Genome-Scale Methods Converge on Key Mitochondrial Genes for the Survival of Human Cardiomyocytes in Hypoxia

BACKGROUND: Any reduction in myocardial oxygen delivery relative to its demands can impair cardiac contractile performance. Understanding the mitochondrial metabolic response to hypoxia is key to understanding ischemia tolerance in the myocardium. We used a novel combination of 2 genome-scale methods to study key processes underlying human myocardial hypoxia tolerance. In particular, we hypothesized that computational modeling and evolution would identify similar genes as critical to human myocardial hypoxia tolerance. METHODS AND RESULTS: We analyzed a reconstruction of the cardiac mitochondrial metabolic network using constraint-based methods, under conditions of simulated hypoxia. We used flux balance analysis, random sampling, and principal component analysis to explore feasible steady-state solutions. Hypoxia blunted maximal ATP (−17%) and heme (−75%) synthesis and shrank the feasible solution space. Tricarboxylic acid and urea cycle fluxes were also reduced in hypoxia, but phospholipid synthesis was increased. Using mathematical optimization methods, we identified reactions that would be critical to hypoxia tolerance in the human heart. We used data regarding single-nucleotide polymorphism frequency and distribution in the genomes of Tibetans (whose ancestors have resided in persistent high-altitude hypoxia for several millennia). Six reactions were identified by both methods as being critical to mitochondrial ATP production in hypoxia: phosphofructokinase, phosphoglucokinase, complex II, complex IV, aconitase, and fumarase. CONCLUSIONS: Mathematical optimization and evolution converged on similar genes as critical to human myocardial hypoxia tolerance. Our approach is unique and completely novel and demonstrates that genome-scale modeling and genomics can be used in tandem to provide new insights into cardiovascular genetics

Iron Age and Anglo-Saxon genomes from East England reveal British migration history

British population history has been shaped by a series of immigrations, including the early Anglo-Saxon migrations after 400 CE. It remains an open question how these events affected the genetic composition of the current British population. Here, we present whole-genome sequences from 10 individuals excavated close to Cambridge in the East of England, ranging from the late Iron Age to the middle Anglo-Saxon period. By analysing shared rare variants with hundreds of modern samples from Britain and Europe, we estimate that on average the contemporary East English population derives 38% of its ancestry from Anglo-Saxon migrations. We gain further insight with a new method, rarecoal, which infers population history and identifies fine-scale genetic ancestry from rare variants. Using rarecoal we find that the Anglo-Saxon samples are closely related to modern Dutch and Danish populations, while the Iron Age samples share ancestors with multiple Northern European populations including Britain

Age-dependent seroprevalence of dengue and chikungunya: inference from a cross-sectional analysis in Esmeraldas Province in coastal Ecuador

Objectives There are few population-based estimates for prevalence of past exposure to dengue and chikungunya viruses despite common epidemiological features. Here, we have developed a novel statistical method to study patterns of age-dependent prevalence of immunity in a population following exposures to two viruses which share similar epidemiological features including mode of transmission and induction of long-lasting immunity. This statistical technique accounted for sociodemographic characteristics associated with individuals and households. Settings The data consist of a representative sample from an ongoing longitudinal birth cohort set-up in a tropical district in coastal Ecuador (Esmeraldas). Participants We collected data and blood samples from 319 individuals belonging to 152 households following epidemics of the infections in 2015 in Latin America. Primary outcome Plasma was tested for the presence of specific IgG antibodies to dengue and chikungunya viruses by commercial ELISA and defined a bivariate binary outcome indicating individuals’ past exposure status to dengue and chikungunya (ie, presence/absence of IgG antibodies to dengue or chikungunya or both). Results Dengue seroprevalence increased rapidly with age reaching 97% (95% credible interval (CrI): 93%–99%) by 60 years. Chikungunya seroprevalence peaked at 42% (95% CrI: 18%–66%) around 9 years of age and averaged 27% (95% CrI: 8.7%–51.6%) for all ages. Rural areas were more likely to be associated with dengue-only exposure while urban areas and shorter distance to the nearest household were associated with exposures to both. Women living in urban settings were more likely to be chikungunya seropositive while rural men were more likely to be dengue seropositive. Conclusion Dengue seroprevalence was strongly age dependent consistent with endemic exposure while that of chikungunya peaked in childhood consistent with the recent emergence of the virus in the study area. Our findings will inform control strategies for the two arboviruses in Ecuador including recommendations by the WHO on dengue vaccination

