Modular digital holographic fringe data processing system

A software architecture suitable for reducing holographic fringe data into useful engineering data is developed and tested. The results, along with a detailed description of the proposed architecture for a Modular Digital Fringe Analysis System, are presented

Possible mechanism for achieving glass-like thermal conductivities in crystals with off-center atoms

In the filled Ga/Ge clathrate, Eu and Sr are off-center in site 2 but Ba is on-center. All three filler atoms (Ba,Eu,Sr) have low temperature Einstein modes; yet only for the Eu and Sr systems is there a large dip in the thermal conductivity, attributed to the Einstein modes. No dip is observed for Ba. Here we argue that it is the off-center displacement that is crucial for understanding this unexplained difference in behavior. It enhances the coupling between the "rattler" motion and the lattice phonons for the Eu and Sr systems, and turns on/off another scattering mechanism (for 1K < T < 20K) produced by the presence/absence of off-center sites. The random occupation of different off-center sites produces a high density of symmetry-breaking defects which scatters phonons. It may also be important for improving our understanding of other glassy systems.Comment: 4 pages, 1 figure (2 parts) -- v2: intro broadened; strengthened arguments regarding need for additional phonon scattering mechanis

The geomorphological setting of some of Scotland's east coast freshwater mills: a comment on Downward and Skinner (2005) ‘Working rivers: the geomorphological legacy...’

Many of the water mills on Scotland's east coast streams, unlike those discussed recently by Downward and Skinner (2005 Area 37 138–47), are found in predominantly bedrock reaches immediately downstream of knickpoints (i.e. bedrock steps). Bedrock knickpoints in the lower reaches of Scottish rivers are a widespread fluvial response to the glacio-isostatic rebound of northern Britain. These steps in the river profile propagate headward over time, but for intervals of a few centuries or so they are sufficiently stable to be exploited for the elevational fall necessary to power the mill wheel. Many of these mills were apparently powered by ‘run-of-the-river’, as are some today that formerly had mill dams. The typical lack of sediment storage along the erosional lower reaches of many Scottish rivers means that failure of mill structures in Scotland will probably have less dramatic geomorphological and management implications than those suggested by Downward and Skinner for southern English rivers

Efficient Genotyping of KRAS Mutant Non-Small Cell Lung Cancer Using a Multiplexed Droplet Digital PCR Approach

© 2015 Pender et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Droplet digital PCR (ddPCR) can be used to detect low frequency mutations in oncogenedriven lung cancer. The range of KRAS point mutations observed in NSCLC necessitates a multiplex approach to efficient mutation detection in circulating DNA. Here we report the design and optimisation of three discriminatory ddPCR multiplex assays investigating nine different KRAS mutations using PrimePCRddPCRMutation Assays and the Bio-Rad QX100 system. Together these mutations account for 95% of the nucleotide changes found in KRAS in human cancer. Multiplex reactions were optimised on genomic DNA extracted from KRAS mutant cell lines and tested on DNA extracted from fixed tumour tissue from a cohort of lung cancer patients without prior knowledge of the specific KRAS genotype. The multiplex ddPCR assays had a limit of detection of better than 1 mutant KRAS molecule in 2,000 wild-type KRAS molecules, which compared favourably with a limit of detection of 1 in 50 for next generation sequencing and 1 in 10 for Sanger sequencing. Multiplex ddPCR assays thus provide a highly efficient methodology to identify KRAS mutations in lung adenocarcinoma

JunD, not c-Jun, is the AP-1 transcription factor required for Ras-induced lung cancer.

The AP-1 transcription factor c-Jun is required for Ras-driven tumorigenesis in many tissues and is considered as a classical proto-oncogene. To determine the requirement for c-Jun in a mouse model of K-RasG12D-induced lung adenocarcinoma, we inducibly deleted c-Jun in the adult lung. Surprisingly, we found that inactivation of c-Jun, or mutation of its JNK phosphorylation sites, actually increased lung tumor burden. Mechanistically, we found that protein levels of the Jun family member JunD were increased in the absence of c-Jun. In c-Jun-deficient cells, JunD phosphorylation was increased, and expression of a dominant-active JNKK2-JNK1 transgene further increased lung tumor formation. Strikingly, deletion of JunD completely abolished Ras-driven lung tumorigenesis. This work identifies JunD, not c-Jun, as the crucial substrate of JNK signaling and oncogene required for Ras-induced lung cancer

Targeting of Ras-mediated FGF signaling suppresses Pten-deficient skin tumor.

