Cross-representational interactions: Interface and overlap mechanisms

A crucial question facing cognitive science concerns the nature of conceptual representations as well as the constraints on the interactions between them. One specific question we address in this paper is what makes cross representational interplay possible? We offer two distinct theoretical scenarios: According to the first scenario, co-activated knowledge representations interact with the help of an interface established between them via congruent activation in a mediating third party general cognitive mechanism, e.g., attention. According to the second scenario, co-activated knowledge representations interact due to an overlap between their features, for example when they share a magnitude component. First, we make a case for cross-representational interplay based on grounded and situated theories of cognition. Second, we discuss interface-based interactions between distinct (i.e., non-overlapping) knowledge representations. Third, we discuss how co-activated representations may share their architecture via partial overlap. Finally, we outline constraints regarding the flexibility of these proposed mechanisms

False-Belief Reasoning From 3 to 92 Years of Age

False-belief reasoning, defined as the ability to reason about another person’s beliefs and appreciate that beliefs can differ from reality, is an important aspect of perspective taking. We tested 266 individuals, at various ages ranging from 3 to 92 years, on a continuous measure of false-belief reasoning (the Sandbox task). All age groups had difficulty suppressing their own knowledge when estimating what a naïve person knew. After controlling for task-specific memory, our results showed similar false-belief reasoning abilities across the preschool years and from older childhood to younger adulthood, followed by a small reduction in this ability from younger to older adulthood. These results highlight the relative similarity in false-belief reasoning abilities at different developmental periods across the lifespan

Theory of inelastic lifetimes of low-energy electrons in metals

Electron dynamics in the bulk and at the surface of solid materials are well known to play a key role in a variety of physical and chemical phenomena. In this article we describe the main aspects of the interaction of low-energy electrons with solids, and report extensive calculations of inelastic lifetimes of both low-energy electrons in bulk materials and image-potential states at metal surfaces. New calculations of inelastic lifetimes in a homogeneous electron gas are presented, by using various well-known representations of the electronic response of the medium. Band-structure calculations, which have been recently carried out by the authors and collaborators, are reviewed, and future work is addressed.Comment: 28 pages, 18 figures, to appear in Chem. Phy

Intimate Pride: a Tri-Nation Study on Associations between Positive Minority Identity Aspects and Relationship Quality in Sexual Minorities from German-Speaking Countries

Investigations into the intimate relationships of sexual minorities are proliferating, but often adopt a deficit-oriented and US-centered perspective. In this tri-nation online study with sexual minority participants from Austria, Germany, and Switzerland (N = 571), we (i) assessed the construct validity of the German version of a well-known measure for positive minority identity aspects (the Lesbian, Gay, Bisexual Positive Identity Measure; LGB-PIM), and (ii) explored associations between these aspects (self-awareness, authenticity, community, capacity for intimacy, and social justice) and self-reported relationship quality. Model fit of the German version of the LGB-PIM was deemed acceptable. Higher levels of positive minority identity aspects showed small to moderate associations with higher levels of relationship quality in bivariate analyses, but only capacity for intimacy was linked to relationship quality in higher-order models (controlling for country, age, sexual orientation, gender identity, relationship length, and psychological distress). Results remained robust in several sensitivity analyses. Our results highlight the differential role of positive identity aspects for relationship functioning, with capacity for intimacy as a fruitful leverage point for therapeutic work

