Eye Movements in Ephedrone-Induced Parkinsonism

Patients with ephedrone parkinsonism (EP) show a complex, rapidly progressive, irreversible, and levodopa non-responsive parkinsonian and dystonic syndrome due to manganese intoxication. Eye movements may help to differentiate parkinsonian syndromes providing insights into which brain networks are affected in the underlying disease, but they have never been systematically studied in EP. Horizontal and vertical eye movements were recorded in 28 EP and compared to 21 Parkinson''s disease (PD) patients, and 27 age- and gender-matched healthy subjects using standardized oculomotor tasks with infrared videooculography. EP patients showed slow and hypometric horizontal saccades, an increased occurrence of square wave jerks, long latencies of vertical antisaccades, a high error rate in the horizontal antisaccade task, and made more errors than controls when pro- and antisaccades were mixed. Based on oculomotor performance, a direct differentiation between EP and PD was possible only by the velocity of horizontal saccades. All remaining metrics were similar between both patient groups. EP patients present extensive oculomotor disturbances probably due to manganese-induced damage to the basal ganglia, reflecting their role in oculomotor system.     

Discriminating physiological from non-physiological interfaces in structures of protein complexes: A community-wide study

Reliably scoring and ranking candidate models of protein complexes and assigning their oligomeric state from the structure of the crystal lattice represent outstanding challenges. A community-wide effort was launched to tackle these challenges. The latest resources on protein complexes and interfaces were exploited to derive a benchmark dataset consisting of 1677 homodimer protein crystal structures, including a balanced mix of physiological and non-physiological complexes. The non-physiological complexes in the benchmark were selected to bury a similar or larger interface area than their physiological counterparts, making it more difficult for scoring functions to differentiate between them. Next, 252 functions for scoring protein-protein interfaces previously developed by 13 groups were collected and evaluated for their ability to discriminate between physiological and non-physiological complexes. A simple consensus score generated using the best performing score of each of the 13 groups, and a cross-validated Random Forest (RF) classifier were created. Both approaches showed excellent performance, with an area under the Receiver Operating Characteristic (ROC) curve of 0.93 and 0.94, respectively, outperforming individual scores developed by different groups. Additionally, AlphaFold2 engines recalled the physiological dimers with significantly higher accuracy than the non-physiological set, lending support to the reliability of our benchmark dataset annotations. Optimizing the combined power of interface scoring functions and evaluating it on challenging benchmark datasets appears to be a promising strategy.     

MicroRNA-24 Suppression of N-Deacetylase/N-Sulfotransferase-1 (NDST1) Reduces Endothelial Cell Responsiveness to Vascular Endothelial Growth Factor A (VEGFA)

Heparan sulfate (HS) proteoglycans, present at the plasma membrane of vascular endothelial cells, bind to the angiogenic growth factor VEGFA to modulate its signaling through VEGFR2. The interactions between VEGFA and proteoglycan co-receptors require sulfated domains in the HS chains. To date, it is essentially unknown how the formation of sulfated protein-binding domains in HS can be regulated by microRNAs. In the present study, we show that microRNA-24 (miR-24) targets NDST1 to reduce HS sulfation and thereby the binding affinity of HS for VEGFA. Elevated levels of miR-24 also resulted in reduced levels of VEGFR2 and blunted VEGFA signaling. Similarly, suppression of NDST1 using siRNA led to a reduction in VEGFR2 expression. Consequently, not only VEGFA binding, but also VEGFR2 protein expression is dependent on NDST1 function. Furthermore, overexpression of miR-24, or siRNA-mediated reduction of NDST1, reduced endothelial cell chemotaxis in response to VEGFA. These findings establish NDST1 as a target of miR-24 and demonstrate how such NDST1 suppression in endothelial cells results in reduced responsiveness to VEGFA.     

Glass-like characteristics of intracellular motion in human cells

The motion in the cytosol of microorganisms such as bacteria and yeast has been observed to undergo a dramatic slowing down upon cell energy depletion. These observations have been interpreted as the motion being “glassy,” but whether this notion is useful also for active, motor-protein-driven transport in eukaryotic cells is less clear. Here, we use fluorescence microscopy of beads in human (HeLa) cells to probe the motion of membrane-surrounded structures that are carried along the cytoskeleton by motor proteins. Evaluating several hallmarks of glassy dynamics, we show that at short length scales, the motion is heterogeneous, is nonergodic, is well described by a model for the displacement distribution in glassy systems, and exhibits a decoupling of the exchange and persistence times. Overall, these results suggest that the short length scale behavior of objects that can be transported actively by motor proteins in human cells shares features with the motion in glassy systems.     

Pancreatic cancer risk in relation to sex,lifestyle factors,and pre-diagnostic anthropometry in the Malmö Diet and Cancer Study

Background

Lifestyle factors may influence the risk of developing pancreatic cancer. Whereas cigarette smoking is an established risk factor, the effects of high alcohol intake and obesity are more uncertain. The aim of the present study was to examine the associations of pre-diagnostic anthropometry, alcohol consumption, and smoking habits with pancreatic cancer risk in a Swedish prospective, population-based cohort, with particular reference to potential sex differences.

