Shelled pteropods in peril: Assessing vulnerability in a high CO2 ocean

The impact of anthropogenic ocean acidification (OA) on marine ecosystems is a vital concern facing marine scientists and managers of ocean resources. Euthecosomatous pteropods (holoplanktonic gastropods) represent an excellent sentinel for indicating exposure to anthropogenic OA because of the sensitivity of their aragonite shells to the OA conditions less favorable for calcification. However, an integration of observations, experiments and modelling efforts is needed to make accurate predictions of how these organisms will respond to future changes to their environment. Our understanding of the underlying organismal biology and life history is far from complete and must be improved if we are to comprehend fully the responses of these organisms to the multitude of stressors in their environment beyond OA. This review considers the present state of research and understanding of euthecosomatous pteropod biology and ecology of these organisms and considers promising new laboratory methods, advances in instrumentation (such as molecular, trace elements, stable isotopes, palaeobiology alongside autonomous sampling platforms, CT scanning and high-quality video recording) and novel field-based approaches (i.e. studies of upwelling and CO2 vent regions) that may allow us to improve our predictive capacity of their vulnerability and/or resilience. In addition to playing a critical ecological and biogeochemical role, pteropods can offer a significant value as an early-indicator of anthropogenic OA. This role as a sentinel species should be developed further to consolidate their potential use within marine environmental management policy making

What motivates academic dishonesty in students? A reinforcement sensitivity theory explanation

BACKGROUND: Academic dishonesty (AD) is an increasing challenge for universities worldwide. The rise of the Internet has further increased opportunities for students to cheat. AIMS: In this study, we investigate the role of personality traits defined within Reinforcement Sensitivity Theory (RST) as potential determinants of AD. RST defines behaviour as resulting from approach (Reward Interest/reactivity, goal-drive, and Impulsivity) and avoidance (behavioural inhibition and Fight-Flight-Freeze) motivations. We further consider the role of deep, surface, or achieving study motivations in mediating/moderating the relationship between personality and AD. SAMPLE: A sample of UK undergraduates (N = 240). METHOD: All participants completed the RST Personality Questionnaire, a short-form version of the study process questionnaire and a measure of engagement in AD, its perceived prevalence, and seriousness. RESULTS: Results showed that RST traits account for additional variance in AD. Mediation analysis suggested that GDP predicted dishonesty indirectly via a surface study approach while the indirect effect via deep study processes suggested dishonesty was not likely. Likelihood of engagement in AD was positively associated with personality traits reflecting Impulsivity and Fight-Flight-Freeze behaviours. Surface study motivation moderated the Impulsivity effect and achieving motivation the FFFS effect such that cheating was even more likely when high levels of these processes were used. CONCLUSIONS: The findings suggest that motivational personality traits defined within RST can explain variance in the likelihood of engaging in dishonest academic behaviours

Aberrant MEK5/ERK5 signalling contributes to human colon cancer progression via NF-κB activation

© 2015 Macmillan Publishers Limited All rights reserved. Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0This study was designed to evaluate MEK5 and ERK5 expression in colon cancer progression and to ascertain the relevance of MEK5/ERK5 signalling in colon cancer. Expression of MEK5 and ERK5 was evaluated in 323 human colon cancer samples. To evaluate the role of MEK5/ERK5 signalling in colon cancer, we developed a stable cell line model with differential MEK5/ERK5 activation. Impact of differential MEK5/ERK5 signalling was evaluated on cell cycle progression by flow cytometry and cell migration was evaluated by wound healing and transwell migration assays. Finally, we used an orthotopic xenograft mouse model of colon cancer to assess tumour growth and progression. Our results demonstrated that MEK5 and ERK5 are overexpressed in human adenomas (P<0.01) and adenocarcinomas (P<0.05), where increased ERK5 expression correlated with the acquisition of more invasive and metastatic potential (P<0.05). Interestingly, we observed a significant correlation between ERK5 expression and NF-κB activation in human adenocarcinomas (P<0.001). We also showed that ERK5 overactivation significantly accelerated cell cycle progression (P<0.05) and increased cell migration (P<0.01). Furthermore, cells with overactivated ERK5 displayed increased NF-κB nuclear translocation and transcriptional activity (P<0.05), together with increased expression of the mesenchymal marker vimentin (P<0.05). We further demonstrated that increased NF-κB activation was associated with increased IκB phosphorylation and degradation (P<0.05). Finally, in the mouse model, lymph node metastasis was exclusively seen in orthotopically implanted tumours with overactivated MEK5/ERK5, and not in tumours with inhibited MEK5/ERK5. Our results suggested that MEK5/ERK5/NF-κB signalling pathway is important for tumour onset, progression and metastasis, possibly representing a novel relevant therapeutic target in colon cancer treatment.This study was supported by Fundação para a Ciência e Tecnologia (HMSP-ICT/0018/2011, SFRH/BD/96517/2013, SFRH/BD/88619/2012 and SFRH/BD/79356/2011).info:eu-repo/semantics/publishedVersio

