Genes under positive selection in Escherichia coli

We used a comparative genomics approach to identify genes that are under positive selection in six strains of Escherichia coli and Shigella flexneri, including five strains that are human pathogens. We find that positive selection targets a wide range of different functions in the E. coli genome, including cell surface proteins such as beta barrel porins, presumably because of the involvement of these genes in evolutionary arms races with other bacteria, phages, and/or the host immune system. Structural mapping of positively selected sites on trans-membrane beta barrel porins reveals that the residues under positive selection occur almost exclusively in the extracellular region of the proteins that are enriched with sites known to be targets of phages, colicins, or the host immune system. More surprisingly, we also find a number of other categories of genes that show very strong evidence for positive selection, such as the enigmatic rhs elements and transposases. Based on structural evidence, we hypothesize that the selection acting on transposases is related to the genomic conflict between transposable elements and the host genome.     

The effect of stimulus duty cycle and "off" duration on BOLD response linearity

An ongoing question in functional MRI is precisely how measured signal changes relate to neuronal activity. While this question has been probed using animal models and electrophysiologic measures of neuronal activity, it has also been probed by examining, in humans, the spatial location, magnitude, and temporal dynamics of signal changes to well understood stimuli. With regard to dynamics, several earlier studies have revealed a larger than expected response to brief stimuli, hypothesized to result from nonlinearities in either the hemodynamics or the neuronal activity. In this study, we investigate the linearity of the increase in blood oxygenation level dependent (BOLD) contrast as a function of stimulus duty cycle, as well as the linearity of the decrease in BOLD as a function stimulus "off" duration. These findings not only shed further light on the mechanisms behind BOLD contrast but also give practical information as to what to keep in mind when performing and interpreting event related fMRI experiments. These experiments demonstrated: a) the BOLD signal decrease, on stimulus cessation, was smaller than predicted by a linear system--opposite to what has been reported in the literature associated with a signal increase, and b) the deconvolved event-related BOLD signal is highly dependent on duty cycle (the fraction of time activated vs. non-activated), Several potential mechanisms explaining these dynamics are discussed and modeled. We find that the experimental results are most consistent with a nonlinear neuronal response, but do not rule out significant effects of nonlinear hemodynamic factors, in particular the nonlinear relationship between oxygen extraction fraction and blood flow.     

Variability of quantitative coronary angiography: an evaluation of on-site versus core laboratory analysis

To assess the validity of locally performed off-line quantitative coronary angiography (QCA) measurement in clinical trials, we carried out a comparative study between on-site QCA analysis and analysis performed at an independent external core laboratory. One local operator analyzed the pre, post and follow-up angiograms of 116 patients participating in the Stenting in Small Coronary Arteries Study (SISCA) prior to final QCA analysis in the core laboratory. The mean values of the reference diameter (RD), minimal lumen diameter (MLD) and diameter stenosis (DS) showed acceptable agreement between study site and core laboratory. However, on the level of individuals the interobserver differences were large, affecting the outcome of restenosis rate significantly, and in a such way that the conclusions in the SISCA trial might have come out differently if a core laboratory had not been used. This emphasizes the importance of using independent core laboratories in coronary interventional trials.     

Ejection fraction in left bundle branch block is disproportionately reduced in relation to amount of myocardial scar

Introduction

The relationship between left ventricular (LV) ejection fraction (EF) and LV myocardial scar can identify potentially reversible causes of LV dysfunction. Left bundle branch block (LBBB) alters the electrical and mechanical activation of the LV. We hypothesized that the relationship between LVEF and scar extent is different in LBBB compared to controls.

Blocking protein quality control to counter hereditary cancers

Inhibitors of molecular chaperones and the ubiquitin‐proteasome system have already been clinically implemented to counter certain cancers, including multiple myeloma and mantle cell lymphoma. The efficacy of this treatment relies on genomic alterations in cancer cells causing a proteostatic imbalance, which makes them more dependent on protein quality control (PQC) mechanisms than normal cells. Accordingly, blocking PQC, e.g. by proteasome inhibitors, may cause a lethal proteotoxic crisis in cancer cells, while leaving normal cells unaffected. Evidence, however, suggests that the PQC system operates by following a better‐safe‐than‐sorry principle and is thus prone to target proteins that are only slightly structurally perturbed, but still functional. Accordingly, implementing PQC inhibitors may also, through an entirely different mechanism, hold potential for other cancers. Several inherited cancer susceptibility syndromes, such as Lynch syndrome and von Hippel‐Lindau disease, are caused by missense mutations in tumor suppressor genes, and in some cases, the resulting amino acid substitutions in the encoded proteins cause the cellular PQC system to target them for degradation, although they may still retain function. As a consequence of this over‐meticulous PQC mechanism, the cell may end up with an insufficient amount of the abnormal, but functional, protein, which in turn leads to a loss‐of‐function phenotype and manifestation of the disease. Increasing the amounts of such proteins by stabilizing with chemical chaperones, or by targeting molecular chaperones or the ubiquitin‐proteasome system, may thus avert or delay the disease onset. Here, we review the potential of targeting the PQC system in hereditary cancer susceptibility syndromes.     

Default‐mode network functional connectivity is closely related to metabolic activity

Over the last decade, the brain's default‐mode network (DMN) and its function has attracted a lot of attention in the field of neuroscience. However, the exact underlying mechanisms of DMN functional connectivity, or more specifically, the blood‐oxygen level‐dependent (BOLD) signal, are still incompletely understood. In the present study, we combined 2‐deoxy‐2‐[¹⁸F]fluoroglucose positron emission tomography (FDG‐PET), proton magnetic resonance spectroscopy (¹H‐MRS), and resting‐state functional magnetic resonance imaging (rs‐fMRI) to investigate more directly the association between local glucose consumption, local glutamatergic neurotransmission and DMN functional connectivity during rest. The results of the correlation analyzes using the dorsal posterior cingulate cortex (dPCC) as seed region showed spatial similarities between fluctuations in FDG‐uptake and fluctuations in BOLD signal. More specifically, in both modalities the same DMN areas in the inferior parietal lobe, angular gyrus, precuneus, middle, and medial frontal gyrus were positively correlated with the dPCC. Furthermore, we could demonstrate that local glucose consumption in the medial frontal gyrus, PCC and left angular gyrus was associated with functional connectivity within the DMN. We did not, however, find a relationship between glutamatergic neurotransmission and functional connectivity. In line with very recent findings, our results lend further support for a close association between local metabolic activity and functional connectivity and provide further insights towards a better understanding of the underlying mechanism of the BOLD signal. Hum Brain Mapp 36:2027–2038, 2015. © 2015 Wiley Periodicals, Inc.