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

The Caesar New Frontiers Mission: 2. Sample Science

No abstract availabl

The 2010 Canadian Cardiovascular Society guidelines for the diagnosis and management of heart failure update: Heart failure in ethnic minority populations, heart failure and pregnancy, disease management, and quality improvement/assurance programs

Since 2006, the Canadian Cardiovascular Society heart failure (HF) guidelines have published annual focused updates for cardiovascular care providers. The 2010 Canadian Cardiovascular Society HF guidelines update focuses on an increasing issue in the western world - HF in ethnic minorities - and in an uncommon but important setting - the pregnant patient. Additionally, due to increasing attention recently given to the assessment of how care is delivered and measured, two critically important topics - disease management programs in HF and quality assurance - have been included. Both of these topics were written from a clinical perspective. It is hoped that the present update will become a useful tool for health care providers and planners in the ongoing evolution of care for HF patients in Canada. © 2010 Pulsus Group Inc. All rights reserved

The Golden Meteorite Fall: Fireball Trajectory, Orbit and Meteorite Characterization

The Golden (British Columbia, Canada) meteorite fall occurred on Oct 4, 2021 at 0534 UT with the first recovered fragment (1.3 kg) landing on an occupied bed. The meteorite is an unbrecciated, low-shock (S2) ordinary chondrite of intermediate composition, typed as an L/LL5. From noble gas measurements the cosmic ray exposure age is 25 Ma while gas retention ages are all >2 Ga. Short-lived radionuclides and noble gas measurements of the pre-atmospheric size overlap with estimates from infrasound and lightcurve modelling producing a preferred pre-atmospheric mass of 70-200 kg. The orbit of Golden has a high inclination (23.5 degs) and is consistent with delivery from the inner main belt. The highest probability (60%) of an origin is from the Hungaria group. We propose that Golden may originate among the background S-type asteroids found interspersed in the Hungaria region. The current collection of 18 L and LL chondrite orbits shows a strong preference for origins in the inner main belt, suggesting multiple parent bodies may be required to explain the diversity in CRE ages and shock states.Comment: 92 Pages, 20 Tables, 21 Figures, plus 3 appendices, accepted in Meteoritics and Planetary Science Oct 26 202

An Oral Recombinant Vaccine in Dogs against Echinococcus granulosus, the Causative Agent of Human Hydatid Disease: A Pilot Study

Dogs are the main source of human cystic echinococcosis. An oral vaccine would be an important contribution to control programs in endemic countries. We conducted two parallel experimental trials in Morocco and Tunisia of a new oral vaccine candidate against Echinococcus granulosus in 28 dogs. The vaccine was prepared using two recombinant proteins from adult worms, a tropomyosin (EgTrp) and a fibrillar protein similar to paramyosin (EgA31), cloned and expressed in a live attenuated strain of Salmonella enterica serovar typhimurium

The CAESAR New Frontiers Mission: 1. Expected Nature of the Returned Comet Sample

Comets are time capsules from the birth of our Solar System that record pre-solar history, the initial stages of planet formation, and the sources of prebiotic organics and volatiles for the origin of life. These capsules can only be opened in laboratories on Earth. CAESAR (Comet Astrobiology Exploration Sample Return)s sample analysis objectives are to understand the nature of Solar System starting materials and how these components came together to form planets and give rise to life. Examination of these comet nucleus surface samples in laboratories around the world will also provide ground truth to remote observations of the innumerable icy bodies of the Solar System

Consequences of concurrent Ascaridia galli and Escherichia coli infections in chickens

Three experiments were carried out to examine the consequences of concurrent infections with Ascaridia galli and Escherichia coli in chickens raised for table egg production. Characteristic pathological lesions including airsacculitis, peritonitis and/or polyserositis were seen in all groups infected with E. coli. Furthermore, a trend for increased mortality rates was observed in groups infected with both organisms which, however, could not be confirmed statistically. The mean worm burden was significantly lower in combined infection groups compared to groups infected only with A. galli. It was also shown that combined infections of E. coli and A. galli had an added significant negative impact on weight gain

Transcriptome analysis of mRNA and miRNA in skeletal muscle indicates an important network for differential Residual Feed Intake in pigs

