Mutagen-Specific Mutation Signature Determines Global microRNA Binding

Micro-RNAs (miRNAs) are small non-coding RNAs that regulate gene products at the post-transcriptional level. It is thought that loss of cell regulation by miRNAs supports cancer development. Based on whole genome sequencing of a melanoma tumor, we predict, using three different computational algorithms, that the melanoma somatic mutations globally reduce binding of miRNAs to the mutated 3′UTRs. This phenomenon reflects the nature of the characteristic UV-induced mutation, C-to-T. Furthermore, we show that seed regions are enriched with Guanine, thus rendering miRNAs prone to reduced binding to UV-mutated 3′UTRs. Accordingly, mutation patterns in non UV-induced malignancies e.g. lung cancer and leukemia do not yield similar predictions. It is suggested that UV-induced disruption of miRNA-mediated gene regulation plays a carcinogenic role. Remarkably, dark-skinned populations have significantly higher GC content in 3′UTR SNPs than light-skinned populations, which implies on evolutionary pressure to preserve regulation by trans-acting oligonucleotides under conditions with excess UV radiation

CEACAM1 Promotes Melanoma Cell Growth through Sox-2

AbstractThe prognostic value of the carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) in melanoma was demonstrated more than a decade ago as superior to Breslow score. We have previously shown that intercellular homophilic CEACAM1 interactions protect melanoma cells from lymphocyte-mediated elimination. Here, we study the direct effects of CEACAM1 on melanoma cell biology. By employing tissue microarrays and low-passage primary cultures of metastatic melanoma, we show that CEACAM1 expression gradually increases from nevi to metastatic specimens, with a strong dominance of the CEACAM1-Long tail splice variant. Using experimental systems of CEACAM1 knockdown and overexpression of selective variants or truncation mutants, we prove that only the full-length long tail variant enhances melanoma cell proliferation in vitro and in vivo. This effect is not reversed with a CEACAM1-blocking antibody, suggesting that it is not mediated by intercellular homophilic interactions. Downstream, CEACAM1-Long increases the expression of Sox-2, which we show to be responsible for the CEACAM1-mediated enhanced proliferation. Furthermore, analysis of the CEACAM1 promoter reveals two single-nucleotide polymorphisms (SNPs) that significantly enhance the promoter's activity compared with the consensus nucleotides. Importantly, case-control genetic SNP analysis of 134 patients with melanoma and matched healthy donors show that patients with melanoma do not exhibit the Hardy-Weinberg balance and that homozygous SNP genotype enhances the hazard ratio to develop melanoma by 35%. These observations shed new mechanistic light on the role of CEACAM1 in melanoma, forming the basis for development of novel therapeutic and diagnostic technologies

How is Existential Threat Related to Intergroup Conflict? Introducing the Multidimensional Existential Threat (MET) Model

Existential threat lies at the heart of intergroup conflict, but the literature on existential concerns lacks clear conceptualization and integration. To address this problem, we offer a new conceptualization and measurement of existential threat. We establish the reliability and validity of our measure, and to illustrate its utility, we examine whether different existential threats underlie the association between political ideology and support for specific political policies. Study 1 (N = 798) established the construct validity of the scale, and revealed four distinct existential threats: personal death (PD), physical collective annihilation (PA), symbolic collective annihilation (SA), and past victimization (PV). Study 2 (N = 424) confirmed the 4-factor structure, and the convergent and discriminant validity of the scale. Study 3 (N = 170) revealed that the association between a hawkish political ideology and support for hardline policies was mediated by PV, whereas the association between a dovish political ideology and conciliatory policies was mediated by concerns over collective symbolic annihilation. Study 4 (N = 503) conceptually replicated the pattern of findings found in Study 3, and showed that at times of conflict, PA concerns also mediate the relationship between hawkish ideologies and support for hardline policies. In both Studies 3 and 4, when controlling for other threats, PD did not play a significant role. These results underscore the need to consider the multidimensional nature of existential threat, especially in the context of political conflict

Non-unitarity of CKM matrix from the vector singlet quark mixing and neutron electric dipole moment

In the standard model (SM) the lowest order contribution to the quark electric dipole moment (EDM) occurs at the three loop level. We show that the non-unitarity of the CKM matrix in models with an extended quark sector typically gives rise to a quark EDM at the two loop level which has no GIM-like suppression factors except the external quark mass. The induced neutron EDM is of order 10^{-29} e cm and can be well within the reach of the next generation of experiments if it is further enhanced by long distance physics as happens in the SM.Comment: Some typos are corrected. References are updated. Discussion on FCNC contributions is adde

Families\u27 healthcare experiences for children with inherited metabolic diseases: Protocol for a mixed methods cohort study