Widespread Hypomethylation Occurs Early and Synergizes with Gene Amplification during Esophageal Carcinogenesis

Although a combination of genomic and epigenetic alterations are implicated in the multistep transformation of normal squamous esophageal epithelium to Barrett esophagus, dysplasia, and adenocarcinoma, the combinatorial effect of these changes is unknown. By integrating genome-wide DNA methylation, copy number, and transcriptomic datasets obtained from endoscopic biopsies of neoplastic progression within the same individual, we are uniquely able to define the molecular events associated progression of Barrett esophagus. We find that the previously reported global hypomethylation phenomenon in cancer has its origins at the earliest stages of epithelial carcinogenesis. Promoter hypomethylation synergizes with gene amplification and leads to significant upregulation of a chr4q21 chemokine cluster and other transcripts during Barrett neoplasia. In contrast, gene-specific hypermethylation is observed at a restricted number of loci and, in combination with hemi-allelic deletions, leads to downregulatation of selected transcripts during multistep progression. We also observe that epigenetic regulation during epithelial carcinogenesis is not restricted to traditionally defined “CpG islands,” but may also occur through a mechanism of differential methylation outside of these regions. Finally, validation of novel upregulated targets (CXCL1 and 3, GATA6, and DMBT1) in a larger independent panel of samples confirms the utility of integrative analysis in cancer biomarker discovery

Tracing the dynamic life story of a Bronze Age Female

YesAncient human mobility at the individual level is conventionally studied by the diverse application of suitable techniques (e.g. aDNA, radiogenic strontium isotopes, as well as oxygen and lead isotopes) to either hard and/or soft tissues. However, the limited preservation of coexisting hard and soft human tissues hampers the possibilities of investigating high-resolution diachronic mobility periods in the life of a single individual. Here, we present the results of a multidisciplinary study of an exceptionally well preserved circa 3.400-year old Danish Bronze Age female find, known as the Egtved Girl. We applied biomolecular, biochemical and geochemical analyses to reconstruct her mobility and diet. We demonstrate that she originated from a place outside present day Denmark (the island of Bornholm excluded), and that she travelled back and forth over large distances during the final months of her life, while consuming a terrestrial diet with intervals of reduced protein intake. We also provide evidence that all her garments were made of non-locally produced wool. Our study advocates the huge potential of combining biomolecular and biogeochemical provenance tracer analyses to hard and soft tissues of a single ancient individual for the reconstruction of high-resolution human mobility.The Danish National Research Foundation; The Carlsberg Foundation, L'Oreal Denmark-UNESCO; The ERC agreement no. 26944

Investigation of attentional bias in obsessive compulsive disorder with and without depression in visual search

Copyright: © 2013 Morein-Zamir et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedWhether Obsessive Compulsive Disorder (OCD) is associated with an increased attentional bias to emotive stimuli remains controversial. Additionally, it is unclear whether comorbid depression modulates abnormal emotional processing in OCD. This study examined attentional bias to OC-relevant scenes using a visual search task. Controls, non-depressed and depressed OCD patients searched for their personally selected positive images amongst their negative distractors, and vice versa. Whilst the OCD groups were slower than healthy individuals in rating the images, there were no group differences in the magnitude of negative bias to concern-related scenes. A second experiment employing a common set of images replicated the results on an additional sample of OCD patients. Although there was a larger bias to negative OC-related images without pre-exposure overall, no group differences in attentional bias were observed. However, OCD patients subsequently rated the images more slowly and more negatively, again suggesting post-attentional processing abnormalities. The results argue against a robust attentional bias in OCD patients, regardless of their depression status and speak to generalized difficulties disengaging from negative valence stimuli. Rather, post-attentional processing abnormalities may account for differences in emotional processing in OCD.Peer reviewedFinal Published versio

