HIT family genes: FHIT but not PKCI-1/HINT produces altered transcripts in colorectal cancer

Forty-five colorectal adenocarcinomas were examined for alterations in the HIT family genes FHIT and PKCI-1/HINT by a combination of reverse transcriptase polymerase chain reaction and DNA sequencing. In all cases a single transcript corresponding to the reported sequence was detected using primers specific for the PKCI-1/HINT gene. In contrast multiple transcripts were detected using primers specific for the FHIT gene transcript. 6% (3/45) of tumours evinced no detectable expression of any FHIT transcript and a further 12% (6/45) produced only the normal full length transcripts. Ninety-six aberrant transcripts were characterized from the remaining tumours. Deviations from the normal full length sequence characterized included deletions, insertions of novel sequences, a point mutation as well as the usage of a putative alternate splice site in exon 10. Message variants were detected with approximately equal frequency in all tumour stages with the exception that templates with insertions were found solely in Dukes’ stage B tumours (P < 0.001). With the exception of the putative alternate splice site, aberrant transcripts were not detected in matched normal mucosa. These results suggest that members of the HIT family of genes are only selectively involved in tumorigenesis and that perturbation of FHIT gene expression is an early event in colorectal tumorigenesis. © 1999 Cancer Research Campaig

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Maternal experiences of ethnic discrimination and subsequent birth outcomes in Aotearoa New Zealand

Background Interpersonal discrimination experience has been associated with adverse birth outcomes. Limited research has evaluated this relationship within multicultural contexts outside the United States where the nature and salience of discrimination experiences may differ. Such research is important in order to help identify protective and risk factors that may mediate the relationship between discrimination experience and adverse birth outcomes. Methods Evaluated the relationship between perceived discrimination, as measured in pregnancy, with birth weight and gestation length among Māori, Pacific, and Asian women from Aotearoa New Zealand (N = 1653). Results Thirty percent of the sample reported some type of unfair treatment that they attributed to their ethnicity. For Māori women specifically, unfair treatment at work (β = − 243 g) and in acquiring housing (β = − 146 g) were associated with lower birth weight when compared to Māori women not experiencing these types of discrimination, while an ethnically motivated physical attack (β = − 1.06 week), and unfair treatment in the workplace (β = − 0.95 week), in the criminal justice system (β = − 0.55 week), or in banking (β = − 0.73 week) were associated with significantly shorter gestation. Conclusions Despite a high prevalence of discrimination experience among women from all ethnic groups, discrimination experience was a strong predictor of lower birth weight and shorter gestation length among indigenous Māori women only. Additional research is needed to better understand the risk and protective factors that may moderate the relationship between discrimination experience and adverse birth outcomes among women from different ethnic groups

TBC1D3, a Hominoid-Specific Gene, Delays IRS-1 Degradation and Promotes Insulin Signaling by Modulating p70 S6 Kinase Activity

Insulin/IGF-1 signaling plays a pivotal role in the regulation of cellular homeostasis through its control of glucose metabolism as well as due to its effects on cell proliferation. Aberrant regulation of insulin signaling has been repeatedly implicated in uncontrolled cell growth and malignant transformations. TBC1D3 is a hominoid specific gene previously identified as an oncogene in breast and prostate cancers. Our efforts to identify the molecular mechanisms of TBC1D3-induced oncogenesis revealed the role of TBC1D3 in insulin/IGF-1 signaling pathway. We document here that TBC1D3 intensifies insulin/IGF-1-induced signal transduction through intricate, yet elegant fine-tuning of signaling mechanisms. We show that TBC1D3 expression substantially delayed ubiquitination and degradation of insulin receptor substrate-1 (IRS-1). This effect is achieved through suppression of serine phosphorylation at S636/639, S307 and S312 of IRS-1, which are key phosphorylation sites required for IRS-1 degradation. Furthermore, we report that the effect of TBC1D3 on IRS-1:S636/639 phosphorylation is mediated through TBC1D3-induced activation of protein phosphatase 2A (PP2A), followed by suppression of T389 phosphorylation on p70 S6 kinase (S6K). TBC1D3 specifically interacts with PP2A regulatory subunit B56γ, indicating that TBC1D3 and PP2A B56γ operate jointly to promote S6K:T389 dephosphorylation. These findings suggest that TBC1D3 plays an unanticipated and potentially unique role in the fine-tuning of insulin/IGF-1 signaling, while providing novel insights into the regulation of tumorigenesis by a hominoid-specific protein