Deficiency in PTEN (phosphatase and tensin homolog deleted on chromosome 10) is the underlying cause of PTEN hamartoma tumor syndrome and a wide variety of human cancers. In skin epidermis, we have previously identified an autocrine FGF signaling induced by loss of Pten in keratinocytes. In this study, we demonstrate that skin hyperplasia requires FGF receptor adaptor protein Frs2α and tyrosine phosphatase Shp2, two upstream regulators of Ras signaling. Although the PI3-kinase regulatory subunits p85α and p85β are dispensable, the PI3-kinase catalytic subunit p110α requires interaction with Ras to promote hyperplasia in Pten-deficient skin, thus demonstrating an important cross-talk between Ras and PI3K pathways. Furthermore, genetic and pharmacological inhibition of Ras-MAPK pathway impeded epidermal hyperplasia in Pten animals. These results reveal a positive feedback loop connecting Pten and Ras pathways and suggest that FGF-activated Ras-MAPK pathway is an effective therapeutic target for preventing skin tumor induced by aberrant Pten signaling

Heterodinuclear ruthenium(II)-cobalt(III) complexes as models for a new approach to selective cancer treatment

Heterodinuclear ruthenium(ii)-cobalt(iii) complexes have been prepared as part of investigations into a new approach to selective cancer treatment. A cobalt(iii) centre bearing amine ligands, which serve as models for cytotoxic nitrogen mustard ligands, is connected by a bridging ligand to a ruthenium(ii)-polypyridyl moiety. Upon excitation of the ruthenium centre by visible light, electron transfer to the cobalt(iii) centre results in reduction to cobalt(ii) and consequent release of its ligands. We have synthesised several such structures and demonstrated their ability to release ligands upon excitation of the ruthenium centre by visible light

Autophagy inhibition-mediated epithelial–mesenchymal transition augments local myofibroblast differentiation in pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF), the prototypic progressive fibrotic interstitial lung disease, is thought to be a consequence of repetitive micro-injuries to an ageing, susceptible alveolar epithelium. Ageing is a risk factor for IPF and incidence has been demonstrated to increase with age. Decreased (macro)autophagy with age has been reported extensively in a variety of systems and diseases, including IPF. However, it is undetermined whether the role of faulty autophagy is causal or coincidental in the context of IPF. Here, we report that in alveolar epithelial cells inhibition of autophagy promotes epithelial–mesenchymal transition (EMT), a process implicated in embryonic development, wound healing, cancer metastasis and fibrosis. We further demonstrate that this is attained, at least in part, by increased p62/SQSTM1 expression that promotes p65/RELA mediated-transactivation of an EMT transcription factor, Snail2 (SNAI2), which not only controls EMT but also regulates the production of locally acting profibrogenic mediators. Our data suggest that reduced autophagy induces EMT of alveolar epithelial cells and can contribute to fibrosis via aberrant epithelial–fibroblast crosstalk

IGF1-mediated human embryonic stem cell self-renewal recapitulates the embryonic niche.

Our understanding of the signalling pathways regulating early human development is limited, despite their fundamental biological importance. Here, we mine transcriptomics datasets to investigate signalling in the human embryo and identify expression for the insulin and insulin growth factor 1 (IGF1) receptors, along with IGF1 ligand. Consequently, we generate a minimal chemically-defined culture medium in which IGF1 together with Activin maintain self-renewal in the absence of fibroblast growth factor (FGF) signalling. Under these conditions, we derive several pluripotent stem cell lines that express pluripotency-associated genes, retain high viability and a normal karyotype, and can be genetically modified or differentiated into multiple cell lineages. We also identify active phosphoinositide 3-kinase (PI3K)/AKT/mTOR signalling in early human embryos, and in both primed and naïve pluripotent culture conditions. This demonstrates that signalling insights from human blastocysts can be used to define culture conditions that more closely recapitulate the embryonic niche

Characterisation of tumour microenvironment remodelling following oncogene inhibition in preclinical studies with imaging mass cytometry.

Mouse models are critical in pre-clinical studies of cancer therapy, allowing dissection of mechanisms through chemical and genetic manipulations that are not feasible in the clinical setting. In studies of the tumour microenvironment (TME), multiplexed imaging methods can provide a rich source of information. However, the application of such technologies in mouse tissues is still in its infancy. Here we present a workflow for studying the TME using imaging mass cytometry with a panel of 27 antibodies on frozen mouse tissues. We optimise and validate image segmentation strategies and automate the process in a Nextflow-based pipeline (imcyto) that is scalable and portable, allowing for parallelised segmentation of large multi-image datasets. With these methods we interrogate the remodelling of the TME induced by a KRAS G12C inhibitor in an immune competent mouse orthotopic lung cancer model, highlighting the infiltration and activation of antigen presenting cells and effector cells