Joint H.E.S.S. and Fermi-LAT analysis of the region around PSR J1813-1749

HESS J1813-178 is one of the brightest sources detected during the first HESS Galactic Plane survey. The compact source, also detected by MAGIC, is believed to be a pulsar wind nebula powered by one of the most powerful pulsars known in the Galaxy, PSR J1813-1749 with a spin-down luminosity of $\dot{\mathrm{E}} = 5.6 \cdot 10^{37}\,\mathrm{erg}\,\mathrm{s}^{-1}$. With its extreme physical properties, as well as the pulsar's young age of 5.6 kyrs, the $\gamma$-rays detected in this region allow us to study the evolution of a highly atypical system. Previous studies of the region in the GeV energy range show emission extended beyond the size of the compact H.E.S.S. source. Using the archival H.E.S.S. data with improved background methods, we perform a detailed morphological and spectral analysis of the region. Additionally to the compact, bright emission component, we find significantly extended emission, whose position is coincident with HESS J1813-178. We reanalyse the region in GeV and derive a joint-model in order to find a continuous description of the emission in the region from GeV to TeV. Using the results derived in this analysis, as well as X-ray and radio data of the region, we perform multi-wavelength spectral modeling. Possible hadronic or leptonic origins of the $\gamma$-ray emission are investigated, and the diffusion parameters necessary to explain the extended emission are examined.Comment: 8 pages, 4 figures, 1 table, In proceedings of ICRC202

Imaging photomultiplier array with integrated amplifiers and high-speed USB interface

Multianode photomultiplier tube (PMT) arrays are finding application as convenient high-speed light sensitive devices for plasma imaging. This paper describes the development of a USB-based "plug-n-play" 16-channel PMT camera with 16 bits simultaneous acquisition of 16 signal channels at rates up to 2 MSs per channel. The preamplifiers and digital hardware are packaged in a compact housing which incorporates magnetic shielding, on-board generation of the high-voltage PMT bias, an optical filter mount and slits, and F-mount lens adaptor. Triggering, timing, and acquisition are handled by four field-programmable gate arrays (FPGAs) under instruction from a master FPGA controlled by a computer with a LABVIEW interface. We present technical design details and specifications and illustrate performance with high-speed images obtained on the H-1 heliac at the ANU

Seamless Gene Tagging by Endonuclease-Driven Homologous Recombination

Gene tagging facilitates systematic genomic and proteomic analyses but chromosomal tagging typically disrupts gene regulatory sequences. Here we describe a seamless gene tagging approach that preserves endogenous gene regulation and is potentially applicable in any species with efficient DNA double-strand break repair by homologous recombination. We implement seamless tagging in Saccharomyces cerevisiae and demonstrate its application for protein tagging while preserving simultaneously upstream and downstream gene regulatory elements. Seamless tagging is compatible with high-throughput strain construction using synthetic genetic arrays (SGA), enables functional analysis of transcription antisense to open reading frames and should facilitate systematic and minimally-invasive analysis of gene functions

Melanoma cells break down LPA to establish local gradients that drive chemotactic dispersal.

The high mortality of melanoma is caused by rapid spread of cancer cells, which occurs unusually early in tumour evolution. Unlike most solid tumours, thickness rather than cytological markers or differentiation is the best guide to metastatic potential. Multiple stimuli that drive melanoma cell migration have been described, but it is not clear which are responsible for invasion, nor if chemotactic gradients exist in real tumours. In a chamber-based assay for melanoma dispersal, we find that cells migrate efficiently away from one another, even in initially homogeneous medium. This dispersal is driven by positive chemotaxis rather than chemorepulsion or contact inhibition. The principal chemoattractant, unexpectedly active across all tumour stages, is the lipid agonist lysophosphatidic acid (LPA) acting through the LPA receptor LPAR1. LPA induces chemotaxis of remarkable accuracy, and is both necessary and sufficient for chemotaxis and invasion in 2-D and 3-D assays. Growth factors, often described as tumour attractants, cause negligible chemotaxis themselves, but potentiate chemotaxis to LPA. Cells rapidly break down LPA present at substantial levels in culture medium and normal skin to generate outward-facing gradients. We measure LPA gradients across the margins of melanomas in vivo, confirming the physiological importance of our results. We conclude that LPA chemotaxis provides a strong drive for melanoma cells to invade outwards. Cells create their own gradients by acting as a sink, breaking down locally present LPA, and thus forming a gradient that is low in the tumour and high in the surrounding areas. The key step is not acquisition of sensitivity to the chemoattractant, but rather the tumour growing to break down enough LPA to form a gradient. Thus the stimulus that drives cell dispersal is not the presence of LPA itself, but the self-generated, outward-directed gradient

MiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer

Prostate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin