The influence of nutritional level on verminosis in merino lambs

1. A mass mixed infestation of Haemonchus contortus and Oesophagostomum, columbianum larvae dosed to 7-8 month old merino lambs kept on two different planes of nutrition caused a peracute fatal verminosis in all the infested animals. 2. A similar infestation when dosed to 10-11 month old lambs under identical conditions caused a chronic verminosis. In this case the effect of nutrition on the response of the animals to verminosis was clearly demonstrated. 3. This finding demonstrates the greater susceptibility of young lambs to worm infestation, regardless of their diet, and emphasises the necessity of preventing mass infestation in young lambs under all conditions. 4. In the second experiment it was shown that an increase of the maize ration by 300 gm. a day caused a marked superiority in worm infested sheep as regards all of the following factors : - Body weight, appetite for roughage, haemoglobin level, fleece weight and wool fibre thickness. 5. In all the above respects the worm infested sheep receiving 400 gm. of maize per day were superior to the non-infested sheep receiving only 100 gm. of maize per day. 6. The pathological findings in cases of acute verminosis are described and the immediate cause of death was found to be acute, pulmonary oedema. 7. Phenothiazine was found to be superior to either tetrachlorethylene emulsion or copper tartrate and copper arsenate mixture as a vermifuge in that it appeared not only to kill all wire worm present but also to cause removal of the black-stained ingesta from the alimentary tract. It also appeared to promote normal bileflow. 8. The experiment clearly demonstrates the beneficial effects of a higher maize intake on the response of sheep to verminosis.The articles have been scanned in colour with a HP Scanjet 5590; 300dpi. Adobe Acrobat XI Pro was used to OCR the text and also for the merging and conversion to the final presentation PDF-format

Pharmacological Inhibition of polysialyltransferase ST8SiaII Modulates Tumour Cell Migration

YesPolysialic acid (polySia), an α-2,8-glycosidically linked polymer of sialic acid, is a developmentally regulated posttranslational modification predominantly found on NCAM (neuronal cell adhesion molecule). Whilst high levels are expressed during development, peripheral adult organs do not express polySia-NCAM. However, tumours of neural crest-origin re-express polySia-NCAM: its occurrence correlates with aggressive and invasive disease and poor clinical prognosis in different cancer types, notably including small cell lung cancer (SCLC), pancreatic cancer and neuroblastoma. In neuronal development, polySia-NCAM biosynthesis is catalysed by two polysialyltransferases, ST8SiaII and ST8SiaIV, but it is ST8SiaII that is the prominent enzyme in tumours. The aim of this study was to determine the effect of ST8SiaII inhibition by a small molecule on tumour cell migration, utilising cytidine monophosphate (CMP) as a tool compound. Using immunoblotting we showed that CMP reduced ST8iaII-mediated polysialylation of NCAM. Utilizing a novel HPLC-based assay to quantify polysialylation of a fluorescent acceptor (DMB-DP3), we demonstrated that CMP is a competitive inhibitor of ST8SiaII (Ki = 10 μM). Importantly, we have shown that CMP causes a concentration-dependent reduction in tumour cell-surface polySia expression, with an absence of toxicity. When ST8SiaII-expressing tumour cells (SH-SY5Y and C6-STX) were evaluated in 2D cell migration assays, ST8SiaII inhibition led to significant reductions in migration, while CMP had no effect on cells not expressing ST8SiaII (DLD-1 and C6-WT). The study demonstrates for the first time that a polysialyltransferase inhibitor can modulate migration in ST8SiaII-expressing tumour cells. We conclude that ST8SiaII can be considered a druggable target with the potential for interfering with a critical mechanism in tumour cell dissemination in metastatic cancers.Yorkshire Cancer Research; EPSRC; Association for International Cancer Research; Jordanian Government PhD scholarshi

Fock-Darwin-like quantum dot states formed by charged Mn interstitial ions

We report a method of creating electrostatically induced quantum dots by thermal diffusion of interstitial Mn ions out of a p-type (GaMn)As layer into the vicinity of a GaAs quantum well. This approach creates deep, approximately circular, and strongly confined dotlike potential minima in a large (200  μm) mesa diode structure without need for advanced lithography or electrostatic gating. Magnetotunneling spectroscopy of an individual dot reveals the symmetry of its electronic eigenfunctions and a rich energy level spectrum of Fock-Darwin-like states with an orbital angular momentum component |lz| from 0 to 11

Scaling ozone responses of forest trees to the ecosystem level in a changing climate

