Stroke genetics: prospects for personalized medicine.

Epidemiologic evidence supports a genetic predisposition to stroke. Recent advances, primarily using the genome-wide association study approach, are transforming what we know about the genetics of multifactorial stroke, and are identifying novel stroke genes. The current findings are consistent with different stroke subtypes having different genetic architecture. These discoveries may identify novel pathways involved in stroke pathogenesis, and suggest new treatment approaches. However, the already identified genetic variants explain only a small proportion of overall stroke risk, and therefore are not currently useful in predicting risk for the individual patient. Such risk prediction may become a reality as identification of a greater number of stroke risk variants that explain the majority of genetic risk proceeds, and perhaps when information on rare variants, identified by whole-genome sequencing, is also incorporated into risk algorithms. Pharmacogenomics may offer the potential for earlier implementation of 'personalized genetic' medicine. Genetic variants affecting clopidogrel and warfarin metabolism may identify non-responders and reduce side-effects, but these approaches have not yet been widely adopted in clinical practice

Cognitive loading affects motor awareness and movement kinematics but not locomotor trajectories during goal-directed walking in a virtual reality environment.

The primary purpose of this study was to investigate the effects of cognitive loading on movement kinematics and trajectory formation during goal-directed walking in a virtual reality (VR) environment. The secondary objective was to measure how participants corrected their trajectories for perturbed feedback and how participants' awareness of such perturbations changed under cognitive loading. We asked 14 healthy young adults to walk towards four different target locations in a VR environment while their movements were tracked and played back in real-time on a large projection screen. In 75% of all trials we introduced angular deviations of ±5° to ±30° between the veridical walking trajectory and the visual feedback. Participants performed a second experimental block under cognitive load (serial-7 subtraction, counter-balanced across participants). We measured walking kinematics (joint-angles, velocity profiles) and motor performance (end-point-compensation, trajectory-deviations). Motor awareness was determined by asking participants to rate the veracity of the feedback after every trial. In-line with previous findings in natural settings, participants displayed stereotypical walking trajectories in a VR environment. Our results extend these findings as they demonstrate that taxing cognitive resources did not affect trajectory formation and deviations although it interfered with the participants' movement kinematics, in particular walking velocity. Additionally, we report that motor awareness was selectively impaired by the secondary task in trials with high perceptual uncertainty. Compared with data on eye and arm movements our findings lend support to the hypothesis that the central nervous system (CNS) uses common mechanisms to govern goal-directed movements, including locomotion. We discuss our results with respect to the use of VR methods in gait control and rehabilitation

Is Mate Choice in Humans MHC-Dependent?

In several species, including rodents and fish, it has been shown that the Major Histocompatibility Complex (MHC) influences mating preferences and, in some cases, that this may be mediated by preferences based on body odour. In humans, the picture has been less clear. Several studies have reported a tendency for humans to prefer MHC-dissimilar mates, a sexual selection that would favour the production of MHC-heterozygous offspring, who would be more resistant to pathogens, but these results are unsupported by other studies. Here, we report analyses of genome-wide genotype data (from the HapMap II dataset) and HLA types in African and European American couples to test whether humans tend to choose MHC-dissimilar mates. In order to distinguish MHC-specific effects from genome-wide effects, the pattern of similarity in the MHC region is compared to the pattern in the rest of the genome. African spouses show no significant pattern of similarity/dissimilarity across the MHC region (relatedness coefficient, R = 0.015, p = 0.23), whereas across the genome, they are more similar than random pairs of individuals (genome-wide R = 0.00185, p<10−3). We discuss several explanations for these observations, including demographic effects. On the other hand, the sampled European American couples are significantly more MHC-dissimilar than random pairs of individuals (R = −0.043, p = 0.015), and this pattern of dissimilarity is extreme when compared to the rest of the genome, both globally (genome-wide R = −0.00016, p = 0.739) and when broken into windows having the same length and recombination rate as the MHC (only nine genomic regions exhibit a higher level of genetic dissimilarity between spouses than does the MHC). This study thus supports the hypothesis that the MHC influences mate choice in some human populations

Rye kernel breakfast increases satiety in the afternoon - an effect of food structure

<p>Abstract</p> <p>Background</p> <p>The structure of whole grain cereals is maintained to varying degrees during processing and preparation of foods. Food structure can influence metabolism, including perceived hunger and satiety. A diet that enhances satiety per calorie may help to prevent excessive calorie intake. The objective of this work was to compare subjective appetite ratings after consumption of intact and milled rye kernels.</p> <p>Methods</p> <p>Two studies were performed using a randomized, cross-over design. Ratings for appetite (hunger, satiety and desire to eat) were registered during an 8-h period after consumption of whole and milled rye kernels prepared as breads (study 1, n = 24) and porridges (study 2, n = 20). Sifted wheat bread was used as reference in both study parts and the products were eaten in iso-caloric portions with standardized additional breakfast foods. Breads and porridges were analyzed to determine whether structure (whole vs. milled kernels) effected dietary fibre content and composition after preparation of the products. Statistical evaluation of the appetite ratings after intake of the different breakfasts was done by paired t-tests for morning and afternoon ratings separately, with subjects as random effect and type of breakfast and time points as fixed effects.</p> <p>Results</p> <p>All rye breakfasts resulted in higher satiety ratings in the morning and afternoon compared with the iso-caloric reference breakfast with sifted wheat bread. Rye bread with milled or whole kernels affected appetite equally, so no effect of structure was observed. In contrast, after consumption of the rye kernel breakfast, satiety was increased and hunger suppressed in the afternoon compared with the milled rye kernel porridge breakfast. This effect could be related to structural differences alone, because the products were equal in nutritional content including dietary fibre content and composition.</p> <p>Conclusions</p> <p>The study demonstrates that small changes in diet composition such as cereal grain structure have the potential to effect feelings of hunger and satiety.</p> <p>Trial registration</p> <p>This trial was registered at clinicaltrials.gov as <a href="http://www.clinicaltrials.gov/ct2/show/NCT01042418">NCT01042418</a>.</p

