Leveraging Motivations, Personality, and Sensory Cues for Vertebrate Pest Management

Acknowledgments: We wish to thank Manaaki Whenua – Landcare Research staff, particularly Peter Millard and Bruce Warburton, for facilitating and supporting this research. Thanks to Jenna Bytheway for infographic design. This research was supported by Strategic Science Investment funding from the New Zealand Ministry of Business, Innovation and Employment’s Science and Innovation Group, awarded to Manaaki Whenua – Landcare Research. T.W.B. was supported by Marie Skłodowska-Curie grant number 747120, and A.S. was supported by National Science Foundation grant IOS 1456724.Peer reviewedPublisher PD

Are children with Specific Language Impairment competent with the pragmatics and logic of quantification?

Specific Language Impairment (SLI) is understood to be a disorder that predominantly affects phonology, morphosyntax and/or lexical semantics. There is little conclusive evidence on whether children with SLI are challenged with regard to Gricean pragmatic maxims and on whether children with SLI are competent with the logical meaning of quantifying expressions. We use the comprehension of statements quantified with ‘all’, ‘none’, ‘some’, ‘some…not’, ‘most’ and ‘not all’ as a paradigm to study whether Spanish-speaking children with SLI are competent with the pragmatic maxim of informativeness, as well as with the logical meaning of these expressions. Children with SLI performed more poorly than a group of age-matched typically-developing peers, and both groups performed more poorly with pragmatics than with logical meaning. Moreover, children with SLI were disproportionately challenged by pragmatic meaning compared to their age-matched peers. However, the performance of children with SLI was comparable to that of a group of younger language-matched typically-developing children. The findings document that children with SLI do face difficulties with employing the maxim of informativeness, as well as with understanding the logical meaning of quantifiers, but also that these difficulties are in keeping with their overall language difficulties rather than exceeding them. The implications of these findings for SLI, linguistic theory, and clinical practice are discussed

OLTARIS: On-Line Tool for the Assessment of Radiation in Space

The On-Line Tool for the Assessment of Radiation In Space (OLTARIS) is a World Wide Web based tool that assesses the effects of space radiation to humans in items such as spacecraft, habitats, rovers, and spacesuits. This document explains the basis behind the interface and framework used to input the data, perform the assessment, and output the results to the user as well as the physics, engineering, and computer science used to develop OLTARIS. The physics is based on the HZETRN2005 and NUCFRG2 research codes. The OLTARIS website is the successor to the SIREST website from the early 2000 s. Modifications have been made to the code to enable easy maintenance, additions, and configuration management along with a more modern web interface. Over all, the code has been verified, tested, and modified to enable faster and more accurate assessments. The next major areas of modification are more accurate transport algorithms, better uncertainty estimates, and electronic response functions. Improvements in the existing algorithms and data occur continuously and are logged in the change log section of the website

Cytoplasmic p21(WAF1/CIP1 )expression is correlated with HER-2/ neu in breast cancer and is an independent predictor of prognosis

