Mechanisms of Cognitive Impairment in Cerebral Small Vessel Disease: Multimodal MRI Results from the St George's Cognition and Neuroimaging in Stroke (SCANS) Study.

Cerebral small vessel disease (SVD) is a common cause of vascular cognitive impairment. A number of disease features can be assessed on MRI including lacunar infarcts, T2 lesion volume, brain atrophy, and cerebral microbleeds. In addition, diffusion tensor imaging (DTI) is sensitive to disruption of white matter ultrastructure, and recently it has been suggested that additional information on the pattern of damage may be obtained from axial diffusivity, a proposed marker of axonal damage, and radial diffusivity, an indicator of demyelination. We determined the contribution of these whole brain MRI markers to cognitive impairment in SVD. Consecutive patients with lacunar stroke and confluent leukoaraiosis were recruited into the ongoing SCANS study of cognitive impairment in SVD (n = 115), and underwent neuropsychological assessment and multimodal MRI. SVD subjects displayed poor performance on tests of executive function and processing speed. In the SVD group brain volume was lower, white matter hyperintensity volume higher and all diffusion characteristics differed significantly from control subjects (n = 50). On multi-predictor analysis independent predictors of executive function in SVD were lacunar infarct count and diffusivity of normal appearing white matter on DTI. Independent predictors of processing speed were lacunar infarct count and brain atrophy. Radial diffusivity was a stronger DTI predictor than axial diffusivity, suggesting ischaemic demyelination, seen neuropathologically in SVD, may be an important predictor of cognitive impairment in SVD. Our study provides information on the mechanism of cognitive impairment in SVD

The plight of the sense-making ape

This is a selective review of the published literature on object-choice tasks, where participants use directional cues to find hidden objects. This literature comprises the efforts of researchers to make sense of the sense-making capacities of our nearest living relatives. This chapter is written to highlight some nonsensical conclusions that frequently emerge from this research. The data suggest that when apes are given approximately the same sense-making opportunities as we provide our children, then they will easily make sense of our social signals. The ubiquity of nonsensical contemporary scientific claims to the effect that humans are essentially--or inherently--more capable than other great apes in the understanding of simple directional cues is, itself, a testament to the power of preconceived ideas on human perception

Brief report: a comparison of the preference for viewing social and non-social movies in typical and autistic adolescents

The recently proposed Social Motivation theory (Chevallier et al., Trends in cognitive sciences 16(4):231–239, 2012) suggests that social difficulties in Autism Spectrum Condition (ASC) might be caused by a difference in the motivation to engage with other people. Here we compared adolescents with (N = 31) and without (N = 37) ASC on the Choose-a-Movie paradigm that measures the social seeking. The results showed a preference for viewing objects over smiling faces in ASC, which is in line with the theory of low social motivation. However, typical adolescents did not show any stimuli preferences, raising questions about developmental changes in social motivation. Age was found to play a significant role in moderating the choice behaviour of the participants. We discuss the implications of these findings in detail

Child categorization

Categorization is a process that spans all of development, beginning in earliest infancy yet changing as children's knowledge and cognitive skills develop. In this review article, we address three core issues regarding childhood categorization. First, we discuss the extent to which early categories are rooted in perceptual similarity versus knowledge-enriched theories. We argue for a composite perspective in which categories are steeped in commonsense theories from a young age but also are informed by low-level similarity and associative learning cues. Second, we examine the role of language in early categorization. We review evidence to suggest that language is a powerful means of expressing, communicating, shaping, and supporting category knowledge. Finally, we consider categories in context. We discuss sources of variability and flexibility in children's categories, as well as the ways in which children's categories are used within larger knowledge systems (e.g., to form analogies, make inferences, or construct theories). Categorization is a process that is intrinsically tied to nearly all aspects of cognition, and its study provides insight into cognitive development, broadly construed. WIREs Cogn Sci 2011 2 95–105 DOI: 10.1002/wcs.96 For further resources related to this article, please visit the WIREs websitePeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78491/1/96_ftp.pd

Overcoming Multidrug Resistance via Photodestruction of ABCG2-Rich Extracellular Vesicles Sequestering Photosensitive Chemotherapeutics

