society. This approach recognises DLT and SCs are not a panacea in and of themselves and should be used in conjunction with advancements across the four dimensions to de-risk any potential failure of these systems. The framework is made up of several conceptual constructs for use at meso and macro scales to support evaluation of the as-is to achieve a desired state and offers progressive roadmaps to reach the point of implementation. The findings demonstrate the requirement for DLT and SCs to integrate with other systems (e.g., BIM, IoT, AI) to add value. Furthermore, technology alone is insufficient to solve the sector’s problems also requiring reform of outdated practices (e.g., procurement, payments, contract management). Contributions to knowledge include: the first known socio-technical framework for systematic and progressive implementation of DLT and SCs in construction. This places equal importance on society and technology for the implementation of these new technological systems and will facilitate their success to unlock benefits for the sector amid the myriad challenges it faces; through this socio-technical approach, the framework encourages active involvement of stakeholders placing importance on the realisation that engaging with users of the system is central to its success; the position of an organisation (or group) looking to develop DLT- or SC-based applications at the meso scale or the position of the sector with regard to how it wants to incorporate these technologies into its existing systems and processes at the macro scale can be evaluated using the framework’s progressive approach that considers every stage of developing and implementing an application; the constructs considering both meso and macro scales minimise any potential decoupling between policy and practice in terms of implementation; and the framework aims to provide a flexible set of tools to encourage the sector to create an ecosystem ready to support these applications as well as provide guidance in the development of applications

Exploring Halo Substructure with Giant Stars. XV. Discovery of a Connection between the Monoceros Ring and the Triangulum-Andromeda Overdensity?

Thanks to modern sky surveys, over twenty stellar streams and overdensity structures have been discovered in the halo of the Milky Way. In this paper, we present an analysis of spectroscopic observations of individual stars from one such structure, "A13", first identified as an overdensity using the M giant catalog from the Two Micron All-Sky Survey. Our spectroscopic observations show that stars identified with A13 have a velocity dispersion of $\lesssim$ 40 $\mathrm{km~s^{-1}}$, implying that it is a genuine coherent structure rather than a chance super-position of random halo stars. From its position on the sky, distance ($\sim$15~kpc heliocentric), and kinematical properties, A13 is likely to be an extension of another low Galactic latitude substructure -- the Galactic Anticenter Stellar Structure (also known as the Monoceros Ring) -- towards smaller Galactic longitude and farther distance. Furthermore, the kinematics of A13 also connect it with another structure in the southern Galactic hemisphere -- the Triangulum-Andromeda overdensity. We discuss these three connected structures within the context of a previously proposed scenario that one or all of these features originate from the disk of the Milky Way.Comment: 12 pages, 9 figures. Accepted for publication in Ap

Alterations to the Gastrointestinal Microbiome Associated with Methamphetamine Use among Young Men who have Sex with Men.

Methamphetamine (MA) use is a major public health problem in the United States, especially among people living with HIV (PLWH). Many MA-induced neurotoxic effects are mediated by inflammation and gut microbiota may play a role in this process, yet the effects of MA on the microbiome have not been adequately explored. Therefore, we performed 16S rRNA gene sequencing on rectal swab samples from 381 men who have sex with men, 48% of whom were PLWH and 41% of whom used MA. We compared microbiome composition between MA users and non-users while testing for potential interactions with HIV and controlling for numerous confounders using inverse probability of treatment weighting. We found that MA use explained significant variation in overall composition (R2 = 0.005, p = 0.008) and was associated with elevated Finegoldia, Parvimonas, Peptoniphilus, and Porphyromonas and reduced Butyricicoccus and Faecalibacterium, among others. Genera including Actinomyces and Streptobacillus interacted with HIV status, such that they were increased in HIV+ MA users. Finegoldia and Peptoniphilus increased with increasing frequency of MA use, among others. In summary, MA use was associated with a microbial imbalance favoring pro-inflammatory bacteria, including some with neuroactive potential and others that have previously been associated with poor HIV outcomes

Comprehensive behavioral testing in the R6/2 mouse model of Huntington's disease shows no benefit from CoQ10 or minocycline

Previous studies of the effects of coenzyme Q10 and minocycline on mouse models of Huntington’s disease have produced conflicting results regarding their efficacy in behavioral tests. Using our recently published best practices for husbandry and testing for mouse models of Huntington’s disease, we report that neither coenzyme Q10 nor minocycline had significant beneficial effects on measures of motor function, general health (open field, rotarod, grip strength, rearing-climbing, body weight and survival) in the R6/2 mouse model. The higher doses of minocycline, on the contrary, reduced survival. We were thus unable to confirm the previously reported benefits for these two drugs, and we discuss potential reasons for these discrepancies, such as the effects of husbandry and nutrition

A preexisting rare PIK3CA e545k subpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling

Combined MEK and CDK4/6 inhibition (MEKi + CDK4i) has shown promising clinical outcomes in patients with NRAS- mutant melanoma. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi + CDK4i therapy but subsequently developed resistance. Whole-exome sequencing and functional validation identified an acquired PIK3CA E545K mutation as conferring drug resistance. We demonstrate that PIK3CA E545K preexisted in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multiregion sampling due to PIK3CA E545K being nonuniformly distributed. This resistant population rapidly expanded after the initiation of MEKi + CDK4i therapy and persisted in all successive samples even after immune checkpoint therapy and distant metastasis. Functional studies identified activated S6K1 as both a key marker and specific therapeutic vulnerability downstream of PIK3CA E545K -induced resistance. These results demonstrate that difficult-to-detect preexisting resistance mutations may exist more often than previously appreciated and also posit S6K1 as a common downstream therapeutic nexus for the MAPK, CDK4/6, and PI3K pathways. SIGNIFICANCE: We report the first characterization of clinical acquired resistance to MEKi + CDK4i, identifying a rare preexisting PIK3CA E545K subpopulation that expands upon therapy and exhibits drug resistance. We suggest that single-region pretreatment biopsy is insufficient to detect rare, spatially segregated drug-resistant subclones. Inhibition of S6K1 is able to resensitize PIK3CA E545K -expressing NRAS-mutant melanoma cells to MEKi + CDK4i. © 2018 AAC

Frequency-aware optical coherence tomography image super-resolution via conditional generative adversarial neural network

Optical coherence tomography (OCT) has stimulated a wide range of medical image-based diagnosis and treatment in fields such as cardiology and ophthalmology. Such applications can be further facilitated by deep learning-based super-resolution technology, which improves the capability of resolving morphological structures. However, existing deep learning-based method only focuses on spatial distribution and disregard frequency fidelity in image reconstruction, leading to a frequency bias. To overcome this limitation, we propose a frequency-aware super-resolution framework that integrates three critical frequency-based modules (i.e., frequency transformation, frequency skip connection, and frequency alignment) and frequency-based loss function into a conditional generative adversarial network (cGAN). We conducted a large-scale quantitative study from an existing coronary OCT dataset to demonstrate the superiority of our proposed framework over existing deep learning frameworks. In addition, we confirmed the generalizability of our framework by applying it to fish corneal images and rat retinal images, demonstrating its capability to super-resolve morphological details in eye imaging.Comment: 13 pages, 7 figures, submitted to Biomedical Optics Express special issu