BACKGROUND: HER-2 (c-erbB2/Neu) predicts the prognosis of and may influence treatment responses in breast cancer. HER-2 activity induces the cytoplasmic location of p21(WAFI/CIPI )in cell culture, accompanied by resistance to apoptosis. p21(WAFI/CIPI )is a cyclin-dependent kinase inhibitor activated by p53 to produce cell cycle arrest in association with nuclear localisation of p21(WAFI/CIPI). We previously showed that higher levels of cytoplasmic p21(WAFI/CIPI )in breast cancers predicted reduced survival at 5 years. The present study examined HER-2 and p21(WAFI/CIPI )expression in a series of breast cancers with up to 9 years of follow-up, to evaluate whether in vitro findings were related to clinical data and the effect on outcome. METHODS: The CB11 anti-HER2 monoclonal antibody and the DAKO Envision Plus system were used to evaluate HER-2 expression in 73 patients. p21(WAFI/CIPI )staining was performed as described previously using the mouse monoclonal antibody Ab-1 (Calbiochem, Cambridge, MA, USA). RESULTS: HER-2 was evaluable in 67 patients and was expressed in 19% of cases, predicting reduced overall survival (P = 0.02) and reduced relapse-free survival (P = 0.004; Cox regression model). HER-2-positive tumours showed proportionately higher cytoplasmic p21(WAFI/CIPI )staining using an intensity distribution score (median, 95) compared with HER-2-negative cancers (median, 47) (P = 0.005). There was a much weaker association between nuclear p21(WAFI/CIPI )and HER-2 expression (P = 0.05), suggesting an inverse relationship between nuclear p21(WAF1/CIP1 )and HER-2. CONCLUSION: This study highlights a new pathway by which HER-2 may modify cancer behaviour. HER-2 as a predictor of poor prognosis may partly relate to its ability to influence the relocalisation of p21(WAFI/CIPI )from the nucleus to the cytoplasm, resulting in a loss of p21(WAFI/CIPI)tumour suppressor functions. Cytoplasmic p21(WAFI/CIPI )may be a surrogate marker of functional HER-2 in vivo

The INT6 Cancer Gene and MEK Signaling Pathways Converge during Zebrafish Development

BACKGROUND: Int-6 (integration site 6) was identified as an oncogene in a screen of tumorigenic mouse mammary tumor virus (MMTV) insertions. INT6 expression is altered in human cancers, but the precise role of disrupted INT6 in tumorigenesis remains unclear, and an animal model to study Int-6 physiological function has been lacking. PRINCIPAL FINDINGS: Here, we create an in vivo model of Int6 function in zebrafish, and through genetic and chemical-genetic approaches implicate Int6 as a tissue-specific modulator of MEK-ERK signaling. We find that Int6 is required for normal expression of MEK1 protein in human cells, and for Erk signaling in zebrafish embryos. Loss of either Int6 or Mek signaling causes defects in craniofacial development, and Int6 and Erk-signaling have overlapping domains of tissue expression. SIGNIFICANCE: Our results provide new insight into the physiological role of vertebrate Int6, and have implications for the treatment of human tumors displaying altered INT6 expression

Proteasome inhibitors as anti-cancer agents

The ubiquitin (Ub)-proteasome pathway is the major nonlysosomal pathway of proteolysis in human cells and accounts for the degradation of most short-lived, misfolded or damaged proteins. This pathway is important in the regulation of a number of key biological regulatory mechanisms. Proteins are usually targeted for proteasome-mediated degradation by polyubiquitinylation, the covalent addition of multiple units of the 76 amino acid protein Ub, which are ligated to 1-amino groups of lysine residues in the substrate. Polyubiquitinylated proteins are degraded by the 26S proteasome, a large, ATP-dependent multicatalytic protease complex, which also regenerates monomeric Ub. The targets of this pathway include key regulators of cell proliferation and cell death. An alternative form of the proteasome, termed the immunoproteasome, also has important functions in the generation of peptides for presentation by MHC class I molecules. In recent years there has been a great deal of interest in the possibility that proteasome inhibitors, through elevation of the levels of proteasome targets, might prove useful as a novel class of anti-cancer drugs. Here we review the progress made to date in this area and highlight the potential advantages and weaknesses of this approach

