Depth perception not found in human observers for static or dynamic anti-correlated random dot stereograms

One of the greatest challenges in visual neuroscience is that of linking neural activity with perceptual experience. In the case of binocular depth perception, important insights have been achieved through comparing neural responses and the perception of depth, for carefully selected stimuli. One of the most important types of stimulus that has been used here is the anti-correlated random dot stereogram (ACRDS). In these stimuli, the contrast polarity of one half of a stereoscopic image is reversed. While neurons in cortical area V1 respond reliably to the binocular disparities in ACRDS, they do not create a sensation of depth. This discrepancy has been used to argue that depth perception must rely on neural activity elsewhere in the brain. Currently, the psychophysical results on which this argument rests are not clear-cut. While it is generally assumed that ACRDS do not support the perception of depth, some studies have reported that some people, some of the time, perceive depth in some types of these stimuli. Given the importance of these results for understanding the neural correlates of stereopsis, we studied depth perception in ACRDS using a large number of observers, in order to provide an unambiguous conclusion about the extent to which these stimuli support the perception of depth. We presented observers with random dot stereograms in which correlated dots were presented in a surrounding annulus and correlated or anti-correlated dots were presented in a central circular region. While observers could reliably report the depth of the central region for correlated stimuli, we found no evidence for depth perception in static or dynamic anti-correlated stimuli. Confidence ratings for stereoscopic perception were uniformly low for anti-correlated stimuli, but showed normal variation with disparity for correlated stimuli. These results establish that the inability of observers to perceive depth in ACRDS is a robust phenomenon

Have the log-population processes stationary and independent increments? Empirical evidence for Italy, Spain and the USA along more than a century.

We review the classical Gibrat’s process for the population of city sizes. In particular, we are interested in whether the log-population process has stationary and independent (Gibrat’s Law for cities) increments. We have tested these characteristics for the case of the municipalities of Italy and Spain and the places of USA for a time span of more than one century. The results are clear: stationarity and independence are empirically rejected by standard tests. These results open theoretically the way for the observance of other city size distributions other than the lognormal and the double Pareto lognormal, something that in fact has already happened in the literature

Rhomboid family member 2 regulates cytoskeletal stress-associated Keratin 16.

Keratin 16 (K16) is a cytoskeletal scaffolding protein highly expressed at pressure-bearing sites of the mammalian footpad. It can be induced in hyperproliferative states such as wound healing, inflammation and cancer. Here we show that the inactive rhomboid protease RHBDF2 (iRHOM2) regulates thickening of the footpad epidermis through its interaction with K16. K16 expression is absent in the thinned footpads of irhom2-/- mice compared with irhom2+/+mice, due to reduced keratinocyte proliferation. Gain-of-function mutations in iRHOM2 underlie Tylosis with oesophageal cancer (TOC), characterized by palmoplantar thickening, upregulate K16 with robust downregulation of its type II keratin binding partner, K6. By orchestrating the remodelling and turnover of K16, and uncoupling it from K6, iRHOM2 regulates the epithelial response to physical stress. These findings contribute to our understanding of the molecular mechanisms underlying hyperproliferation of the palmoplantar epidermis in both physiological and disease states, and how this 'stress' keratin is regulated

Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms

Research on iRHOM2 in the Kelsell group is funded by an MRC project grant, a MRC Clinical Fellowship (to TM) and a Cancer Research UK program grant

Bcl-2 protein family: Implications in vascular apoptosis and atherosclerosis

Apoptosis has been recognized as a central component in the pathogenesis of atherosclerosis, in addition to the other human pathologies such as cancer and diabetes. The pathophysiology of atherosclerosis is complex, involving both apoptosis and proliferation at different phases of its progression. Oxidative modification of lipids and inflammation differentially regulate the apoptotic and proliferative responses of vascular cells during progression of the atherosclerotic lesion. Bcl-2 proteins act as the major regulators of extrinsic and intrinsic apoptosis signalling pathways and more recently it has become evident that they mediate the apoptotic response of vascular cells in response to oxidation and inflammation either in a provocative or an inhibitory mode of action. Here we address Bcl-2 proteins as major therapeutic targets for the treatment of atherosclerosis and underscore the need for the novel preventive and therapeutic interventions against atherosclerosis, which should be designed in the light of molecular mechanisms regulating apoptosis of vascular cells in atherosclerotic lesions

Exosome-Related Multi-Pass Transmembrane Protein TSAP6 Is a Target of Rhomboid Protease RHBDD1-Induced Proteolysis

We have previously reported that rhomboid domain containing 1 (RHBDD1), a mammalian rhomboid protease highly expressed in the testis, can cleave the Bcl-2 protein Bik. In this study, we identified a multi-pass transmembrane protein, tumor suppressor activated pathway-6 (TSAP6) as a potential substrate of RHBDD1. RHBDD1 was found to induce the proteolysis of TSAP6 in a dose- and activity-dependent manner. The cleavage of TSAP6 was not restricted to its glycosylated form and occurred in three different regions. In addition, mass spectrometry and mutagenesis analyses both indicated that the major cleavage site laid in the C-terminal of the third transmembrane domain of TSAP6. A somatic cell knock-in approach was used to genetically inactivate the endogenous RHBDD1 in HCT116 and RKO colon cancer cells. Exosome secretion was significantly elevated when RHBDD1 was inactivated in the two cells lines. The increased exosome secretion was verfied through the detection of certain exosomal components, including Tsg101, Tf-R, FasL and Trail. In addition, the elevation of exosome secretion by RHBDD1 inactivation was reduced when TSAP6 was knocked down, indicating that the role of RHBDD1 in regulating exosomal trafficking is very likely to be TSAP6-dependent. We found that the increase in FasL and Trail increased exosome-induced apoptosis in Jurkat cells. Taken together, our findings suggest that RHBDD1 is involved in the regulation of a nonclassical exosomal secretion pathway through the restriction of TSAP6

Synergistic induction of cell death in liver tumor cells by TRAIL and chemotherapeutic drugs via the BH3-only proteins Bim and Bid

Although death receptors and chemotherapeutic drugs activate distinct apoptosis signaling cascades, crosstalk between the extrinsic and intrinsic apoptosis pathway has been recognized as an important amplification mechanism. Best known in this regard is the amplification of the Fas (CD95) signal in hepatocytes via caspase 8-mediated cleavage of Bid and activation of the mitochondrial apoptosis pathway. Recent evidence, however, indicates that activation of other BH3-only proteins may also be critical for the crosstalk between death receptors and mitochondrial triggers. In this study, we show that TNF-related apoptosis-inducing ligand (TRAIL) and chemotherapeutic drugs synergistically induce apoptosis in various transformed and untransformed liver-derived cell lines, as well as in primary human hepatocytes. Both, preincubation with TRAIL as well as chemotherapeutic drugs could sensitize cells for apoptosis induction by the other respective trigger. TRAIL induced a strong and long lasting activation of Jun kinase, and activation of the BH3-only protein Bim. Consequently, synergistic induction of apoptosis by TRAIL and chemotherapeutic drugs was dependent on Jun kinase activity, and expression of Bim and Bid. These findings confirm a previously defined role of TRAIL and Bim in the regulation of hepatocyte apoptosis, and demonstrate that the TRAIL–Jun kinase–Bim axis is a major and important apoptosis amplification pathway in primary hepatocytes and liver tumor cells