Methylation of hMLH1 promoter correlates with the gene silencing with a region-specific manner in colorectal cancer

Microsatellite instability is present in over 80% of the hereditary non-polyposis colorectal carcinoma and about 15–20% of the sporadic cancer. Microsatellite instability is caused by the inactivation of the mismatch repair genes, such as primarily hMLH1, hMSH2. To study the mechanisms of the inactivation of mismatch repair genes in colorectal cancers, especially the region-specific methylation of hMLH1 promoter and its correlation with gene expression, we analysed microsatellite instability, expression and methylation of hMLH1 and loss of heterozygosity at hMLH1 locus in these samples. Microsatellite instability was present in 17 of 71 primary tumours of colorectal cancer, including 14 of 39 (36%) mucinous cancer and three of 32 (9%) non-mucinous cancer. Loss of hMLH1 and hMSH2 expression was detected in nine and three of 16 microsatellite instability tumours respectively. Methylation at CpG sites in a proximal region of hMLH1 promoter was detected in seven of nine tumours that showed no hMLH1 expression, while no methylation was present in normal mucosa and tumours which express hMLH1. However, methylation in the distal region was observed in all tissues including normal mucosa and hMLH1 expressing tumours. This observation indicates that methylation of hMLH1 promoter plays an important role in microsatellite instability with a region-specific manner in colorectal cancer. Loss of heterozygosity at hMLH1 locus was present in four of 17 cell lines and 16 of 54 tumours with normal hMLH1 status, while loss of heterozygosity was absent in all nine cell lines and nine tumours with abnormal hMLH1 status (mutation or loss of expression), showing loss of heterozygosity is not frequently involved in the inactivation of hMLH1 gene in sporadic colorectal cancer

Colorectal cancer linkage on chromosomes 4q21, 8q13, 12q24, and 15q22

A substantial proportion of familial colorectal cancer (CRC) is not a consequence of known susceptibility loci, such as mismatch repair (MMR) genes, supporting the existence of additional loci. To identify novel CRC loci, we conducted a genome-wide linkage scan in 356 white families with no evidence of defective MMR (i.e., no loss of tumor expression of MMR proteins, no microsatellite instability (MSI)-high tumors, or no evidence of linkage to MMR genes). Families were ascertained via the Colon Cancer Family Registry multi-site NCI-supported consortium (Colon CFR), the City of Hope Comprehensive Cancer Center, and Memorial University of Newfoundland. A total of 1,612 individuals (average 5.0 per family including 2.2 affected) were genotyped using genome-wide single nucleotide polymorphism linkage arrays; parametric and non-parametric linkage analysis used MERLIN in a priori-defined family groups. Five lod scores greater than 3.0 were observed assuming heterogeneity. The greatest were among families with mean age of diagnosis less than 50 years at 4q21.1 (dominant HLOD = 4.51, α = 0.84, 145.40 cM, rs10518142) and among all families at 12q24.32 (dominant HLOD = 3.60, α = 0.48, 285.15 cM, rs952093). Among families with four or more affected individuals and among clinic-based families, a common peak was observed at 15q22.31 (101.40 cM, rs1477798; dominant HLOD = 3.07, α = 0.29; dominant HLOD = 3.03, α = 0.32, respectively). Analysis of families with only two affected individuals yielded a peak at 8q13.2 (recessive HLOD = 3.02, α = 0.51, 132.52 cM, rs1319036). These previously unreported linkage peaks demonstrate the continued utility of family-based data in complex traits and suggest that new CRC risk alleles remain to be elucidated. © 2012 Cicek et al

