Primary and malignant cholangiocytes undergo CD40 mediated Fas dependent Apoptosis, but are insensitive to direct activation with exogenous fas ligand

Introduction Cholangiocarcinoma is a rare malignancy of the biliary tract, the incidence of which is rising, but the pathogenesis of which remains uncertain. No common genetic defects have been described but it is accepted that chronic inflammation is an important contributing factor. We have shown that primary human cholangiocyte and hepatocyte survival is tightly regulated via co-operative interactions between two tumour necrosis family (TNF) receptor family members; CD40 and Fas (CD95). Functional deficiency of CD154, the ligand for CD40, leads to a failure of clearance of biliary tract infections and a predisposition to cholangiocarcinoma implying a direct link between TNF receptor-mediated apoptosis and the development of cholangiocarcinoma. Aims To determine whether malignant cholangiocytes display defects in CD40 mediated apoptosis. By comparing CD40 and Fas-mediated apoptosis and intracellular signalling in primary human cholangiocytes and three cholangiocyte cell lines. Results Primary cholangiocytes and cholangiocyte cell lines were relatively insensitive to direct Fas-mediated killing with exogenous FasL when compared with Jurkat cells, which readily underwent Fas-mediated apoptosis, but were extremely sensitive to CD154 stimulation. The sensitivity of cells to CD40 activation was similar in magnitude in both primary and malignant cells and was STAT-3 and AP-1 dependent in both. Conclusions 1) Both primary and malignant cholangiocytes are relatively resistant to Fas–mediated killing but show exquisite sensitivity to CD154, suggesting that the CD40 pathway is intact and fully functional in both primary and malignant cholangiocytes 2) The relative insensitivity of cholangiocytes to Fas activation demonstrates the importance of CD40 augmentation of Fas dependent death in these cells. Agonistic therapies which target CD40 and associated intracellular signalling pathways may be effective in promoting apoptosis of malignant cholangiocytes

Whole animal experiments should be more like human randomized controlled trials

Beverly S. Muhlhausler, Frank H. Bloomfield, Matthew W. Gillma

Facial expressions depicting compassionate and critical emotions: the development and validation of a new emotional face stimulus set

Attachment with altruistic others requires the ability to appropriately process affiliative and kind facial cues. Yet there is no stimulus set available to investigate such processes. Here, we developed a stimulus set depicting compassionate and critical facial expressions, and validated its effectiveness using well-established visual-probe methodology. In Study 1, 62 participants rated photographs of actors displaying compassionate/kind and critical faces on strength of emotion type. This produced a new stimulus set based on N = 31 actors, whose facial expressions were reliably distinguished as compassionate, critical and neutral. In Study 2, 70 participants completed a visual-probe task measuring attentional orientation to critical and compassionate/kind faces. This revealed that participants lower in self-criticism demonstrated enhanced attention to compassionate/kind faces whereas those higher in self-criticism showed no bias. To sum, the new stimulus set produced interpretable findings using visual-probe methodology and is the first to include higher order, complex positive affect displays

Functional Diversity and Structural Disorder in the Human Ubiquitination Pathway

The ubiquitin-proteasome system plays a central role in cellular regulation and protein quality control (PQC). The system is built as a pyramid of increasing complexity, with two E1 (ubiquitin activating), few dozen E2 (ubiquitin conjugating) and several hundred E3 (ubiquitin ligase) enzymes. By collecting and analyzing E3 sequences from the KEGG BRITE database and literature, we assembled a coherent dataset of 563 human E3s and analyzed their various physical features. We found an increase in structural disorder of the system with multiple disorder predictors (IUPred - E1: 5.97%, E2: 17.74%, E3: 20.03%). E3s that can bind E2 and substrate simultaneously (single subunit E3, ssE3) have significantly higher disorder (22.98%) than E3s in which E2 binding (multi RING-finger, mRF, 0.62%), scaffolding (6.01%) and substrate binding (adaptor/substrate recognition subunits, 17.33%) functions are separated. In ssE3s, the disorder was localized in the substrate/adaptor binding domains, whereas the E2-binding RING/HECT-domains were structured. To demonstrate the involvement of disorder in E3 function, we applied normal modes and molecular dynamics analyses to show how a disordered and highly flexible linker in human CBL (an E3 that acts as a regulator of several tyrosine kinase-mediated signalling pathways) facilitates long-range conformational changes bringing substrate and E2-binding domains towards each other and thus assisting in ubiquitin transfer. E3s with multiple interaction partners (as evidenced by data in STRING) also possess elevated levels of disorder (hubs, 22.90% vs. non-hubs, 18.36%). Furthermore, a search in PDB uncovered 21 distinct human E3 interactions, in 7 of which the disordered region of E3s undergoes induced folding (or mutual induced folding) in the presence of the partner. In conclusion, our data highlights the primary role of structural disorder in the functions of E3 ligases that manifests itself in the substrate/adaptor binding functions as well as the mechanism of ubiquitin transfer by long-range conformational transitions. © 2013 Bhowmick et al

Human place and response learning: navigation strategy selection, pupil size and gaze behavior.