Methods

The studied cohort consists of 28,098 participants, including all incident cases of pancreatic cancer, in the Malmö Diet and Cancer Study up until December 31, 2013 (n?=?163). Non-parametric and chi-squared tests were applied to compare the distribution of risk factors between cases and non-cases. Cox regression proportional hazards models were used to estimate the relationship between investigative factors and pancreatic cancer risk. Anthropometric factors included height, weight, body mass index (BMI), waist and hip circumference, waist-hip ratio (WHR), and body fat percentage.

Results

BMI was not a significant risk factor for pancreatic cancer, but a higher WHR was significantly associated with an increased risk in the entire cohort (hazard ratio (HR) 2.36, 95% confidence interval (CI) 1.28–4.35, p for trend?=?0.009). Regular smoking was a significant risk factor among both women (HR 2.62, 95% CI 1.61–4.27) and men (HR 3.57, 95% CI 1.70–7.47), whereas occasional smoking was a significant risk factor only in women (HR 3.29, 95% CI 1.50–7.19). Passive smoking at work for >20 years was significantly associated with an increased risk in the entire cohort (HR 1.73, 95% CI 1.15–2.58) and in women selectively (HR 2.01, 95% CI 1.21–3.31). Alcohol consumption was not a significant risk factor. A significant interaction was found between female sex and age (p?=?0.045), but no other factor, in relation to pancreatic cancer risk.

Conclusions

WHR was the only pre-diagnostic anthropometric factor associated with pancreatic cancer risk, with no sex-related differences. Regular smoking was confirmed as a significant risk factor in both sexes, whereas occasional and passive smoking were significant risk factors only in women. Despite the lack of a significant interaction between smoking and sex in relation with pancreatic cancer risk, potential sex differences should be considered in future epidemiological studies.

     

Human mate choice and the wedding ring effect

Individuals are often restricted to indirect cues when assessing the mate value of a potential partner. Females of some species have been shown to copy each other’s choice; in other words, the probability of a female choosing a particular male increases if he has already been chosen by other females. Recently it has been suggested that mate-choice copying could be an important aspect of human mate choice as well. We tested one of the hypotheses, the so-called wedding ring effect—that women would prefer men who are already engaged or married—in a series of live interactions between men and women. The results show that women do not find men signaling engagement, or being perceived as having a partner, more attractive or higher in socioeconomic status. Furthermore, signs of engagement did not influence the women’s reported willingness to engage in short-term or long-term relationships with the men. Thus, this study casts doubt on some simplified theories of human mate-choice copying, and alternative, more complex scenarios are outlined and discussed. Tobias Uller works on broad issues in evolutionary biology, such as life-history evolution and evolutionary genetics. Christoffer Johansson recently received his Ph.D. with a dissertation on biomechanics of swimming birds. Their collaborative work on humans is focused on mate choice.     

No genetic footprints of the fat mass and obesity associated (FTO) gene in human plasma 1H CPMG NMR metabolic profiles

In this paper it was investigated if any genotypic footprints from the fat mass and obesity associated (FTO) SNP could be found in 600 MHz ¹H CPMG NMR profiles of around 1,000 human plasma samples from healthy Danish twins. The problem was addressed with a combination of univariate and multivariate methods. The NMR data was substantially compressed using principal component analysis or multivariate curve resolution-alternating least squares with focus on chemically meaningful feature selection reflecting the nature of chemical signals in an NMR spectrum. The possible existence of an FTO signature in the plasma samples was investigated at the subject level using supervised multivariate classification in the form of extended canonical variate analysis, classification tree modeling and Lasso (L1) regularized linear logistic regression model (GLMNET). Univariate hypothesis testing of peak intensities was used to explore the genotypic effect on the plasma at the population level. The multivariate classification approaches indicated poor discriminative power of the metabolic profiles whereas univariate hypothesis testing provided seven spectral regions with p < 0.05. Applying false discovery rate control, no reliable markers could be identified, which was confirmed by test set validation. We conclude that it is very unlikely that an FTO-correlated signal can be identified in these ¹H CPMG NMR plasma metabolic profiles and speculate that high-throughput un-targeted genotype-metabolic correlations will in many cases be a difficult path to follow.     

A simple procedure for estimating the false discovery rate

MOTIVATION: The most used criterion in microarray data analysis is nowadays the false discovery rate (FDR). In the framework of estimating procedures based on the marginal distribution of the P-values without any assumption on gene expression changes, estimators of the FDR are necessarily conservatively biased. Indeed, only an upper bound estimate can be obtained for the key quantity pi0, which is the probability for a gene to be unmodified. In this paper, we propose a novel family of estimators for pi0 that allows the calculation of FDR. RESULTS: The very simple method for estimating pi0 called LBE (Location Based Estimator) is presented together with results on its variability. Simulation results indicate that the proposed estimator performs well in finite sample and has the best mean square error in most of the cases as compared with the procedures QVALUE, BUM and SPLOSH. The different procedures are then applied to real datasets. AVAILABILITY: The R function LBE is available at http://ifr69.vjf.inserm.fr/lbe CONTACT: broet@vjf.inserm.fr.