The peritoneal tumour microenvironment of high-grade serous ovarian cancer

High-grade serous ovarian cancer (HGSC) disseminates early and extensively throughout the peritoneal space, causing multiple lesions that are a major clinical problem. The aim of this study was to investigate the cellular composition of peritoneal tumour deposits in patient biopsies and their evolution in mouse models using immunohistochemistry, intravital microscopy, confocal microscopy, and 3D modelling. Tumour deposits from the omentum of HGSC patients contained a prominent leukocyte infiltrate of CD3(+) T cells and CD68(+) macrophages, with occasional neutrophils. Alpha-smooth muscle actin(+) (α-SMA(+) ) pericytes and/or fibroblasts surrounded these well-vascularized tumour deposits. Using the murine bowel mesentery as an accessible mouse peritoneal tissue that could be easily imaged, and two different transplantable models, we found multiple microscopic tumour deposits after i.p. injection of malignant cells. Attachment to the peritoneal surface was rapid (6-48 h) with an extensive CD45(+) leukocyte infiltrate visible by 48 h. This infiltrate persisted until end point and in the syngeneic murine ID8 model, it primarily consisted of CD3(+) T lymphocytes and CD68(+) macrophages with α-SMA(+) cells also involved from the earliest stages. A majority of tumour deposits developed above existing mesenteric blood vessels, but in avascular spaces new blood vessels tracked towards the tumour deposits by 2-3 weeks in the IGROV-1 xenografts and 6 weeks in the ID8 syngeneic model; a vigorous convoluted blood supply was established by end point. Inhibition of tumour cell cytokine production by stable expression of shRNA to CXCR4 in IGROV-1 cells did not influence the attachment of cells to the mesentery but delayed neovascularization and reduced tumour deposit size. We conclude that the multiple peritoneal tumour deposits found in HGSC patients can be modelled in the mouse. The techniques described here may be useful for assessing treatments that target the disseminated stage of this disease

One Millimeter Continuum Observations of High Redshift Quasars

Upper limits to the one-millimeter continuum flux densities of the high redshift quasars 82 1225 + 31, Ton 490, and PHL 957 are presented. The upper limit to the power observed from these quasars at I mm is, on average, ½ the observed power in the continuum at Lɑ. These observations are used to constrain the temperature of a hypothètical dust shell which reddens the quasar line and continuum emission by an extinction optical depth sufficient to account for the anomalously low Lɑ/Hɑ emission line ratio observed in each of these quasars. For the quasars studied, dust shell temperatures between 25 K and 50 to 95 K are prohibited by the present data. A dust shell at a temperature within this span reradiating all the power absorbed from the quasar ultraviolet continuum would produce a one-millimeter flux density greater than the measured upper limit. The average radius of the model dust shell cannot be between 70 kpc and 1 Mpc

The Behavior of Granular Materials under Cyclic Shear

The design and development of a parallel plate shear cell for the study of large scale shear flows in granular materials is presented. The parallel plate geometry allows for shear studies without the effects of curvature found in the more common Couette experiments. A system of independently movable slats creates a well with side walls that deform in response to the motions of grains within the pack. This allows for true parallel plate shear with minimal interference from the containing geometry. The motions of the side walls also allow for a direct measurement of the velocity profile across the granular pack. Results are presented for applying this system to the study of transients in granular shear and for shear-induced crystallization. Initial shear profiles are found to vary from packing to packing, ranging from a linear profile across the entire system to an exponential decay with a width of approximately 6 bead diameters. As the system is sheared, the velocity profile becomes much sharper, resembling an exponential decay with a width of roughly 3 bead diameters. Further shearing produces velocity profiles which can no longer be fit to an exponential decay, but are better represented as a Gaussian decay or error function profile. Cyclic shear is found to produce large scale ordering of the granular pack, which has a profound impact on the shear profile. There exist periods of time in which there is slipping between layers as well as periods of time in which the layered particles lock together resulting in very little relative motion.Comment: 10 pages including 12 figure

Nuclear Shell Model by the Quantum Monte Carlo Diagonalization Method

The feasibility of shell-model calculations is radically extended by the Quantum Monte Carlo Diagonalization method with various essential improvements. The major improvements are made in the sampling for the generation of shell-model basis vectors, and in the restoration of symmetries such as angular momentum and isospin. Consequently the level structure of low-lying states can be studied with realistic interactions. After testing this method on $^{24}$Mg, we present first results for energy levels and $E2$ properties of $^{64}$Ge, indicating its large and $\gamma$-soft deformation.Comment: 12 pages, RevTex, 2 figures, to be published in Physical Review Letter

Metastable austenite driven work-hardening behaviour in a TRIP-assisted dual phase steel

The mechanically-induced transformation behaviour of the metastable austenite phase in a high-strength industrial TRIP-assisted Dual Phase steel was monitored in situ using high-energy synchrotron diffraction under uniaxial loading. This allowed direct quantification of the impact of the transformation of the metastable austenite phase (16 vol %), embedded in a ferrite-bainite-martensite matrix, on the work hardening behaviour of this steel. Our results show that the mechanically induced transformation of austenite does not begin until the onset of matrix yielding. We provide experimental evidence which demonstrates for the first time that the austenite transformation increases the work-hardening contribution, σw thereby supporting a driving force approach to transformation induced plasticity. The transformation work required leads to an increase in the macroscopic work-hardening rate after matrix yielding and continues to offset the decrease in the work-hardening rate in the ferrite and martensite phases up to the UTS. Further we show conclusively that martensite yielding does not occur until the completion of the mechanically induced transformation of austenite. Plastic deformation of martensite is immediately followed by local plastic instability leading to necking and ultimate failure of this material

