The simulation of action disorganisation in complex activities of daily living

Action selection in everyday goal-directed tasks of moderate complexity is known to be subject to breakdown following extensive frontal brain injury. A model of action selection in such tasks is presented and used to explore three hypotheses concerning the origins of action disorganisation: that it is a consequence of reduced top-down excitation within a hierarchical action schema network coupled with increased bottom-up triggering of schemas from environmental sources, that it is a more general disturbance of schema activation modelled by excessive noise in the schema network, and that it results from a general disturbance of the triggering of schemas by object representations. Results suggest that the action disorganisation syndrome is best accounted for by a general disturbance to schema activation, while altering the balance between top-down and bottom-up activation provides an account of a related disorder - utilisation behaviour. It is further suggested that ideational apraxia (which may result from lesions to left temporoparietal areas and which has similar behavioural consequences to action disorganisation syndrome on tasks of moderate complexity) is a consequence of a generalised disturbance of the triggering of schemas by object representations. Several predictions regarding differences between action disorganisation syndrome and ideational apraxia that follow from this interpretation are detailed

A novel class of microRNA-recognition elements that function only within open reading frames.

MicroRNAs (miRNAs) are well known to target 3' untranslated regions (3' UTRs) in mRNAs, thereby silencing gene expression at the post-transcriptional level. Multiple reports have also indicated the ability of miRNAs to target protein-coding sequences (CDS); however, miRNAs have been generally believed to function through similar mechanisms regardless of the locations of their sites of action. Here, we report a class of miRNA-recognition elements (MREs) that function exclusively in CDS regions. Through functional and mechanistic characterization of these 'unusual' MREs, we demonstrate that CDS-targeted miRNAs require extensive base-pairing at the 3' side rather than the 5' seed; cause gene silencing in an Argonaute-dependent but GW182-independent manner; and repress translation by inducing transient ribosome stalling instead of mRNA destabilization. These findings reveal distinct mechanisms and functional consequences of miRNAs that target CDS versus the 3' UTR and suggest that CDS-targeted miRNAs may use a translational quality-control-related mechanism to regulate translation in mammalian cells

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

Salience-based selection: attentional capture by distractors less salient than the target

Current accounts of attentional capture predict the most salient stimulus to be invariably selected first. However, existing salience and visual search models assume noise in the map computation or selection process. Consequently, they predict the first selection to be stochastically dependent on salience, implying that attention could even be captured first by the second most salient (instead of the most salient) stimulus in the field. Yet, capture by less salient distractors has not been reported and salience-based selection accounts claim that the distractor has to be more salient in order to capture attention. We tested this prediction using an empirical and modeling approach of the visual search distractor paradigm. For the empirical part, we manipulated salience of target and distractor parametrically and measured reaction time interference when a distractor was present compared to absent. Reaction time interference was strongly correlated with distractor salience relative to the target. Moreover, even distractors less salient than the target captured attention, as measured by reaction time interference and oculomotor capture. In the modeling part, we simulated first selection in the distractor paradigm using behavioral measures of salience and considering the time course of selection including noise. We were able to replicate the result pattern we obtained in the empirical part. We conclude that each salience value follows a specific selection time distribution and attentional capture occurs when the selection time distributions of target and distractor overlap. Hence, selection is stochastic in nature and attentional capture occurs with a certain probability depending on relative salience

Ablation of the renal stroma defines its critical role in nephron progenitor and vasculature patterning