Impact of Circulating Cholesterol Levels on Growth and Intratumoral Androgen Concentration of Prostate Tumors

Prostate cancer (PCa) is the second most common cancer in men. Androgen deprivation therapy (ADT) leads to tumor involution and reduction of tumor burden. However, tumors eventually reemerge that have overcome the absence of gonadal androgens, termed castration resistant PCa (CRPC). Theories underlying the development of CRPC include androgen receptor (AR) mutation allowing for promiscuous activation by non-androgens, AR amplification and overexpression leading to hypersensitivity to low androgen levels, and/or tumoral uptake and conversion of adrenally derived androgens. More recently it has been proposed that prostate tumor cells synthesize their own androgens through de novo steroidogenesis, which involves the step-wise synthesis of androgens from cholesterol. Using the in vivo LNCaP PCa xenograft model, previous data from our group demonstrated that a hypercholesterolemia diet potentiates prostatic tumor growth via induction of angiogenesis. Using this same model we now demonstrate that circulating cholesterol levels are significantly associated with tumor size (R = 0.3957, p = 0.0049) and intratumoral levels of testosterone (R = 0.41, p = 0.0023) in LNCaP tumors grown in hormonally intact mice. We demonstrate tumoral expression of cholesterol uptake genes as well as the spectrum of steroidogenic enzymes necessary for androgen biosynthesis from cholesterol. Moreover, we show that circulating cholesterol levels are directly correlated with tumoral expression of CYP17A, the critical enzyme required for de novo synthesis of androgens from cholesterol (R = 0.4073, p = 0.025) Since hypercholesterolemia does not raise circulating androgen levels and the adrenal gland of the mouse synthesizes minimal androgens, this study provides evidence that hypercholesterolemia increases intratumoral de novo steroidogenesis. Our results are consistent with the hypothesis that cholesterol-fueled intratumoral androgen synthesis may accelerate the growth of prostate tumors, and suggest that treatment of CRPC may be optimized by inclusion of cholesterol reduction therapies in conjunction with therapies targeting androgen synthesis and the AR

Exploring medical student learning in the large group teaching environment: examining current practice to inform curricular development

Background Lectures continue to be an efficient and standardised way to deliver information to large groups of students. It has been well documented that students prefer interactive lectures, based on active learning principles, to didactic teaching in the large group setting. Despite this, it is often the case than many students do not engage with active learning tasks and attempts at interaction. By exploring student experiences, expectations and how they use lectures in their learning we will provide recommendations for faculty to support student learning both in the lecture theatre and during personal study time. Methods This research employed a hermeneutic phenomenological approach. Three focus groups, consisting of 19 students in total, were used to explore the experiences of second year medical students in large group teaching sessions. Using generic thematic data analysis, these accounts have been developed into a meaningful account of experience. Results This study found there to be a well-established learning culture amongst students and with it, expectations as to the format of teaching sessions. Furthermore, there were set perceptions about the student role within the learning environment which had many implications, including the way that innovative teaching methods were received. Student learning was perceived to take place outside the lecture theatre, with a large emphasis placed on creating resources that can be taken away to use in personal study time. Conclusions Presented here is a constructive review of reasons for student participation, interaction and engagement in large group teaching sessions. Based on this are recommendations constructed with the view to aid educators in engaging students within this setting. Short term, educators can implement strategies that monopolise on the established learning culture of students to encourage engagement with active learning strategies. Long term, it would be beneficial for educators to consider ways to shift the current student learning culture to one that embraces an active learning curriculum

Association of MC1R Variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study

<p><b>Background</b> Carrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited.</p> <p><b>Methods</b> We included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, ≥2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided.</p> <p><b>Results</b> Carrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 × 10−6 ≤ P ≤ .0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 [95% confidence interval = 3.60 to 9.46] vs 2.25 [95% confidence interval = 1.44 to 3.52]; Ptrend = 1.86 × 10−8). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 ≤ P ≤ .04), hair color (.006 ≤ P ≤ .06), and number of nevi (6.9 × 10−6 ≤ P ≤ .02).</p> <p><b>Conclusion</b> Results show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings.</p&gt