Mutual Regulation of Bcl-2 Proteins Independent of the BH3 Domain as Shown by the BH3-Lacking Protein Bcl-xAK

The BH3 domain of Bcl-2 proteins was regarded as indispensable for apoptosis induction and for mutual regulation of family members. We recently described Bcl-xAK, a proapoptotic splice product of the bcl-x gene, which lacks BH3 but encloses BH2, BH4 and a transmembrane domain. It remained however unclear, how Bcl-xAK may trigger apoptosis

Dietary soy and meat proteins induce distinct physiological and gene expression changes in rats

This study reports on a comprehensive comparison of the effects of soy and meat proteins given at the recommended level on physiological markers of metabolic syndrome and the hepatic transcriptome. Male rats were fed semi-synthetic diets for 1 wk that differed only regarding protein source, with casein serving as reference. Body weight gain and adipose tissue mass were significantly reduced by soy but not meat proteins. The insulin resistance index was improved by soy, and to a lesser extent by meat proteins. Liver triacylglycerol contents were reduced by both protein sources, which coincided with increased plasma triacylglycerol concentrations. Both soy and meat proteins changed plasma amino acid patterns. The expression of 1571 and 1369 genes were altered by soy and meat proteins respectively. Functional classification revealed that lipid, energy and amino acid metabolic pathways, as well as insulin signaling pathways were regulated differently by soy and meat proteins. Several transcriptional regulators, including NFE2L2, ATF4, Srebf1 and Rictor were identified as potential key upstream regulators. These results suggest that soy and meat proteins induce distinct physiological and gene expression responses in rats and provide novel evidence and suggestions for the health effects of different protein sources in human diets

Methods for specifying the target difference in a randomised controlled trial : the Difference ELicitation in TriAls (DELTA) systematic review

Peer reviewedPublisher PD

A Novel System of Polymorphic and Diverse NK Cell Receptors in Primates

There are two main classes of natural killer (NK) cell receptors in mammals, the killer cell immunoglobulin-like receptors (KIR) and the structurally unrelated killer cell lectin-like receptors (KLR). While KIR represent the most diverse group of NK receptors in all primates studied to date, including humans, apes, and Old and New World monkeys, KLR represent the functional equivalent in rodents. Here, we report a first digression from this rule in lemurs, where the KLR (CD94/NKG2) rather than KIR constitute the most diverse group of NK cell receptors. We demonstrate that natural selection contributed to such diversification in lemurs and particularly targeted KLR residues interacting with the peptide presented by MHC class I ligands. We further show that lemurs lack a strict ortholog or functional equivalent of MHC-E, the ligands of non-polymorphic KLR in “higher” primates. Our data support the existence of a hitherto unknown system of polymorphic and diverse NK cell receptors in primates and of combinatorial diversity as a novel mechanism to increase NK cell receptor repertoire

Empirical Distributions of F-ST from Large-Scale Human Polymorphism Data

Studies of the apportionment of human genetic variation have long established that most human variation is within population groups and that the additional variation between population groups is small but greatest when comparing different continental populations. These studies often used Wright’s FST that apportions the standardized variance in allele frequencies within and between population groups. Because local adaptations increase population differentiation, high-FST may be found at closely linked loci under selection and used to identify genes undergoing directional or heterotic selection. We re-examined these processes using HapMap data. We analyzed 3 million SNPs on 602 samples from eight worldwide populations and a consensus subset of 1 million SNPs found in all populations. We identified four major features of the data: First, a hierarchically FST analysis showed that only a paucity (12%) of the total genetic variation is distributed between continental populations and even a lesser genetic variation (1%) is found between intra-continental populations. Second, the global FST distribution closely follows an exponential distribution. Third, although the overall FST distribution is similarly shaped (inverse J), FST distributions varies markedly by allele frequency when divided into non-overlapping groups by allele frequency range. Because the mean allele frequency is a crude indicator of allele age, these distributions mark the time-dependent change in genetic differentiation. Finally, the change in mean-FST of these groups is linear in allele frequency. These results suggest that investigating the extremes of the FST distribution for each allele frequency group is more efficient for detecting selection. Consequently, we demonstrate that such extreme SNPs are more clustered along the chromosomes than expected from linkage disequilibrium for each allele frequency group. These genomic regions are therefore likely candidates for natural selection

Adaptations to Climate-Mediated Selective Pressures in Humans

Humans inhabit a remarkably diverse range of environments, and adaptation through natural selection has likely played a central role in the capacity to survive and thrive in extreme climates. Unlike numerous studies that used only population genetic data to search for evidence of selection, here we scan the human genome for selection signals by identifying the SNPs with the strongest correlations between allele frequencies and climate across 61 worldwide populations. We find a striking enrichment of genic and nonsynonymous SNPs relative to non-genic SNPs among those that are strongly correlated with these climate variables. Among the most extreme signals, several overlap with those from GWAS, including SNPs associated with pigmentation and autoimmune diseases. Further, we find an enrichment of strong signals in gene sets related to UV radiation, infection and immunity, and cancer. Our results imply that adaptations to climate shaped the spatial distribution of variation in humans

A genome-wide association study for late-onset Alzheimer's disease using DNA pooling

