Piperidinols that show anti-tubercular activity as inhibitors of arylamine N-acetyltransferase: an essential enzyme for mycobacterial survival inside macrophages

Latent M. tuberculosis infection presents one of the major obstacles in the global eradication of tuberculosis (TB). Cholesterol plays a critical role in the persistence of M. tuberculosis within the macrophage during latent infection. Catabolism of cholesterol contributes to the pool of propionyl-CoA, a precursor that is incorporated into cell-wall lipids. Arylamine N-acetyltransferase (NAT) is encoded within a gene cluster that is involved in the cholesterol sterol-ring degradation and is essential for intracellular survival. The ability of the NAT from M. tuberculosis (TBNAT) to utilise propionyl-CoA links it to the cholesterol-catabolism pathway. Deleting the nat gene or inhibiting the NAT enzyme prevents intracellular survival and results in depletion of cell-wall lipids. TBNAT has been investigated as a potential target for TB therapies. From a previous high-throughput screen, 3-benzoyl-4-phenyl-1-methylpiperidinol was identified as a selective inhibitor of prokaryotic NAT that exhibited antimycobacterial activity. The compound resulted in time-dependent irreversible inhibition of the NAT activity when tested against NAT from M. marinum (MMNAT). To further evaluate the antimycobacterial activity and the NAT inhibition of this compound, four piperidinol analogues were tested. All five compounds exert potent antimycobacterial activity against M. tuberculosis with MIC values of 2.3-16.9 µM. Treatment of the MMNAT enzyme with this set of inhibitors resulted in an irreversible time-dependent inhibition of NAT activity. Here we investigate the mechanism of NAT inhibition by studying protein-ligand interactions using mass spectrometry in combination with enzyme analysis and structure determination. We propose a covalent mechanism of NAT inhibition that involves the formation of a reactive intermediate and selective cysteine residue modification. These piperidinols present a unique class of antimycobacterial compounds that have a novel mode of action different from known anti-tubercular drugs

Cytogerontology since 1881: A reappraisal of August Weismann and a review of modern progress

Cytogerontology, the science of cellular ageing, originated in 1881 with the prediction by August Weismann that the somatic cells of higher animals have limited division potential. Weismann's prediction was derived by considering the role of natural selection in regulating the duration of an organism's life. For various reasons, Weismann's ideas on ageing fell into neglect following his death in 1914, and cytogerontology has only reappeared as a major research area following the demonstration by Hayflick and Moorhead in the early 1960s that diploid human fibroblasts are restricted to a finite number of divisions in vitro. In this review we give a detailed account of Weismann's theory, and we reveal that his ideas were both more extensive in their scope and more pertinent to current research than is generally recognised. We also appraise the progress which has been made over the past hundred years in investigating the causes of ageing, with particular emphasis being given to (i) the evolution of ageing, and (ii) ageing at the cellular level. We critically assess the current state of knowledge in these areas and recommend a series of points as primary targets for future research

To respond or not to respond - a personal perspective of intestinal tolerance

For many years, the intestine was one of the poor relations of the immunology world, being a realm inhabited mostly by specialists and those interested in unusual phenomena. However, this has changed dramatically in recent years with the realization of how important the microbiota is in shaping immune function throughout the body, and almost every major immunology institution now includes the intestine as an area of interest. One of the most important aspects of the intestinal immune system is how it discriminates carefully between harmless and harmful antigens, in particular, its ability to generate active tolerance to materials such as commensal bacteria and food proteins. This phenomenon has been recognized for more than 100 years, and it is essential for preventing inflammatory disease in the intestine, but its basis remains enigmatic. Here, I discuss the progress that has been made in understanding oral tolerance during my 40 years in the field and highlight the topics that will be the focus of future research

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

Comparative Phylogeography in a Specific and Obligate Pollination Antagonism

In specific and obligate interactions the nature and abundance of a given species can have important effects on the survival and population dynamics of associated organisms. In a phylogeographic framework, we therefore expect that the fates of organisms interacting specifically are also tightly interrelated. Here we investigate such a scenario by analyzing the genetic structures of species interacting in an obligate plant-insect pollination lure-and-trap antagonism, involving Arum maculatum (Araceae) and its specific psychodid (Diptera) visitors Psychoda phalaenoides and Psycha grisescens. Because the interaction is asymmetric (i.e., only the plant depends on the insect), we expect the genetic structure of the plant to be related with the historical pollinator availability, yielding incongruent phylogeographic patterns between the interacting organisms