Many uncertainties remain regarding how climate change will alter the structure and function of forest ecosystems. At the Aspen FACE experiment in northern Wisconsin, we are attempting to understand how an aspen/birch/maple forest ecosystem responds to long-term exposure to elevated carbon dioxide (CO 2 ) and ozone (O 3 ), alone and in combination, from establishment onward. We examine how O 3 affects the flow of carbon through the ecosystem from the leaf level through to the roots and into the soil micro-organisms in present and future atmospheric CO 2 conditions. We provide evidence of adverse effects of O 3 , with or without co-occurring elevated CO 2 , that cascade through the entire ecosystem impacting complex trophic interactions and food webs on all three species in the study: trembling aspen ( Populus tremuloides Michx . ), paper birch ( Betula papyrifera Marsh), and sugar maple ( Acer saccharum Marsh). Interestingly, the negative effect of O 3 on the growth of sugar maple did not become evident until 3 years into the study. The negative effect of O 3 effect was most noticeable on paper birch trees growing under elevated CO 2 . Our results demonstrate the importance of long-term studies to detect subtle effects of atmospheric change and of the need for studies of interacting stresses whose responses could not be predicted by studies of single factors. In biologically complex forest ecosystems, effects at one scale can be very different from those at another scale. For scaling purposes, then, linking process with canopy level models is essential if O 3 impacts are to be accurately predicted. Finally, we describe how outputs from our long-term multispecies Aspen FACE experiment are being used to develop simple, coupled models to estimate productivity gain/loss from changing O 3 .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72464/1/j.1365-3040.2005.01362.x.pd

Defining the Critical Hurdles in Cancer Immunotherapy

ABSTRACT: Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators, others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet be overcome to improve outcomes of patients with cancer

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

G-protein-dependent and -independent pathways regulate proteinase-activated receptor-2 mediated p65 nf kappa b serine 536 phosphorylation in human keratinocytes

The mechanisms underpinning the coupling of GPCRs, such as PAR-2, to the phosphorylation of p65 NFκB have not been investigated. In the current study we found that trypsin and the selective PAR-2 activating peptide, 2f-LIGKV-OH, stimulated large and sustained increases in the serine 536 phosphorylation of p65/RelA in a transfected skin epithelial cell line and primary keratinocytes. Parallel experiments showed that in both cell types, p65 NFκB phosphorylation is mediated through the selective activation of IKK2. Treatment with PKC inhibitor GF109203X or PKCα siRNA reduced phosphorylation at 15 min but not 30 min, whilst rottlerin, a selective PKCδ inhibitor and PKCδ siRNA reduced the response at both time points. Pre-treatment of cells with the novel Gq/11 inhibitor YM-254890 and Gq/11 siRNA caused a similar pattern of inhibition and also reduced PAR-2-mediated NFκB transcriptional activity. Furthermore, stimulation of cells through a novel PAR-2 mutant PAR-234-43, delayed p65 phosphorylation but was without effect on the kinetics of ERK activation. Inhibition of Gi or G12/13 pathways by pertussis toxin pre-treatment or over-expression of the RGS mutant Lsc, also did not effect NFκB phosphorylation. Taken together these data indicate dependency for Gq/11 in early phosphorylation of p65 NFκB and this subsequently affects initial NFκB-dependent gene transcriptional activity, however later regulation of p65 is unaffected. Overall these novel data demonstrate an IKK2-dependent, predominantly G-protein-independent pathway involved in PAR-2 regulation of NFκB phosphorylation in keratinocytes

The South African perennial legume Lebeckia ambigua sustainably supports livestock production on infertile soils in rain-fed agro-ecosystems

Lebeckia ambigua is a perennial legume endemic to rangeland South Africa that is adapted to dry (< 400-mm annual rainfall), infertile and acidic (below pH 5.5Ca) soils. Although it is considered that the legume was grazed by mammalian ungulates during its evolution, little is known about its production, nutritive value for grazing animals or optimal management in an agricultural context, in either its centre of the origin or in Australia. Experiments were conducted to test the hypotheses that sheep would graze L. ambigua in autumn without adverse effects on either the animal or the plant. Lebeckia ambigua was established at two sites in Western Australia. In experiment 1, three grazing intensities were imposed by exclusion cages introduced during a single intensive grazing period, to provide differing residual pasture heights. The metabolisable energy and crude protein content of L. ambigua were more than 11.4 MJ/kg dry matter and 21%, respectively for all treatments. Un-grazed L. ambigua produced 1740 kg DM/ha while a single moderate or severe grazing reduced total biomass production by about 50% over 10 weeks post-grazing (P < 0.001). In experiment 2, continuous grazing of L. ambigua for 64 days had no negative impacts on biochemical health indicators of merino wethers. Grazing had no effect on plant density in either experiment indicating that L. ambigua is adapted to substantial grazing pressure in autumn. Lebeckia ambigua could become a valuable plant for sustainably increasing livestock production on infertile soils in rain-fed agro-ecosystems where other legumes fail