Multidrug resistance (MDR) remains a dominant impediment to curative cancer chemotherapy. Efflux transporters of the ATP-binding cassette (ABC) superfamily including ABCG2, ABCB1 and ABCC1 mediate MDR to multiple structurally and functionally distinct antitumor agents. Recently we identified a novel mechanism of MDR in which ABCG2-rich extracellular vesicles (EVs) form in between attached neighbor breast cancer cells and highly concentrate various chemotherapeutics in an ABCG2-dependent manner, thereby sequestering them away from their intracellular targets. Hence, development of novel strategies to overcome MDR modalities is a major goal of cancer research. Towards this end, we here developed a novel approach to selectively target and kill MDR cancer cells. We show that illumination of EVs that accumulated photosensitive cytotoxic drugs including imidazoacridinones (IAs) and topotecan resulted in intravesicular formation of reactive oxygen species (ROS) and severe damage to the EVs membrane that is shared by EVs-forming cells, thereby leading to tumor cell lysis and the overcoming of MDR. Furthermore, consistent with the weak base nature of IAs, MDR cells that are devoid of EVs but contained an increased number of lysosomes, highly accumulated IAs in lysosomes and upon photosensitization were efficiently killed via ROS-dependent lysosomal rupture. Combining targeted lysis of IAs-loaded EVs and lysosomes elicited a synergistic cytotoxic effect resulting in MDR reversal. In contrast, topotecan, a bona fide transport substrate of ABCG2, accumulated exclusively in EVs of MDR cells but was neither detected in lysosomes of normal breast epithelial cells nor in non-MDR breast cancer cells. This exclusive accumulation in EVs enhanced the selectivity of the cytotoxic effect exerted by photodynamic therapy to MDR cells without harming normal cells. Moreover, lysosomal alkalinization with bafilomycin A1 abrogated lysosomal accumulation of IAs, consequently preventing lysosomal photodestruction of normal breast epithelial cells. Thus, MDR modalities including ABCG2-dependent drug sequestration within EVs can be rationally converted to a pharmacologically lethal Trojan horse to selectively eradicate MDR cancer cells

Gravitational Waves from Gravitational Collapse

Gravitational wave emission from the gravitational collapse of massive stars has been studied for more than three decades. Current state of the art numerical investigations of collapse include those that use progenitors with realistic angular momentum profiles, properly treat microphysics issues, account for general relativity, and examine non--axisymmetric effects in three dimensions. Such simulations predict that gravitational waves from various phenomena associated with gravitational collapse could be detectable with advanced ground--based and future space--based interferometric observatories.Comment: 68 pages including 13 figures; revised version accepted for publication in Living Reviews in Relativity (http://www.livingreviews.org

Growth and characterization of gold catalyzed SiGe nanowires and alternative metal-catalyzed Si nanowires

The growth of semiconductor (SC) nanowires (NW) by CVD using Au-catalyzed VLS process has been widely studied over the past few years. Among others SC, it is possible to grow pure Si or SiGe NW thanks to these techniques. Nevertheless, Au could deteriorate the electric properties of SC and the use of other metal catalysts will be mandatory if NW are to be designed for innovating electronic. First, this article's focus will be on SiGe NW's growth using Au catalyst. The authors managed to grow SiGe NW between 350 and 400°C. Ge concentration (x) in Si1-xGex NW has been successfully varied by modifying the gas flow ratio: R = GeH4/(SiH4 + GeH4). Characterization (by Raman spectroscopy and XRD) revealed concentrations varying from 0.2 to 0.46 on NW grown at 375°C, with R varying from 0.05 to 0.15. Second, the results of Si NW growths by CVD using alternatives catalysts such as platinum-, palladium- and nickel-silicides are presented. This study, carried out on a LPCVD furnace, aimed at defining Si NW growth conditions when using such catalysts. Since the growth temperatures investigated are lower than the eutectic temperatures of these Si-metal alloys, VSS growth is expected and observed. Different temperatures and HCl flow rates have been tested with the aim of minimizing 2D growth which induces an important tapering of the NW. Finally, mechanical characterization of single NW has been carried out using an AFM method developed at the LTM. It consists in measuring the deflection of an AFM tip while performing approach-retract curves at various positions along the length of a cantilevered NW. This approach allows the measurement of as-grown single NW's Young modulus and spring constant, and alleviates uncertainties inherent in single point measurement