AMULET: a novel read count-based method for effective multiplet detection from single nucleus ATAC-seq data.

Detecting multiplets in single nucleus (sn)ATAC-seq data is challenging due to data sparsity and limited dynamic range. AMULET (ATAC-seq MULtiplet Estimation Tool) enumerates regions with greater than two uniquely aligned reads across the genome to effectively detect multiplets. We evaluate the method by generating snATAC-seq data in the human blood and pancreatic islet samples. AMULET has high precision, estimated via donor-based multiplexing, and high recall, estimated via simulated multiplets, compared to alternatives and identifies multiplets most effectively when a certain read depth of 25K median valid reads per nucleus is achieved

Mutations in the Human naked cuticle Homolog NKD1 Found in Colorectal Cancer Alter Wnt/Dvl/β-Catenin Signaling

BACKGROUND:Mutation of Wnt signal antagonists Apc or Axin activates beta-catenin signaling in many cancers including the majority of human colorectal adenocarcinomas. The phenotype of apc or axin mutation in the fruit fly Drosophila melanogaster is strikingly similar to that caused by mutation in the segment-polarity gene, naked cuticle (nkd). Nkd inhibits Wnt signaling by binding to the Dishevelled (Dsh/Dvl) family of scaffold proteins that link Wnt receptor activation to beta-catenin accumulation and TCF-dependent transcription, but human NKD genes have yet to be directly implicated in cancer. METHODOLOGY/PRINCIPAL FINDINGS:We identify for the first time mutations in NKD1--one of two human nkd homologs--in a subset of DNA mismatch repair-deficient colorectal tumors that are not known to harbor mutations in other Wnt-pathway genes. The mutant Nkd1 proteins are defective at inhibiting Wnt signaling; in addition, the mutant Nkd1 proteins stabilize beta-catenin and promote cell proliferation, in part due to a reduced ability of each mutant Nkd1 protein to bind and destabilize Dvl proteins. CONCLUSIONS/SIGNIFICANCE:Our data raise the hypothesis that specific NKD1 mutations promote Wnt-dependent tumorigenesis in a subset of DNA mismatch-repair-deficient colorectal adenocarcinomas and possibly other Wnt-signal driven human cancers

Characterisation of Familial Colorectal Cancer Type X, Lynch syndrome and non-familial colorectal cancer

Background:Familial Colorectal Cancer Type X (FCCTX) is defined as individuals with colorectal cancer (CRC) who families meet Amsterdam Criteria-1 (AC1), but whose tumours are DNA-mismatch-repair-proficient, unlike Lynch syndrome (LS). FCCTX does not have an increased risk of extra-colonic cancers. This analysis compares epidemiologic and clinicopathologic features among FCCTX, LS, and ‘non-familial' (non-AC1) CRC cases.Methods:From the Colon Cancer Family Registry, FCCTX (n=173), LS (n=303), and non-AC1 (n=9603) CRC cases were identified. Questionnaire-based epidemiologic information and CRC pathologic features were compared across case groups using polytomous logistic regression.Results:Compared with LS, FCCTX cases were less likely to be current (vs never) smokers; have a proximal subsite (vs rectal) tumour; or have mucinous histology, poor differentiation, or tumour-infiltrating lymphocytes. There were no observed differences in co-morbidities or medication usage.Conclusions:FCCTX were less likely to be current tobacco users; other exposures were similar between these groups. Histopathologic differences highly suggestive of LS CRCs do not appear to be shared by FCCTX