Lost in Translation? On the Need for Convergence in Animal and Human Studies on the Role of Dopamine in Diet-Induced Obesity

Purpose of Review: Animal and human studies suggest that diet-induced obesity and plasticity in the central dopaminergic system are linked. However, it is unclear whether observed changes depend on diet or obesity, and whether they are specific to brain regions and cognitive functions. Here, we focus on neural and cognitive changes in frontostriatal circuits. Recent Findings: Both diet and obesity affect dopaminergic transmission. However, site and direction of effects are inconsistent across species and studies. Non-specific changes are observed spanning all frontostriatal loops, from sensory input to motivated behaviour. Given the impact of peripheral signals on central dopaminergic signalling and the interaction between the frontostriatal loops, modulation of dopamine likely propagates through all loops and, thus, affects behaviour on various levels of complexity. Summary: To improve convergence between animal and human studies on diet-induced obesity, animal studies should include sophisticated cognitive measures and diets resembling human obesogenic diets, and human studies should adopt diet interventions and longitudinal designs.Peer reviewe

DNA methylation at quantitative trait loci (mQTLs) varies with cell type and nonheritable factors and may improve breast cancer risk assessment

To individualise breast cancer (BC) prevention, markers to follow a person’s changing environment and health extending beyond static genetic risk scores are required. Here, we analysed cervical and breast DNA methylation (n = 1848) and single nucleotide polymorphisms (n = 1442) and demonstrate that a linear combination of methylation levels at 104 BC-associated methylation quantitative trait loci (mQTL) CpGs, termed the WID™-qtBC index, can identify women with breast cancer in hormone-sensitive tissues (AUC = 0.71 [95% CI: 0.65–0.77] in cervical samples). Women in the highest combined risk group (high polygenic risk score and WID™-qtBC) had a 9.6-fold increased risk for BC [95% CI: 4.7–21] compared to the low-risk group and tended to present at more advanced stages. Importantly, the WID™-qtBC is influenced by non-genetic BC risk factors, including age and body mass index, and can be modified by a preventive pharmacological intervention, indicating an interaction between genome and environment recorded at the level of the epigenome. Our findings indicate that methylation levels at mQTLs in relevant surrogate tissues could enable integration of heritable and non-heritable factors for improved disease risk stratification

Towards a Critical Understanding of Music, Emotion and Self-Identity

The article begins by outlining a dominant conception of these relations in sociologically informed analysis of music, which sees music primarily as a positive resource for active self-making. My argument is that this conception rests on a problematic notion of the self and also on an overly optimistic understanding of music, which implicitly sees music as highly independent of negative social and historical processes. I then attempt to construct a) a more adequately critical conception of personal identity in modern societies; and b) a more balanced appraisal of music-society relations. I suggest two ways in which relations between self, music and society may not always be quite so positive or as healthy as the dominant conception suggests: 1) Music is now bound up with the incorporation of authenticity and creativity into capitalism, and with intensified consumption habits. 2) Emotional self-realisation through music is now linked to status competition. Interviews are analysed

BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition.

Tyrosine kinase inhibitors (TKIs) are widely used to treat patients with leukaemia driven by BCR-ABL1 (ref. 1) and other oncogenic tyrosine kinases. Recent efforts have focused on developing more potent TKIs that also inhibit mutant tyrosine kinases. However, even effective TKIs typically fail to eradicate leukaemia-initiating cells (LICs), which often cause recurrence of leukaemia after initially successful treatment. Here we report the discovery of a novel mechanism of drug resistance, which is based on protective feedback signalling of leukaemia cells in response to treatment with TKI. We identify BCL6 as a central component of this drug-resistance pathway and demonstrate that targeted inhibition of BCL6 leads to eradication of drug-resistant and leukaemia-initiating subclones

All clinically-relevant blood components transmit prion disease following a single blood transfusion: a sheep model of vCJD

Variant CJD (vCJD) is an incurable, infectious human disease, likely arising from the consumption of BSE-contaminated meat products. Whilst the epidemic appears to be waning, there is much concern that vCJD infection may be perpetuated in humans by the transfusion of contaminated blood products. Since 2004, several cases of transfusion-associated vCJD transmission have been reported and linked to blood collected from pre-clinically affected donors. Using an animal model in which the disease manifested resembles that of humans affected with vCJD, we examined which blood components used in human medicine are likely to pose the greatest risk of transmitting vCJD via transfusion. We collected two full units of blood from BSE-infected donor animals during the pre-clinical phase of infection. Using methods employed by transfusion services we prepared red cell concentrates, plasma and platelets units (including leucoreduced equivalents). Following transfusion, we showed that all components contain sufficient levels of infectivity to cause disease following only a single transfusion and also that leucoreduction did not prevent disease transmission. These data suggest that all blood components are vectors for prion disease transmission, and highlight the importance of multiple control measures to minimise the risk of human to human transmission of vCJD by blood transfusion

The WID-BC-index identifies women with primary poor prognostic breast cancer based on DNA methylation in cervical samples