The detection of the J = 3-2 lines of HCN, HNC, and HCO^+ in the Orion molecular cloud

We report the first measurements of the 1.1 mm (J = 3-2) lines of HCN, HNC, and HCO^+ in the Orion molecular cloud. The low-intensity broad velocity wings seen in the (1-0) lines of HCN and HCO^+ are greatly enhanced in the HCN (3-2) line but not in HCO^+ (3-2). No broad wings are seen in the HNC (3-2) line. The HCN observations suggest molecular hydrogen densities ~ 10^6 cm^(-3) in the broad wing source, and the differences between the lines of HCN and HCO^+ suggest that the lines may be formed in different regions within the source

AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis

Background: Deletions in the Xq22.3–Xq23 region, inclusive of COL4A5, have been associated with a contiguous gene deletion syndrome characterised by Alport syndrome with intellectual disability (Mental retardation), Midface hypoplasia and Elliptocytosis (AMME). The extrarenal biological and clinical significance of neighbouring genes to the Alport locus has been largely speculative. We sought to discover a genetic cause for two half-brothers presenting with nephrocalcinosis, early speech and language delay and midface hypoplasia with submucous cleft palate and bifid uvula.Methods: Whole exome sequencing was undertaken on maternal half-siblings. In-house genomic analysis included extraction of all shared variants on the X chromosome in keeping with X-linked inheritance. Patient-specific mutants were transfected into three cell lines and microscopically visualised to assess the nuclear expression pattern of the mutant protein.Results: In the affected half-brothers, we identified a hemizygous novel non-synonymous variant of unknown significance in AMMECR1 (c.G530A; p.G177D), a gene residing in the AMME disease locus. Transfected cell lines with the p.G177D mutation showed aberrant nuclear localisation patterns when compared with the wild type. Blood films revealed the presence of elliptocytes in the older brother.Conclusions: Our study shows that a single missense mutation in AMMECR1 causes a phenotype of midface hypoplasia, mild intellectual disability and the presence of elliptocytes, previously reported as part of a contiguous gene deletion syndrome. Functional analysis confirms mutant-specific protein dysfunction. We conclude that AMMECR1 is a critical gene in the pathogenesis of AMME, causing midface hypoplasia and elliptocytosis and contributing to early speech and language delay, infantile hypotonia and hearing loss, and may play a role in dysmorphism, nephrocalcinosis and submucous cleft palate.<br/

Near-infrared Observations of Nova V574 Puppis (2004)

We present results obtained from extensive near-infrared spectroscopic and photometric observations of nova V574 Pup during its 2004 outburst. The observations were obtained over four months, starting from 2004 November 25 (four days after the nova outburst) to 2005 March 20. The near-IR JHK light curve is presented - no evidence is seen from it for dust formation to have occurred during our observations. In the early decline phase, the JHK spectra of the nova are dominated by emission lines of hydrogen Brackett and Paschen series, OI, CI and HeI. We also detect the fairly uncommon Fe II line at 1.6872 micron in the early part of our observations. The strengths of the HeI lines at 1.0830 micron and 2.0585 micron are found to become very strong towards the end of the observations indicating a progression towards higher excitation conditions in the nova ejecta. The width of the emission lines do not show any significant change during the course of our observations. The slope of the continuum spectrum was found to have a lambda^{-2.75} dependence in the early stages which gradually becomes flatter with time and changes to a free-free spectral dependence towards the later stages. Recombination analysis of the HI lines shows deviations from Case B conditions during the initial stages. However, towards the end of our observations, the line strengths are well simulated with case B model values with electron density n_e = 10^{9-10} cm^{-3} and a temperature equal to 10^4 K. Based on our distance estimate to the nova of 5.5 kpc and the observed free-free continuum emission in the later part of the observations, we estimate the ionized mass of the ejecta to be between 10^{-5} and 10^{-6} solar-mass.Comment: 10 pages, 8 figures, Accepted for publication in MNRA

Experienced tutors' deployment of thinking skills and what might be entailed in enhancing such skills

In the context of research that reports weaknesses in adults' critical thinking skills, the primary aim was to examine adults' use of critical thinking skills that are described in taxonomies and to identify areas for development. Position papers written by an opportunity sample of 32 experienced adult educators formed the data for a descriptive sample survey design intended to reveal participants' use of critical thinking skills. Each 6000-word paper was written during a development programme that supported such skills. A content analysis of the papers revealed that when participants drew on personal and published ideas about learning to derive their proposals for change, they accepted the ideas uncritically, thereby implying that they might find it difficult to help learners to examine ideas critically. The evidence supports research that implies that critical thinking skills are unlikely to develop unless overall course design privileges the development of epistemological understanding (King and Kitchener 1994, Kuhn 1999). A fundamental assumption underlying the study is that this understanding influences effective citizenship and personal development, as well as employability. A proposition that merits attention in future research is that the development of epistemological understanding is largely neglected in current curricula in formal post-16 education