Epigenetic regulation of RhoB loss of expression in lung cancer

<p>Abstract</p> <p>Background</p> <p>RhoB is down-regulated in most lung cancer cell lines and tumor tissues when compared with their normal counterparts. The mechanism of this loss of expression is not yet deciphered.</p> <p>Methods</p> <p>Since no mutation has been reported in the RhoB sequence, we investigated the epigenetic regulation of RhoB expression by analyzing the effect of HDAC inhibitors and methyltransferase inhibitors, by direct sequencing after bisulfite treatment and by methylation specific PCR.</p> <p>Results</p> <p>We first showed that histone deacetylase (HDAC) inhibitors induce a significant RhoB re-expression in lung cancer cell lines whereas only a slight effect was observed with methyl transferase inhibitors. As promoter methylation is the most common epigenetic process in lung cancer, we performed methylation specific PCR and sequence analysis after bisulfite treatment and demonstrated that RhoB was methylated neither in lung cancer cell lines nor in tumor tissues. We also showed that a variable number of tandem repeats sequences in the 5' region of the RhoB gene was involved in HDAC response.</p> <p>Conclusion</p> <p>We thus propose that RhoB regulation of expression occurs mainly by histone deacetylation rather than by promoter hypermethylation and that this process can be modulated by specific 5' sequences within the promoter.</p

Implementation of a parentage control system in Portuguese beef-cattle with a panel of microsatellite markers

A study was conducted to assess the feasibility of applying a panel of 10 microsatellite markers in parentage control of beef cattle in Portugal. In the first stage, DNA samples were collected from 475 randomly selected animals of the Charolais, Limousin and Preta breeds. Across breeds and genetic markers, means for average number of alleles, effective number of alleles, expected heterozygosity and polymorphic information content, were 8.20, 4.43, 0.733 and 0.70, respectively. Enlightenment from the various markers differed among breeds, but the set of 10 markers resulted in a combined probability above 0.9995 in the ability to exclude a random putative parent. The marker-set thus developed was later used for parentage control in a group of 140 calves from several breeds, where there was the suspicion of possible faulty parentage recording. Overall, 76.4% of the calves in this group were compatible with the recorded parents, with most incompatibilities due to misidentification of the dam. Efforts must be made to improve the quality of pedigree information, with particular emphasis on information recorded at the calf's birth

Molecular, Biochemical and Genetic Characteristics of BSE in Canada

The epidemiology and possibly the etiology of bovine spongiform encephalopathy (BSE) have recently been recognized to be heterogeneous. In particular, three types [classical (C) and two atypical (H, L)] have been identified, largely on the basis of characteristics of the proteinase K (PK)-resistant core of the misfolded prion protein associated with the disease (PrPres). The present study was conducted to characterize the 17 Canadian BSE cases which occurred prior to November 2009 based on the molecular and biochemical properties of their PrPres, including immunoreactivity, molecular weight, glycoform profile and relative PK sensitivity. Two cases exhibited molecular weight and glycoform profiles similar to those of previously reported atypical cases, one corresponding to H-type BSE (case 6) and the other to L-type BSE (case 11). All other cases were classified as C-type. PK digestion under mild and stringent conditions revealed a reduced protease resistance in both of these cases compared to the C-type cases. With Western immunoblotting, N-terminal-specific antibodies bound to PrPres from case 6 but not to that from case 11 or C-type cases. C-terminal-specific antibodies revealed a shift in the glycoform profile and detected a fourth protein fragment in case 6, indicative of two PrPres subpopulations in H-type BSE. No mutations suggesting a genetic etiology were found in any of the 17 animals by sequencing the full PrP-coding sequence in exon 3 of the PRNP gene. Thus, each of the three known BSE types have been confirmed in Canadian cattle and show molecular characteristics highly similar to those of classical and atypical BSE cases described from Europe, Japan and the USA. The occurrence of atypical cases of BSE in countries such as Canada with low BSE prevalence and transmission risk argues for the occurrence of sporadic forms of BSE worldwide