Genetic and non-genetic factors contribute to breast cancer development. An epigenome-based signature capturing these components in easily accessible samples could identify women at risk. Here, we analyse the DNA methylome in 2,818 cervical, 357 and 227 matched buccal and blood samples respectively, and 42 breast tissue samples from women with and without breast cancer. Utilising cervical liquid-based cytology samples, we develop the DNA methylation-based Women’s risk IDentification for Breast Cancer index (WID-BC-index) that identifies women with breast cancer with an AUROC (Area Under the Receiver Operator Characteristic) of 0.84 (95% CI: 0.80–0.88) and 0.81 (95% CI: 0.76–0.86) in internal and external validation sets, respectively. CpGs at progesterone receptor binding sites hypomethylated in normal breast tissue of women with breast cancer or in BRCA mutation carriers are also hypomethylated in cervical samples of women with poor prognostic breast cancer. Our data indicate that a systemic epigenetic programming defect is highly prevalent in women who develop breast cancer. Further studies validating the WID-BC-index may enable clinical implementation for monitoring breast cancer risk.publishedVersio

Antiprogestins reduce epigenetic field cancerization in breast tissue of young healthy women

Background: Breast cancer is a leading cause of death in premenopausal women. Progesterone drives expansion of luminal progenitor cells, leading to the development of poor-prognostic breast cancers. However, it is not known if antagonising progesterone can prevent breast cancers in humans. We suggest that targeting progesterone signalling could be a means of reducing features which are known to promote breast cancer formation. Methods: In healthy premenopausal women with and without a BRCA mutation we studied (i) estrogen and progesterone levels in saliva over an entire menstrual cycle (n = 20); (ii) cancer-free normal breast-tissue from a control population who had no family or personal history of breast cancer and equivalently from BRCA1/2 mutation carriers (n = 28); triple negative breast cancer (TNBC) biopsies and healthy breast tissue taken from sites surrounding the TNBC in the same individuals (n = 14); and biopsies of ER+ve/PR+ve stage T1–T2 cancers and healthy breast tissue taken from sites surrounding the cancer in the same individuals (n = 31); and (iii) DNA methylation and DNA mutations in normal breast tissue (before and after treatment) from clinical trials that assessed the potential preventative effects of vitamins and antiprogestins (mifepristone and ulipristal acetate; n = 44). Results: Daily levels of progesterone were higher throughout the menstrual cycle of BRCA1/2 mutation carriers, raising the prospect of targeting progesterone signalling as a means of cancer risk reduction in this population. Furthermore, breast field cancerization DNA methylation signatures reflective of (i) the mitotic age of normal breast epithelium and (ii) the proportion of luminal progenitor cells were increased in breast cancers, indicating that luminal progenitor cells with elevated replicative age are more prone to malignant transformation. The progesterone receptor antagonist mifepristone reduced both the mitotic age and the proportion of luminal progenitor cells in normal breast tissue of all control women and in 64% of BRCA1/2 mutation carriers. These findings were validated by an alternate progesterone receptor antagonist, ulipristal acetate, which yielded similar results. Importantly, mifepristone reduced both the TP53 mutation frequency as well as the number of TP53 mutations in mitotic-age-responders. Conclusions: These data support the potential usage of antiprogestins for primary prevention of poor-prognostic breast cancers

Cross-site analysis of perceived ecosystem service benefits in multifunctional landscapes

Rural development policies in many Organization for Economic Co-operation and Development (OECD) member countries promote sustainable landscape management with the intention of providing multiple ecosystem services (ES). Yet, it remains unclear which ES benefits are perceived in different landscapes and by different people. We present an assessment of ES benefits perceived and mapped by residents (n = 2,301) across 13 multifunctional (deep rural to peri-urban) landscapes in Europe. We identify the most intensively perceived ES benefits, their spatial patterns, and the respondent and landscape characteristics that determine ES benefit perception. We find outdoor recreation, aesthetic values and social interactions are the key ES benefits at local scales. Settlement areas are ES benefit hotspots but many benefits are also related to forests, waters and mosaic landscapes. We find some ES benefits (e.g. culture and heritage values) are spatially clustered, while many others (e.g. aesthetic values) are dispersed. ES benefit perception is linked to people’s relationship with and accessibility to a landscape. Our study discusses how a local perspective can contribute to the development of contextualized and socially acceptable policies for sustainable ES management. We also address conceptual confusion in ES framework and present argumentation regarding the links from services to benefits, and from benefits to different types of values

Cross-site analysis of perceived ecosystem service benefits in multifunctional landscapes

Rural development policies in many Organization for Economic Co-operation and Development (OECD) member countries promote sustainable landscape management with the intention of providing multiple ecosystem services (ES). Yet, it remains unclear which ES benefits are perceived in different landscapes and by different people. We present an assessment of ES benefits perceived and mapped by residents (n = 2,301) across 13 multifunctional (deep rural to peri-urban) landscapes in Europe. We identify the most intensively perceived ES benefits, their spatial patterns, and the respondent and landscape characteristics that determine ES benefit perception. We find outdoor recreation, aesthetic values and social interactions are the key ES benefits at local scales. Settlement areas are ES benefit hotspots but many benefits are also related to forests, waters and mosaic landscapes. We find some ES benefits (e.g. culture and heritage values) are spatially clustered, while many others (e.g. aesthetic values) are dispersed. ES benefit perception is linked to people’s relationship with and accessibility to a landscape. Our study discusses how a local perspective can contribute to the development of contextualized and socially acceptable policies for sustainable ES management. We also address conceptual confusion in ES framework and present argumentation regarding the links from services to benefits, and from benefits to different types of values.</p