A New Integrated Variable Based on Thermometry, Actimetry and Body Position (TAP) to Evaluate Circadian System Status in Humans

The disruption of the circadian system in humans has been associated with the development of chronic illnesses and the worsening of pre-existing pathologies. Therefore, the assessment of human circadian system function under free living conditions using non-invasive techniques needs further research. Traditionally, overt rhythms such as activity and body temperature have been analyzed separately; however, a comprehensive index could reduce individual recording artifacts. Thus, a new variable (TAP), based on the integrated analysis of three simultaneous recordings: skin wrist temperature (T), motor activity (A) and body position (P) has been developed. Furthermore, we also tested the reliability of a single numerical index, the Circadian Function Index (CFI), to determine the circadian robustness. An actimeter and a temperature sensor were placed on the arm and wrist of the non-dominant hand, respectively, of 49 healthy young volunteers for a period of one week. T, A and P values were normalized for each subject. A non-parametric analysis was applied to both TAP and the separate variables to calculate their interdaily stability, intradaily variability and relative amplitude, and these values were then used for the CFI calculation. Modeling analyses were performed in order to determine TAP and CFI reliability. Each variable (T, A, P or TAP) was independently correlated with rest-activity logs kept by the volunteers. The highest correlation (r = −0.993, p<0.0001), along with highest specificity (0.870), sensitivity (0.740) and accuracy (0.904), were obtained when rest-activity records were compared to TAP. Furthermore, the CFI proved to be very sensitive to changes in circadian robustness. Our results demonstrate that the integrated TAP variable and the CFI calculation are powerful methods to assess circadian system status, improving sensitivity, specificity and accuracy in differentiating activity from rest over the analysis of wrist temperature, body position or activity alone

On the Role of Attention in Binocular Rivalry: Electrophysiological Evidence

During binocular rivalry visual consciousness fluctuates between two dissimilar monocular images. We investigated the role of attention in this phenomenon by comparing event-related potentials (ERPs) when binocular-rivalry stimuli were attended with when they were unattended. Stimuli were dichoptic, orthogonal gratings that yielded binocular rivalry and dioptic, identically oriented gratings that yielded binocular fusion. Events were all possible orthogonal changes in orientation of one or both gratings. We had two attention conditions: In the attend-to-grating condition, participants had to report changes in perceived orientation, focussing their attention on the gratings. In the attend-to-fixation condition participants had to report changes in a central fixation target, taking attention away from the gratings. We found, surprisingly, that attending to rival gratings yielded a smaller ERP component (the N1, from 160–210 ms) than attending to the fixation target. To explain this paradoxical effect of attention, we propose that rivalry occurs in the attend-to-fixation condition (we found an ERP signature of rivalry in the form of a sustained negativity from 210–300 ms) but that the mechanism processing the stimulus changes is more adapted in the attend-to-grating condition than in the attend-to-fixation condition. This is consistent with the theory that adaptation gives rise to changes of visual consciousness during binocular rivalry

On the Origin and Trigger of the Notothenioid Adaptive Radiation

Adaptive radiation is usually triggered by ecological opportunity, arising through (i) the colonization of a new habitat by its progenitor; (ii) the extinction of competitors; or (iii) the emergence of an evolutionary key innovation in the ancestral lineage. Support for the key innovation hypothesis is scarce, however, even in textbook examples of adaptive radiation. Antifreeze glycoproteins (AFGPs) have been proposed as putative key innovation for the adaptive radiation of notothenioid fishes in the ice-cold waters of Antarctica. A crucial prerequisite for this assumption is the concurrence of the notothenioid radiation with the onset of Antarctic sea ice conditions. Here, we use a fossil-calibrated multi-marker phylogeny of nothothenioid and related acanthomorph fishes to date AFGP emergence and the notothenioid radiation. All time-constraints are cross-validated to assess their reliability resulting in six powerful calibration points. We find that the notothenioid radiation began near the Oligocene-Miocene transition, which coincides with the increasing presence of Antarctic sea ice. Divergence dates of notothenioids are thus consistent with the key innovation hypothesis of AFGP. Early notothenioid divergences are furthermore congruent with vicariant speciation and the breakup of Gondwana