Introduction Children with inherited metabolic diseases (IMDs) often have complex and intensive healthcare needs and their families face challenges in receiving high-quality, family centred health services. Improvement in care requires complex interventions involving multiple components and stakeholders, customised to specific care contexts. This study aims to comprehensively understand the healthcare experiences of children with IMDs and their families across Canada. Methods and analysis A two-stage explanatory sequential mixed methods design will be used. Stage 1: quantitative data on healthcare networks and encounter experiences will be collected from 100 parent/guardians through a care map, 2 baseline questionnaires and 17 weekly diaries over 5-7 months. Care networks will be analysed using social network analysis. Relationships between demographic or clinical variables and ratings of healthcare experiences across a range of family centred care dimensions will be analysed using generalised linear regression. Other quantitative data related to family experiences and healthcare experiences will be summarised descriptively. Ongoing analysis of quantitative data and purposive, maximum variation sampling will inform sample selection for stage 2: a subset of stage 1 participants will participate in one-on-one videoconference interviews to elaborate on the quantitative data regarding care networks and healthcare experiences. Interview data will be analysed thematically. Qualitative and quantitative data will be merged during analysis to arrive at an enhanced understanding of care experiences. Quantitative and qualitative data will be combined and presented narratively using a weaving approach (jointly on a theme-by-theme basis) and visually in a side-by-side joint display. Ethics and dissemination The study protocol and procedures were approved by the Children\u27s Hospital of Eastern Ontario\u27s Research Ethics Board, the University of Ottawa Research Ethics Board and the research ethics boards of each participating study centre. Findings will be published in peer-reviewed journals and presented at scientific conferences

Regulation of Cancer Aggressive Features in Melanoma Cells by MicroRNAs

MicroRNAs (miRNAs) are small non-coding RNAs with regulatory roles, which are involved in a broad spectrum of physiological and pathological processes, including cancer. A common strategy for identification of miRNAs involved in cell transformation is to compare malignant cells to normal cells. Here we focus on identification of miRNAs that regulate the aggressive phenotype of melanoma cells. To avoid differences due to genetic background, a comparative high-throughput miRNA profiling was performed on two isogenic human melanoma cell lines that display major differences in their net proliferation, invasion and tube formation activities. This screening revealed two major cohorts of differentially expressed miRNAs. We speculated that miRNAs up-regulated in the more-aggressive cell line contribute oncogenic features, while the down-regulated miRNAs are tumor suppressive. This assumption was further tested experimentally on five candidate tumor suppressive miRNAs (miR-31, -34a, -184, -185 and -204) and on one candidate oncogenic miRNA (miR-17-5p), all of which have never been reported before in cutaneous melanoma. Remarkably, all candidate Suppressive-miRNAs inhibited net proliferation, invasion or tube formation, while miR-17-5p enhanced cell proliferation. miR-34a and miR-185 were further shown to inhibit the growth of melanoma xenografts when implanted in SCID-NOD mice. Finally, all six candidate miRNAs were detected in 15 different metastatic melanoma specimens, attesting for the physiological relevance of our findings. Collectively, these findings may prove instrumental for understanding mechanisms of disease and for development of novel therapeutic and staging technologies for melanoma

Cash transfers for sustainable rural livelihoods? Examining the long-term productive effects of the Child Support Grant in South Africa

Cash transfers have received increased scholarly and policy attention, as a means of reducing poverty in the global South. While cash transfers are primarily intended to prevent impoverishment and deprivation, several studies suggest they can have 'productive' impacts, contributing to building sustainable livelihoods. However, pilot projects of unconditional cash transfers have often been too brief or too recent to determine how small, but regular, transfers can improve rural livelihoods over time. This paper explores potential long-term productive effects of cash transfers on rural household's livelihoods. This is done through revisiting, after 14 years, all (273) households in two South African villages included in an extensive livelihood and asset survey in 2002. That survey predated the phasing in of the Child Support Grant (CSG), targeted at impoverished children. When re-surveyed in 2016, some households had cumulatively received significant, while others little or no CSG income. Multivariate regression analysis shows how households that received more CGS income were more likely to invest in productive assets (e.g. small ploughs), and engage in poultry, staple crop and vegetable production

Compassion: From its evolution to a psychotherapy

The concept, benefits and recommendations for the cultivation of compassion have been recognized in the contemplative traditions for thousands of years. In the last 30 years or so, the study of compassion has revealed it to have major physiological and psychological effects influencing well-being, addressing mental health difficulties, and promoting prosocial behavior. This paper outlines an evolution informed biopsychosocial, multicomponent model to caring behavior and its derivative “compassion” that underpins newer approaches to psychotherapy. The paper explores the origins of caring motives and the nature and biopsychosocial functions of caring-attachment behavior. These include providing a secure base (sources of protection, validation, encouragement and guidance) and safe haven (source of soothing and comfort) for offspring along with physiological regulating functions, which are also central for compassion focused therapy. Second, it suggests that it is the way recent human cognitive competencies give rise to different types of “mind awareness” and “knowing intentionality” that transform basic caring motives into potentials for compassion. While we can care for our gardens and treasured objects, the concept of compassion is only used for sentient beings who can “suffer.” As psychotherapy addresses mental suffering, cultivating the motives and competencies of compassion to self and others can be a central focus for psychotherapy.This research was supported by the Compassionate Mind Foundation charity (https://compassionatemind.co.uk/)