Children’s subjective well-being: Multi-group analysis among a sample of children from two socio-economic status groups in the Western Cape, South Africa

Recent advancements in child well-being research have shown an increased importance of subjective well-being in understanding children and adolescents’ quality of life. These advancements have raised questions concerning the extent to which children’s subjective perceptions and experiences of well-being can be compared between countries and across diverse cultures. With a dearth of empirical data on cross-cultural comparisons, the validation of existing measures and cross-cultural comparisons have been identified by a number of researchers as critical in contributing to this process, and ultimately to the international dialogue on children’s overall quality of life. The aim of the current study was to test two measures of subjective well-being (the Students’ Life Satisfaction Scale and the Personal Well-Being Index-School Children) among a sample of children in the Western Cape region of South Africa. Noting the diversity of living experiences between children from different socio-economic status groups in South Africa, the study further aimed to determine the extent to which the measures are comparable across socio-economic status groups. Data from the first wave of the Children’s World Survey were used; and included a sample of 1004 12 year old children randomly selected from 15 schools within the Cape Town Metropole. Located within the goodness of fit theoretical framework, confirmatory factor analysis and structural equation modelling was used to test the overall fit structure; while multi-group factor analysis was used to test measurement invariance across socio-economic status groups. The results show appropriate fit structure for the overall model, with metric and scalar factor invariance tenable across socio-economic status groups. The overall findings suggest that the two measures are appropriate for use with children from low and middle socio-economic status groups in the Western Cape province of South Africa and that the two groups can be compared by correlations, regressions and means.IS

Neuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures

Defects in endolysosomal and autophagic functions are increasingly viewed as key pathological features of neurodegenerative disorders. A master regulator of these functions is phosphatidylinositol-3-phosphate (PI3P), a phospholipid synthesized primarily by class III PI 3-kinase Vps34. Here we report that disruption of neuronal Vps34 function in vitro and in vivo impairs autophagy, lysosomal degradation as well as lipid metabolism, causing endolysosomal membrane damage. PI3P deficiency also promotes secretion of unique exosomes enriched for undigested lysosomal substrates, including amyloid precursor protein C-terminal fragments (APP-CTFs), specific sphingolipids, and the phospholipid bis(monoacylglycero)phosphate (BMP), which normally resides in the internal vesicles of endolysosomes. Secretion of these exosomes requires neutral sphingomyelinase 2 and sphingolipid synthesis. Our results reveal a homeostatic response counteracting lysosomal dysfunction via secretion of atypical exosomes eliminating lysosomal waste and define exosomal APP-CTFs and BMP as candidate biomarkers for endolysosomal dysfunction associated with neurodegenerative disorders.Fan Wang for the kind gift of the Pi3kc3flox/flox mice. We thank Basant Abdulrahman and Hermann Schaetzl for providing the gene-edited Atg5 KO N2a cells. We are also grateful to Zhenyu Yue, Ralph Nixon, and Jean Gruenberg for the kind gift of anti-Atg14L, Cathepsin D, and BMP antibodies, respectively. We thank Thomas Südhof for sharing Cre recombinase lentiviruses. We thank the OCS Microscopy Core of New York University Langone Medical Center for the support of the EM work and Rocio Perez-Gonzalez and Efrat Levy of New York University for their support during optimization of the brain exosome isolation technique. We thank Elizabeta Micevska for the maintenance and genotyping of the animal colony and Bowen Zhou for the preliminary lipidomic analysis of conditional Pi3kc3 cKO mice. We also thank Rebecca Williams and Catherine Marquer for critically reading the manuscript. This work was supported by grants from the Fundação para a Ciência e Tecnologia (PD/BD/105915/2014 to A.M.M.); the National Institute of Health (R01 NS056049 to G.D.P., transferred to Ron Liem, Columbia University; T32-MH015174 to Rene Hen (Z.M.L.)). Z.M.L. and R.B.C. received pilot grants from ADRC grant P50 AG008702 to S.A.S.info:eu-repo/semantics/publishedVersio

Evaluating assumptions of scales for subjective assessment of thermal environments – Do laypersons perceive them the way, we researchers believe?