Background: Late-onset Alzheimer's disease (LOAD) is an age related neurodegenerative disease with a high prevalence that places major demands on healthcare resources in societies with increasingly aged populations. The only extensively replicable genetic risk factor for LOAD is the apolipoprotein E gene. In order to identify additional genetic risk loci we have conducted a genome-wide association (GWA) study in a large LOAD case – control sample, reducing costs through the use of DNA pooling. Methods: DNA samples were collected from 1,082 individuals with LOAD and 1,239 control subjects. Age at onset ranged from 60 to 95 and Controls were matched for age (mean = 76.53 years, SD = 33), gender and ethnicity. Equimolar amounts of each DNA sample were added to either a case or control pool. The pools were genotyped using Illumina HumanHap300 and Illumina Sentrix HumanHap240S arrays testing 561,494 SNPs. 114 of our best hit SNPs from the pooling data were identified and then individually genotyped in the case – control sample used to construct the pools. Results: Highly significant association with LOAD was observed at the APOE locus confirming the validity of the pooled genotyping approach. For 109 SNPs outside the APOE locus, we obtained uncorrected p-values ≤ 0.05 for 74 after individual genotyping. To further test these associations, we added control data from 1400 subjects from the 1958 Birth Cohort with the evidence for association increasing to 3.4 × 10-6 for our strongest finding, rs727153. rs727153 lies 13 kb from the start of transcription of lecithin retinol acyltransferase (phosphatidylcholine – retinol O-acyltransferase, LRAT). Five of seven tag SNPs chosen to cover LRAT showed significant association with LOAD with a SNP in intron 2 of LRAT, showing greatest evidence of association (rs201825, p-value = 6.1 × 10-7). Conclusion: We have validated the pooling method for GWA studies by both identifying the APOE locus and by observing a strong enrichment for significantly associated SNPs. We provide evidence for LRAT as a novel candidate gene for LOAD. LRAT plays a prominent role in the Vitamin A cascade, a system that has been previously implicated in LOAD

Identifying Molecular Effects of Diet through Systems Biology: Influence of Herring Diet on Sterol Metabolism and Protein Turnover in Mice

BACKGROUND: Changes in lifestyle have resulted in an epidemic development of obesity-related diseases that challenge the healthcare systems worldwide. To develop strategies to tackle this problem the focus is on diet to prevent the development of obesity-associated diseases such as cardiovascular disease (CVD). This will require methods for linking nutrient intake with specific metabolic processes in different tissues. METHODOLOGY/PRINCIPAL FINDING: Low-density lipoprotein receptor-deficient (Ldlr -/-) mice were fed a high fat/high sugar diet to mimic a westernized diet, being a major reason for development of obesity and atherosclerosis. The diets were supplemented with either beef or herring, and matched in macronutrient contents. Body composition, plasma lipids and aortic lesion areas were measured. Transcriptomes of metabolically important tissues, e.g. liver, muscle and adipose tissue were analyzed by an integrated approach with metabolic networks to directly map the metabolic effects of diet in these different tissues. Our analysis revealed a reduction in sterol metabolism and protein turnover at the transcriptional level in herring-fed mice. CONCLUSION: This study shows that an integrated analysis of transcriptome data using metabolic networks resulted in the identification of signature pathways. This could not have been achieved using standard clustering methods. In particular, this systems biology analysis could enrich the information content of biomedical or nutritional data where subtle changes in several tissues together affects body metabolism or disease progression. This could be applied to improve diets for subjects exposed to health risks associated with obesity

Becoming original: effects of strategy instruction

Visual arts education focuses on creating original visual art products. A means to improve originality is enhancement of divergent thinking, indicated by fluency, flexibility and originality of ideas. In regular arts lessons, divergent thinking is mostly promoted through brainstorming. In a previous study, we found positive effects of an explicit instruction of metacognition on fluency and flexibility in terms of the generation of ideas, but not on the originality of ideas. Therefore, we redesigned the instruction with a focus on building up knowledge about creative generation strategies by adding more complex types of association, and adding generation through combination and abstraction. In the present study, we examined the effects of this intervention by comparing it with regular brainstorming instruction. In a pretest-posttest control group design, secondary school students in the comparison condition received the brainstorm lesson and students in the experimental condition received the newly developed instruction lesson. To validate the effects, we replicated this study with a second cohort. The results showed that in both cohorts the strategy instruction of 50 min had positive effects on students' fluency, flexibility and originality. This study implies that instructional support in building up knowledge about creative generation strategies may improve students' creative processes in visual arts education

Qubit-flip-induced cavity mode squeezing in the strong dispersive regime of the quantum Rabi model

Squeezed states of light are a set of nonclassical states in which the quantum fluctuations of one quadrature component are reduced below the standard quantum limit. With less noise than the best stabilised laser sources, squeezed light is a key resource in the field of quantum technologies and has already improved sensing capabilities in areas ranging from gravitational wave detection to biomedical applications. In this work we propose a novel technique for generating squeezed states of a confined light field strongly coupled to a two-level system, or qubit, in the dispersive regime. Utilising the dispersive energy shift caused by the interaction, control of the qubit state produces a time-dependent change in the frequency of the light field. An appropriately timed sequence of sudden frequency changes reduces the quantum noise fluctuations in one quadrature of the field well below the standard quantum limit. The degree of squeezing and the time of generation are directly controlled by the number of frequency shifts applied. Even in the presence of realistic noise and imperfections, our protocol promises to be capable of generating a useful degree of squeezing with present experimental capabilities