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

Human Perception of Fear in Dogs Varies According to Experience with Dogs

To investigate the role of experience in humans’ perception of emotion using canine visual signals, we asked adults with various levels of dog experience to interpret the emotions of dogs displayed in videos. The video stimuli had been pre-categorized by an expert panel of dog behavior professionals as showing examples of happy or fearful dog behavior. In a sample of 2,163 participants, the level of dog experience strongly predicted identification of fearful, but not of happy, emotional examples. The probability of selecting the “fearful” category to describe fearful examples increased with experience and ranged from.30 among those who had never lived with a dog to greater than.70 among dog professionals. In contrast, the probability of selecting the “happy” category to describe happy emotional examples varied little by experience, ranging from.90 to.93. In addition, the number of physical features of the dog that participants reported using for emotional interpretations increased with experience, and in particular, more-experienced respondents were more likely to attend to the ears. Lastly, more-experienced respondents provided lower difficulty and higher accuracy self-ratings than less-experienced respondents when interpreting both happy and fearful emotional examples. The human perception of emotion in other humans has previously been shown to be sensitive to individual differences in social experience, and the results of the current study extend the notion of experience-dependent processes from the intraspecific to the interspecific domain

The Internally Truncated LRP5 Receptor Presents a Therapeutic Target in Breast Cancer

BACKGROUND: Breast cancer is a common malignant disease, which may be caused by a number of genes deregulated by genomic or epigenomic events. Deregulated WNT/beta-catenin signaling with accumulation of beta-catenin is common in breast tumors, but mutations in WNT signaling pathway components have been rare. An aberrantly spliced internally truncated LRP5 receptor (LRP5Delta666-809, LRP5Delta) was shown recently to be resistant to DKK1 inhibition, and was required for beta-catenin accumulation in hyperparathyroid tumors and parathyroid tumor growth. METHODOLOGY/PRINCIPAL FINDINGS: Here we show, by reverse transcription PCR and Western blot analysis, that LRP5Delta is frequently expressed in breast tumors of different cancer stage (58-100%), including carcinoma in situ and metastatic carcinoma. LRP5Delta was required in MCF7 breast cancer cells for the non-phosphorylated active beta-catenin level, transcription activity of beta-catenin, cell growth in vitro, and breast tumor growth in a xenograft SCID mouse model. WNT3 ligand, but not WNT1 and WNT3A augmented the endogenous beta-catenin activity of MCF7 cells in a DKK1-insensitive manner. Furthermore, an anti-LRP5 antibody attenuated beta-catenin activity, inhibited cell growth, and induced apoptosis in LRP5Delta-positive MCF7 and T-47D breast cancer cells, but not in control cells. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the LRP5Delta receptor is strongly implicated in mammary gland tumorigenesis and that its aberrant expression present an early event during disease progression. LRP5 antibody therapy may have a significant role in the treatment of breast cancer

Identification of a 4-microRNA Signature for Clear Cell Renal Cell Carcinoma Metastasis and Prognosis

Renal cell carcinoma (RCC) metastasis portends a poor prognosis and cannot be reliably predicted. Early determination of the metastatic potential of RCC may help guide proper treatment. We analyzed microRNA (miRNA) expression in clear cell RCC (ccRCC) for the purpose of developing a miRNA expression signature to determine the risk of metastasis and prognosis. We used the microarray technology to profile miRNA expression of 78 benign kidney and ccRCC samples. Using 28 localized and metastatic ccRCC specimens as the training cohort and the univariate logistic regression and risk score methods, we developed a miRNA signature model in which the expression levels of miR-10b, miR-139-5p, miR-130b and miR-199b-5p were used to determine the status of ccRCC metastasis. We validated the signature in an independent 40-sample testing cohort of different stages of primary ccRCCs using the microarray data. Within the testing cohort patients who had at least 5 years follow-up if no metastasis developed, the signature showed a high sensitivity and specificity. The risk status was proven to be associated with the cancer-specific survival. Using the most stably expressed miRNA among benign and tumorous kidney tissue as the internal reference for normalization, we successfully converted his signature to be a quantitative PCR (qPCR)-based assay, which showed the same high sensitivity and specificity. The 4-miRNA is associated with ccRCC metastasis and prognosis. The signature is ready for and will benefit from further large clinical cohort validation and has the potential for clinical application