Feed efficiency (FE) can be measured by feed conversion ratio (FCR) or residual feed intake (RFI). In this study, we measured the FE related phenotypes of 236 castrated purebred Yorkshire boars, and selected 10 extreme individuals with high and low RFI for transcriptome analysis. We used RNA-seq analyses to determine the differential expression of genes and miRNAs in skeletal muscle. There were 99 differentially expressed genes identified (q ≤ 0.05). The down-regulated genes were mainly involved in mitochondrial energy metabolism, including FABP3, RCAN, PPARGC1 (PGC-1A), HK2 and PRKAG2. The up-regulated genes were mainly involved in skeletal muscle differentiation and proliferation, including IGF2, PDE7A, CEBPD, PIK3R1 and MYH6. Moreover, 15 differentially expressed miRNAs (|log2FC| ≥ 1, total reads count ≥ 20, p ≤ 0.05) were identified. Among them, miR-136, miR-30e-5p, miR-1, miR-208b, miR-199a, miR-101 and miR-29c were up-regulated, while miR-215, miR-365-5p, miR-486, miR-1271, miR-145, miR-99b, miR-191 and miR-10b were down-regulated in low RFI pigs. We conclude that decreasing mitochondrial energy metabolism, possibly through AMPK - PGC-1A pathways, and increasing muscle growth, through IGF-1/2 and TGF-β signaling pathways, are potential strategies for the improvement of FE in pigs (and possibly other livestock). This study provides new insights into the molecular mechanisms that determine RFI and FE in pigs

Modify the redefined: strategic human resource development maturity at a crossroads

This integrative literature review reports on strategic human resource development (SHRD) models that examine the strategic embeddedness of HRD (SHRD maturity) in organizations. A review and critique of all existing SHRD models is provided, exemplifying their limitations and building upon their strengths to inform a modified SHRD framework. The latter suggests an enhanced set of strategic components to assess SHRD maturity. This paper further outlines how SHRD aspirations can be practiced within complex, dynamic, and continually changing business and economic environments. The SHRD literature is advanced by new insights on how HRD scholars and practitioners could assess and enhance the maturity of their HRD interventions in the context of constantly changing (dynamic) environments. The modified SHRD framework further contributes to the academic literature with its enhanced set of strategic characteristics, as well as with its SHRD pointers, all of which can offer a better evaluation of SHRD maturity during periods of business and economic complexity and uncertainty

A systematic genome-wide analysis of zebrafish protein-coding gene function

Since the publication of the human reference genome, the identities of specific genes associated with human diseases are being discovered at a rapid rate. A central problem is that the biological activity of these genes is often unclear. Detailed investigations in model vertebrate organisms, typically mice, have been essential for understanding the activities of many orthologues of these disease-associated genes. Although gene-targeting approaches1, 2, 3 and phenotype analysis have led to a detailed understanding of nearly 6,000 protein-coding genes3, 4, this number falls considerably short of the more than 22,000 mouse protein-coding genes5. Similarly, in zebrafish genetics, one-by-one gene studies using positional cloning6, insertional mutagenesis7, 8, 9, antisense morpholino oligonucleotides10, targeted re-sequencing11, 12, 13, and zinc finger and TAL endonucleases14, 15, 16, 17 have made substantial contributions to our understanding of the biological activity of vertebrate genes, but again the number of genes studied falls well short of the more than 26,000 zebrafish protein-coding genes18. Importantly, for both mice and zebrafish, none of these strategies are particularly suited to the rapid generation of knockouts in thousands of genes and the assessment of their biological activity. Here we describe an active project that aims to identify and phenotype the disruptive mutations in every zebrafish protein-coding gene, using a well-annotated zebrafish reference genome sequence18, 19, high-throughput sequencing and efficient chemical mutagenesis. So far we have identified potentially disruptive mutations in more than 38% of all known zebrafish protein-coding genes. We have developed a multi-allelic phenotyping scheme to efficiently assess the effects of each allele during embryogenesis and have analysed the phenotypic consequences of over 1,000 alleles. All mutant alleles and data are available to the community and our phenotyping scheme is adaptable to phenotypic analysis beyond embryogenesis