The renal stroma is an embryonic cell population located in the cortex that provides a structural framework as well as a source of endothelial progenitors for the developing kidney. The exact role of the renal stroma in normal kidney development hasn't been clearly defined. However, previous studies have shown that the genetic deletion of Foxd1, a renal stroma specific gene, leads to severe kidney malformations confirming the importance of stroma in normal kidney development. This study further investigates the role of renal stroma by ablating Foxd1-derived stroma cells themselves and observing the response of the remaining cell populations. A Foxd1cre (renal stroma specific) mouse was crossed with a diphtheria toxin mouse (DTA) to specifically induce apoptosis in stromal cells. Histological examination of kidneys at embryonic day 13.5-18.5 showed a lack of stromal tissue, mispatterning of renal structures, and dysplastic and/or fused horseshoe kidneys. Immunofluorescence staining of nephron progenitors, vasculature, ureteric epithelium, differentiated nephron progenitors, and vascular supportive cells revealed that mutants had thickened nephron progenitor caps, cortical regions devoid of nephron progenitors, aberrant vessel patterning and thickening, ureteric branching defects and migration of differentiated nephron structures into the medulla. The similarities between the renal deformities caused by Foxd1 genetic knockout and Foxd1DTA mouse models reveal the importance of Foxd1 in mediating and maintaining the functional integrity of the renal stroma. © 2014 Hum et al

The Hubble Constant

I review the current state of determinations of the Hubble constant, which gives the length scale of the Universe by relating the expansion velocity of objects to their distance. There are two broad categories of measurements. The first uses individual astrophysical objects which have some property that allows their intrinsic luminosity or size to be determined, or allows the determination of their distance by geometric means. The second category comprises the use of all-sky cosmic microwave background, or correlations between large samples of galaxies, to determine information about the geometry of the Universe and hence the Hubble constant, typically in a combination with other cosmological parameters. Many, but not all, object-based measurements give $H_0$ values of around 72-74km/s/Mpc , with typical errors of 2-3km/s/Mpc. This is in mild discrepancy with CMB-based measurements, in particular those from the Planck satellite, which give values of 67-68km/s/Mpc and typical errors of 1-2km/s/Mpc. The size of the remaining systematics indicate that accuracy rather than precision is the remaining problem in a good determination of the Hubble constant. Whether a discrepancy exists, and whether new physics is needed to resolve it, depends on details of the systematics of the object-based methods, and also on the assumptions about other cosmological parameters and which datasets are combined in the case of the all-sky methods.Comment: Extensively revised and updated since the 2007 version: accepted by Living Reviews in Relativity as a major (2014) update of LRR 10, 4, 200

Qualia: The Geometry of Integrated Information

According to the integrated information theory, the quantity of consciousness is the amount of integrated information generated by a complex of elements, and the quality of experience is specified by the informational relationships it generates. This paper outlines a framework for characterizing the informational relationships generated by such systems. Qualia space (Q) is a space having an axis for each possible state (activity pattern) of a complex. Within Q, each submechanism specifies a point corresponding to a repertoire of system states. Arrows between repertoires in Q define informational relationships. Together, these arrows specify a quale—a shape that completely and univocally characterizes the quality of a conscious experience. Φ— the height of this shape—is the quantity of consciousness associated with the experience. Entanglement measures how irreducible informational relationships are to their component relationships, specifying concepts and modes. Several corollaries follow from these premises. The quale is determined by both the mechanism and state of the system. Thus, two different systems having identical activity patterns may generate different qualia. Conversely, the same quale may be generated by two systems that differ in both activity and connectivity. Both active and inactive elements specify a quale, but elements that are inactivated do not. Also, the activation of an element affects experience by changing the shape of the quale. The subdivision of experience into modalities and submodalities corresponds to subshapes in Q. In principle, different aspects of experience may be classified as different shapes in Q, and the similarity between experiences reduces to similarities between shapes. Finally, specific qualities, such as the “redness” of red, while generated by a local mechanism, cannot be reduced to it, but require considering the entire quale. Ultimately, the present framework may offer a principled way for translating qualitative properties of experience into mathematics

Measured and Simulated Nitrous Oxide Emissions from Ryegrass- and Ryegrass/White Clover-Based Grasslands in a Moist Temperate Climate