People's subjective response to any thermal environment is commonly investigated by using rating scales describing the degree of thermal sensation, comfort, and acceptability. Subsequent analyses of results collected in this way rely on the assumption that specific distances between verbal anchors placed on the scale exist and that relationships between verbal anchors from different dimensions that are assessed (e.g. thermal sensation and comfort) do not change. Another inherent assumption is that such scales are independent of the context in which they are used (climate zone, season, etc.). Despite their use worldwide, there is indication that contextual differences influence the way the scales are perceived and therefore question the reliability of the scales’ interpretation. To address this issue, a large international collaborative questionnaire study was conducted in 26 countries, using 21 different languages, which led to a dataset of 8225 questionnaires. Results, analysed by means of robust statistical techniques, revealed that only a subset of the responses are in accordance with the mentioned assumptions. Significant differences appeared between groups of participants in their perception of the scales, both in relation to distances of the anchors and relationships between scales. It was also found that respondents’ interpretations of scales changed with contextual factors, such as climate, season, and language. These findings highlight the need to carefully consider context-dependent factors in interpreting and reporting results from thermal comfort studies or post-occupancy evaluations, as well as to revisit the use of rating scales and the analysis methods used in thermal comfort studies to improve their reliability

The Scales Project, a cross-national dataset on the interpretation of thermal perception scales

Thermal discomfort is one of the main triggers for occupants' interactions with components of the built environment such as adjustments of thermostats and/or opening windows and strongly related to the energy use in buildings. Understanding causes for thermal (dis-)comfort is crucial for design and operation of any type of building. The assessment of human thermal perception through rating scales, for example in post-occupancy studies, has been applied for several decades; however, long-existing assumptions related to these rating scales had been questioned by several researchers. The aim of this study was to gain deeper knowledge on contextual influences on the interpretation of thermal perception scales and their verbal anchors by survey participants. A questionnaire was designed and consequently applied in 21 language versions. These surveys were conducted in 57 cities in 30 countries resulting in a dataset containing responses from 8225 participants. The database offers potential for further analysis in the areas of building design and operation, psycho-physical relationships between human perception and the built environment, and linguistic analyses

Complete Genome Sequence of Crohn's Disease-Associated Adherent-Invasive E. coli Strain LF82

International audienceBACKGROUND: Ileal lesions of Crohn's disease (CD) patients are abnormally colonized by pathogenic adherent-invasive Escherichia coli (AIEC) able to invade and to replicate within intestinal epithelial cells and macrophages. PRINCIPAL FINDINGS: We report here the complete genome sequence of E. coli LF82, the reference strain of adherent-invasive E. coli associated with ileal Crohn's disease. The LF82 genome of 4,881,487 bp total size contains a circular chromosome with a size of 4,773,108 bp and a plasmid of 108,379 bp. The analysis of predicted coding sequences (CDSs) within the LF82 flexible genome indicated that this genome is close to the avian pathogenic strain APEC_01, meningitis-associated strain S88 and urinary-isolated strain UTI89 with regards to flexible genome and single nucleotide polymorphisms in various virulence factors. Interestingly, we observed that strains LF82 and UTI89 adhered at a similar level to Intestine-407 cells and that like LF82, APEC_01 and UTI89 were highly invasive. However, A1EC strain LF82 had an intermediate killer phenotype compared to APEC-01 and UTI89 and the LF82 genome does not harbour most of specific virulence genes from ExPEC. LF82 genome has evolved from those of ExPEC B2 strains by the acquisition of Salmonella and Yersinia isolated or clustered genes or CDSs located on pLF82 plasmid and at various loci on the chromosome. CONCLUSION: LF82 genome analysis indicated that a number of genes, gene clusters and pathoadaptative mutations which have been acquired may play a role in virulence of AIEC strain LF82