Regulation Of the Human RNA Nucleotidyl Transferase ZCCHC11

Terminal uridylation of RNA 3ꞌ ends has recently been recognised as an important biological regulatory mechanism. The human terminal uridyl transferase ZCCHC11 was shown previously to uridylate and thereby regulate replication-dependent histone mRNAs and several miRNA precursors and mature miRNAs. Studies in cancer cell lines, mouse models and patient samples suggest that ZCCHC11 is a potential oncogene. However, very little is known about regulation of its expression and subcellular localisation. In this study, the regulation of the expression of ZCCHC11 was investigated, especially in relation to the roles played by the untranslated regions of its mRNA. The second aim of this study was to investigate the subcellular localisation of ZCCHC11, both under physiological conditions and under cellular stress. The results presented show that ZCCHC11 expression is regulated negatively through its 5ꞌ and 3ꞌUTRs. Upstream open reading frames in the 5ꞌUTR decrease its translation, while regulation through the 3ꞌUTR involves the combined activity of positive and negative factors. In this study it was shown that HuR positively regulates ZCCHC11 expression, whereas TTP contributes to its negative regulation. An homologous enzyme, ZCCHC6, negatively regulates ZCCHC11 expression. Regulation through the 3ꞌUTR of ZCCHC11 is particularly marked following S-phase arrest. ZCCHC11 expression increases under cellular stress and both UTRs take part in this regulation. Regulation under cellular stress also involves an alteration in sub-cellular localisation. ZCCHC11 is predominantly cytoplasmic in unstressed cells, but re-localises to p-bodies and stress granules under cellular stress. Mutating one of three zinc knuckle motifs within ZCCHC11 significantly decreased differential co-localisation with stress granule marker TIA-1 under oxidative stress. Taken together, the data presented provide insights into the post-transcriptional regulation of this post-transcriptional regulatory protein and its subcellular localisation, especially under cellular stress.This thesis is not currently available in ORA

Characterisation of cytoplasmic uridyl transferases in yeast and human cells

Regulation of gene expression by terminal addition of uridyl residues to RNA substrates has recently emerged as a widespread phenomenon in eukaryotes. Studies in organisms ranging from fission yeast to human cells have shown that uridylation of RNA 3' ends stimulates rapid RNA degradation. However, many questions regarding the specificity of the uridyl transferases, the broad range of their substrates and the consequences of their loss are still unanswered. In light of this, the uridyl transferases Cid1 in Schizosaccharomyces pombe and ZCCHC11 in human cells and their roles in the regulation of gene expression were further characterised in this study. To begin with, the biochemistry of the Cid1 protein complex responsible for uridylation in Schizosaccharomyces pombe was analysed in more detail by mass spectrometry and in vitro assays. These experiments provided insights into the modulation of Cid1 activity by accessory factors. Next, the role of the human uridyl transferase ZCCHC11 in the regulation of replication- dependent histone mRNAs was examined. Results showed that ZCCHC11 is required for efficient destabilisation of histone mRNAs following inhibition or completion of DNA replication. In agreement with this finding, cDNA sequencing experiments showed that ZCCHC11-mediated uridylation is particularly prevalent at the end of S phase. Finally, this thesis also explored the phenotype resulting from ZCCHC11 knock-down with respect to the human cell cycle. Depletion of ZCCHC11 led to the occurrence of DNA damage and activation of the DNA integrity checkpoint, which in turn resulted in cell cycle delay. Taken together, the data presented in this thesis extend current knowledge of the uridyl transferases and their actions in fission yeast and human cells and provide a link between RNA regulation and cell cycle control.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The human cytoplasmic RNA terminal U-transferase ZCCHC11 targets histone mRNAs for degradation

Inhibition of eukaryotic DNA replication leads to the rapid suppression of histone synthesis, via 3′ uridylation of cytoplasmic histone mRNAs followed by their Lsm1–7-mediated decapping and degradation. Here we show that the human cytoplasmic RNA terminal U-transferase ZCCHC11, recently implicated in microRNA metabolism, associates with replication-dependent histone mRNAs. Knockdown of ZCCHC11 selectively blocked histone mRNA degradation following inhibition of DNA replication, whereas knockdown of PAPD1 or PAPD5, previously proposed as candidate histone mRNA U-transferases, had no such effect. Furthermore, a reduction in the proportion of histone transcripts that were uridylated was observed following ZCCHC11 knockdown. Our data indicate that ZCCHC11 is the terminal U-transferase responsible for targeting human histone mRNAs for degradation following inhibition or completion of DNA replication