In this study, we examined the cognitive processes and ocular behavior associated with on-going navigation strategy choice using a route learning paradigm that distinguishes between three different wayfinding strategies: an allocentric place strategy, and the egocentric associative cue and beacon response strategies. Participants approached intersections of a known route from a variety of directions, and were asked to indicate the direction in which the original route continued. Their responses in a subset of these test trials allowed the assessment of strategy choice over the course of six experimental blocks. The behavioral data revealed an initial maladaptive bias for a beacon response strategy, with shifts in favor of the optimal configuration place strategy occurring over the course of the experiment. Response time analysis suggests that the configuration strategy relied on spatial transformations applied to a viewpoint-dependent spatial representation, rather than direct access to an allocentric representation. Furthermore, pupillary measures reflected the employment of place and response strategies throughout the experiment, with increasing use of the more cognitively demanding configuration strategy associated with increases in pupil dilation. During test trials in which known intersections were approached from different directions, visual attention was directed to the landmark encoded during learning as well as the intended movement direction. Interestingly, the encoded landmark did not differ between the three navigation strategies, which is discussed in the context of initial strategy choice and the parallel acquisition of place and response knowledge

Study of Bc+B_c^+ decays to the K+K−π+K^+K^-\pi^+ final state and evidence for the decay Bc+→χc0π+B_c^+\to\chi_{c0}\pi^+

A study of $B_c^+\to K^+K^-\pi^+$ decays is performed for the first time using data corresponding to an integrated luminosity of 3.0 $\mathrm{fb}^{-1}$ collected by the LHCb experiment in $pp$ collisions at centre-of-mass energies of $7$ and $8$ TeV. Evidence for the decay $B_c^+\to\chi_{c0}(\to K^+K^-)\pi^+$ is reported with a significance of 4.0 standard deviations, resulting in the measurement of $\frac{\sigma(B_c^+)}{\sigma(B^+)}\times\mathcal{B}(B_c^+\to\chi_{c0}\pi^+)$ to be $(9.8^{+3.4}_{-3.0}(\mathrm{stat})\pm 0.8(\mathrm{syst}))\times 10^{-6}$. Here $\mathcal{B}$ denotes a branching fraction while $\sigma(B_c^+)$ and $\sigma(B^+)$ are the production cross-sections for $B_c^+$ and $B^+$ mesons. An indication of $\bar b c$ weak annihilation is found for the region $m(K^-\pi^+)<1.834\mathrm{\,Ge\kern -0.1em V\!/}c^2$, with a significance of 2.4 standard deviations.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2016-022.html, link to supplemental material inserted in the reference

Numerical Simulation of a Passive Control of the Flow Around an Aerofoil Using a Flexible, Self Adaptive Flaplet

© 2018 The Author(s) Self-activated feathers are used by almost all birds to adapt their wing characteristics to delay stall or to moderate its adverse effects (e.g., during landing or sudden increase in angle of attack due to gusts). Some of the feathers are believed to pop up as a consequence of flow separation and to interact with the flow and produce beneficial modifications of the unsteady vorticity field. The use of self adaptive flaplets in aircrafts, inspired by birds feathers, requires the understanding of the physical mechanisms leading to the mentioned aerodynamic benefits and the determination of the characteristics of optimal flaps including their size, positioning and ideal fabrication material. In this framework, this numerical study is divided in two parts. Firstly, in a simplified scenario, we determine the main characteristics that render a flap mounted on an aerofoil at high angle of attack able to deliver increased lift and improved aerodynamic efficiency, by varying its length, position and its natural frequency. Later on, a detailed direct numerical simulation analysis is used to understand the origin of the aerodynamic benefits introduced by the flaplet movement induced by the interaction with the flow field. The parametric study that has been carried out, reveals that an optimal flap can deliver a mean lift increase of about 20% on a NACA0020 aerofoil at an incidence of 20 o degrees. The results obtained from the direct numerical simulation of the flow field around the aerofoil equipped with the optimal flap at a chord Reynolds number of 2 × 10 4 shows that the flaplet movement is mainly induced by a cyclic passage of a large recirculation bubble on the aerofoil suction side. In turns, when the flap is pushed downward, the induced plane jet displaces the trailing edge vortices further downstream, away from the wing, moderating the downforce generated by those vortices and regularising the shedding cycle that appears to be much more organised when the optimal flaplet configuration is selected

The Eyes Have It: Sex and Sexual Orientation Differences in Pupil Dilation Patterns

Recent research suggests profound sex and sexual orientation differences in sexual response. These results, however, are based on measures of genital arousal, which have potential limitations such as volunteer bias and differential measures for the sexes. The present study introduces a measure less affected by these limitations. We assessed the pupil dilation of 325 men and women of various sexual orientations to male and female erotic stimuli. Results supported hypotheses. In general, self-reported sexual orientation corresponded with pupil dilation to men and women. Among men, substantial dilation to both sexes was most common in bisexual-identified men. In contrast, among women, substantial dilation to both sexes was most common in heterosexual-identified women. Possible reasons for these differences are discussed. Because the measure of pupil dilation is less invasive than previous measures of sexual response, it allows for studying diverse age and cultural populations, usually not included in sexuality research

Comparing Methods for Analysis of Pupillary Response

Changes in eye-pupil size index a range of cognitive processes. However, variations in the protocols used to analyze such data exist in the psychological literature. This raises the question of whether different approaches to pupillary response data influence the outcome of the analysis. To address this question, four methods of analysis were compared, using pupillary responses to sexually appetitive visual content as example data. These methods comprised analysis of the unadjusted (raw) pupillary response data,z-scored data, percentage-change data, and data transformed by a prestimulus baseline correction. Across two experiments, these methods yielded near-identical outcomes, leading to similar conclusions. This suggests that the range of approaches that are employed in the psychological literature to analyze pupillary response data do not fundamentally influence the outcome of the analysis. However, some systematic carryover effects were observed when a prestimulus baseline correction was applied, whereby dilation effects from an arousing target on one trial still influenced pupil size on the next trial. This indicates that the appropriate application of this analysis might require additional information, such as prior knowledge of the duration of carryover effects