PD-L1 and HIF-2α Upregulation in Head and Neck Paragangliomas after Embolization

Hypoxia activates pathways associated with tumor progression, metastatic spread, and alterations in the immune microenvironment leading to an immunosuppressive phenotype. In particular, the upregulation of PD-L1, a target for therapy with checkpoint inhibitors, is well-studied in several tumors. However, the relationship between hypoxia and PD-L1 regulation in pheochromocytomas and paragangliomas (PPGL), and especially in paragangliomas treated with embolization, is still largely unexplored. We investigated the expression of the hypoxia-marker HIF-2α and of PD-L1 in a PPGL-cohort with and without embolization as potential biomarkers that may predict the response to treatment with HIF-2α and checkpoint inhibitors. A total of 29 tumor samples from 25 patients who were operated at a single center were included and analyzed utilizing immunohistochemistry (IHC) for PD-L1 and HIF-2α. Embolization prior to surgery was performed in seven (24%) tumors. PD-L1 expression in tumor cells of head and neck paragangliomas (HNPGLs) receiving prior embolization (median PD-L1 positivity: 15%) was significantly higher as compared to PD-L1 expression in HNPGLs without prior embolization (median PD-L1 positivity: 0%) (p = 0.008). Consistently, significantly more HNPGLs with prior embolization were positive for HIF-2α (median nuclear HIF-2α positivity: 40%) as compared to HNPGLs without prior embolization (median nuclear HIF-2α positivity: 0%) (p = 0.016). Our results support the hypothesis that embolization with subsequent hypoxia leads to the upregulation of both PD-L1 and HIF-2α in HNPGLs, and could thus facilitate targeted treatment with HIF-2α and checkpoint inhibitors in the case of inoperable, locally advanced, or metastatic disease

The selective PI3Kα inhibitor BYL719 as a novel therapeutic option for neuroendocrine tumors: Results from multiple cell line models

BACKGROUND/AIMS The therapeutic options for metastatic neuroendocrine tumors (NETs) are limited. As PI3K signaling is often activated in NETs, we have assessed the effects of selective PI3Kp110\textgreeka inhibition by the novel agent BYL719 on cell viability, colony formation, apoptosis, cell cycle, signaling pathways, differentiation and secretion in pancreatic (BON-1, QGP-1) and pulmonary (H727) NET cell lines. METHODS Cell viability was investigated by WST-1 assay, colony formation by clonogenic assay, apoptosis by caspase3/7 assay, the cell cycle by FACS, cell signaling by Western blot analysis, expression of chromogranin A and somatostatin receptors 1/2/5 by RT-qPCR, and chromogranin A secretion by ELISA. RESULTS BYL719 dose-dependently decreased cell viability and colony formation with the highest sensitivity in BON-1, followed by H727, and lowest sensitivity in QGP-1 cells. BYL719 induced apoptosis and G0/G1 cell cycle arrest associated with increased p27 expression. Western blots showed inhibition of PI3K downstream targets to a varying degree in the different cell lines, but IGF1R activation. The most sensitive BON-1 cells displayed a significant, and H727 cells a non-significant, GSK3 inhibition after BYL719 treatment, but these effects do not appear to be mediated through the IGF1R. In contrast, the most resistant QGP-1 cells showed no GSK3 inhibition, but a modest activation, which would partially counteract the other anti-proliferative effects. Accordingly, BYL719 enhanced neuroendocrine differentiation with the strongest effect in BON-1, followed by H727 cells indicated by induction of chromogranin A and somatostatin receptor 1/2 mRNA-synthesis, but not in QGP-1 cells. In BON-1 and QGP-1 cells, the BYL719/everolimus combination was synergistic through simultaneous AKT/mTORC1 inhibition, and significantly increased somatostatin receptor 2 transcription compared to each drug separately. CONCLUSION Our results suggest that the agent BYL719 could be a novel therapeutic approach to the treatment of NETs that may sensitize NET cells to somatostatin analogs, and that if there is resistance to its action this may be overcome by combination with everolimus

Mitochondrial uncoupling links lipid catabolism to Akt inhibition and resistance to tumorigenesis

To support growth, tumour cells reprogramme their metabolism to simultaneously upregulate macromolecular biosynthesis while maintaining energy production. Uncoupling proteins (UCPs) oppose this phenotype by inducing futile mitochondrial respiration that is uncoupled from ATP synthesis, resulting in nutrient wasting. Here using a UCP3 transgene targeted to the basal epidermis, we show that forced mitochondrial uncoupling inhibits skin carcinogenesis by blocking Akt activation. Similarly, Akt activation is markedly inhibited in UCP3 overexpressing primary human keratinocytes. Mechanistic studies reveal that uncoupling increases fatty acid oxidation and membrane phospholipid catabolism, and impairs recruitment of Akt to the plasma membrane. Overexpression of Akt overcomes metabolic regulation by UCP3, rescuing carcinogenesis. These findings demonstrate that mitochondrial uncoupling is an effective strategy to limit proliferation and tumorigenesis through inhibition of Akt, and illuminate a novel mechanism of crosstalk between mitochondrial metabolism and growth signalling