There is uncertainty about the potential reduction of soil nitrous oxide (N2O) emission when fertilizer nitrogen (FN) is partially or completely replaced by biological N fixation (BNF) in temperate grassland. The objectives of this study were to 1) investigate the changes in N2O emissions when BNF is used to replace FN in permanent grassland, and 2) evaluate the applicability of the process-based model DNDC to simulate N2O emissions from Irish grasslands. Three grazing treatments were: (i) ryegrass (Lolium perenne) grasslands receiving 226 kg FN ha−1 yr−1 (GG+FN), (ii) ryegrass/white clover (Trifolium repens) grasslands receiving 58 kg FN ha−1 yr−1 (GWC+FN) applied in spring, and (iii) ryegrass/white clover grasslands receiving no FN (GWC-FN). Two background treatments, un-grazed swards with ryegrass only (G–B) or ryegrass/white clover (WC–B), did not receive slurry or FN and the herbage was harvested by mowing. There was no significant difference in annual N2O emissions between G–B (2.38±0.12 kg N ha−1 yr−1 (mean±SE)) and WC-B (2.45±0.85 kg N ha−1 yr−1), indicating that N2O emission due to BNF itself and clover residual decomposition from permanent ryegrass/clover grassland was negligible. N2O emissions were 7.82±1.67, 6.35±1.14 and 6.54±1.70 kg N ha−1 yr−1, respectively, from GG+FN, GWC+FN and GWC-FN. N2O fluxes simulated by DNDC agreed well with the measured values with significant correlation between simulated and measured daily fluxes for the three grazing treatments, but the simulation did not agree very well for the background treatments. DNDC overestimated annual emission by 61% for GG+FN, and underestimated by 45% for GWC-FN, but simulated very well for GWC+FN. Both the measured and simulated results supported that there was a clear reduction of N2O emissions when FN was replaced by BNF

Cervical radiculopathy: Study protocol of a randomised clinical trial evaluating the effect of mobilisations and exercises targeting the opening of intervertebral foramen [NCT01500044]

<p>Abstract</p> <p>Background</p> <p>Cervical radiculopathy is a common form of neck pain and has been shown to lead to severe disability. Clinical rehabilitation approaches for cervical radiculopathies commonly include exercise and manual therapy interventions targeting the opening of intervertebral foramen, but evidence regarding their effectiveness is scarce. The primary objective of this randomised clinical trial is to compare, in terms of pain and disability, a rehabilitation program targeting the opening of intervertebral foramen to a conventional rehabilitation program, for patients presenting acute or subacute cervical radiculopathies. The hypothesis is that the rehabilitation program targeting the opening of intervertebral foramen will be significantly more effective in reducing pain and disability than the conventional rehabilitation program.</p> <p>Methods/Design</p> <p>This study is a double-blind (participants and evaluators blinded) randomised clinical trial that will allow the comparison of patients with a cervical radiculopathy randomly assigned to one of two groups: one group will receive a 4-week rehabilitation program targeting the opening of intervertebral foramen, and the second group will receive a 4-week conventional rehabilitation program. Thirty-six subjects with cervical radiculopathy will be recruited from participating medical and physiotherapy clinics and will be evaluated at baseline, at the end of the 4-week program and four weeks following the end of the program. The primary outcome measure will be the validated Neck Disability Index questionnaire. Secondary outcome measures will include the short version of the Disabilities of the Arm, Shoulder and Hand questionnaire, a numerical pain rating scale, cervicothoracic mobility and patients' perceived global rating of change. During the 4-week rehabilitation program, each participant will take part in eight physiotherapy treatment sessions (2 session/week) and will perform a home exercise program. A mixed-model, 2-way ANOVA will be used to analyze the effects of the rehabilitation programs.</p> <p>Discussion</p> <p>Control trials are needed to define ideal intervention approaches in rehabilitation for this population. This randomised clinical trial will be the first study that directly compares a rehabilitation program targeting the opening of intervertebral foramen to a conventional rehabilitation program for patients with cervical radiculopathy. The results of this study may help to establish best clinical practice guidelines for this patient population.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01500044">NCT01500044</a></p