The reductive activation of CO2 across a Ti═Ti double bond: synthetic, structural, and mechanistic studies

[Image: see text] The reactivity of the bis(pentalene)dititanium double-sandwich compound Ti(2)Pn(†)(2) (1) (Pn(†) = 1,4-{Si(i)Pr(3)}(2)C(8)H(4)) with CO(2) is investigated in detail using spectroscopic, X-ray crystallographic, and computational studies. When the CO(2) reaction is performed at −78 °C, the 1:1 adduct 4 is formed, and low-temperature spectroscopic measurements are consistent with a CO(2) molecule bound symmetrically to the two Ti centers in a μ:η(2),η(2) binding mode, a structure also indicated by theory. Upon warming to room temperature the coordinated CO(2) is quantitatively reduced over a period of minutes to give the bis(oxo)-bridged dimer 2 and the dicarbonyl complex 3. In situ NMR studies indicated that this decomposition proceeds in a stepwise process via monooxo (5) and monocarbonyl (7) double-sandwich complexes, which have been independently synthesized and structurally characterized. 5 is thermally unstable with respect to a μ-O dimer in which the Ti–Ti bond has been cleaved and one pentalene ligand binds in an η(8) fashion to each of the formally Ti(III) centers. The molecular structure of 7 shows a “side-on” bound carbonyl ligand. Bonding of the double-sandwich species Ti(2)Pn(2) (Pn = C(8)H(6)) to other fragments has been investigated by density functional theory calculations and fragment analysis, providing insight into the CO(2) reaction pathway consistent with the experimentally observed intermediates. A key step in the proposed mechanism is disproportionation of a mono(oxo) di-Ti(III) species to yield di-Ti(II) and di-Ti(IV) products. 1 forms a structurally characterized, thermally stable CS(2) adduct 8 that shows symmetrical binding to the Ti(2) unit and supports the formulation of 4. The reaction of 1 with COS forms a thermally unstable complex 9 that undergoes scission to give mono(μ-S) mono(CO) species 10. Ph(3)PS is an effective sulfur transfer agent for 1, enabling the synthesis of mono(μ-S) complex 11 with a double-sandwich structure and bis(μ-S) dimer 12 in which the Ti–Ti bond has been cleaved

Differences in HIV Burden and Immune Activation within the Gut of HIV-Positive Patients Receiving Suppressive Antiretroviral Therapy

Background. The gut is a major reservoir for human immunodeficiency virus (HIV) in patients receiving antiretroviral therapy (ART). We hypothesized that distinct immune environments within the gut may support varying levels of HIV. Methods. In 8 HIV-1-positive adults who were receiving ART and had CD4+ T cell counts of >200 cells/µL and plasma viral loads of <40 copies/mL, levels of HIV and T cell activation were measured in blood samples and endoscopic biopsy specimens from the duodenum, ileum, ascending colon, and rectum. Results. HIV DNA and RNA levels per CD4+ T cell were higher in all 4 gut sites compared with those in the blood. HIV DNA levels increased from the duodenum to the rectum, whereas the median HIV RNA level peaked in the ileum. HIV DNA levels correlated positively with T cell activation markers in peripheral blood mononuclear cells (PBMCs) but negatively with T cell activation markers in the gut. Multiply spliced RNA was infrequently detected in gut, and ratios of unspliced RNA to DNA were lower in the colon and rectum than in PBMCs, which reflects paradoxically low HIV transcription, given the higher level of T cell activation in the gut. Conclusions. HIV DNA and RNA are both concentrated in the gut, but the inverse relationship between HIV DNA levels and T cell activation in the gut and the paradoxically low levels of HIV expression in the large bowel suggest that different processes drive HIV persistence in the blood and gut. Trial registration. ClinicalTrials.gov identifier: NCT00884793 (PLUS1