BBLN-1 is essential for intermediate filament organization and apical membrane morphology

Epithelial tubes are essential components of metazoan organ systems that control the flow of fluids and the exchange of materials between body compartments and the outside environment. The size and shape of the central lumen confer important characteristics to tubular organs and need to be carefully controlled. Here, we identify the small coiled-coil protein BBLN-1 as a regulator of lumen morphology in the C. elegans intestine. Loss of BBLN-1 causes the formation of bubble-shaped invaginations of the apical membrane into the cytoplasm of intestinal cells and abnormal aggregation of the subapical intermediate filament (IF) network. BBLN-1 interacts with IF proteins and localizes to the IF network in an IF-dependent manner. The appearance of invaginations is a result of the abnormal IF aggregation, indicating a direct role for the IF network in maintaining lumen homeostasis. Finally, we identify bublin (BBLN) as the mammalian ortholog of BBLN-1. When expressed in the C. elegans intestine, BBLN recapitulates the localization pattern of BBLN-1 and can compensate for the loss of BBLN-1 in early larvae. In mouse intestinal organoids, BBLN localizes subapically, together with the IF protein keratin 8. Our results therefore may have implications for understanding the role of IFs in regulating epithelial tube morphology in mammals

The role of the right temporoparietal junction in perceptual conflict: detection or resolution?

The right temporoparietal junction (rTPJ) is a polysensory cortical area that plays a key role in perception and awareness. Neuroimaging evidence shows activation of rTPJ in intersensory and sensorimotor conflict situations, but it remains unclear whether this activity reflects detection or resolution of such conflicts. To address this question, we manipulated the relationship between touch and vision using the so-called mirror-box illusion. Participants' hands lay on either side of a mirror, which occluded their left hand and reflected their right hand, but created the illusion that they were looking directly at their left hand. The experimenter simultaneously touched either the middle (D3) or the ring finger (D4) of each hand. Participants judged, which finger was touched on their occluded left hand. The visual stimulus corresponding to the touch on the right hand was therefore either congruent (same finger as touch) or incongruent (different finger from touch) with the task-relevant touch on the left hand. Single-pulse transcranial magnetic stimulation (TMS) was delivered to the rTPJ immediately after touch. Accuracy in localizing the left touch was worse for D4 than for D3, particularly when visual stimulation was incongruent. However, following TMS, accuracy improved selectively for D4 in incongruent trials, suggesting that the effects of the conflicting visual information were reduced. These findings suggest a role of rTPJ in detecting, rather than resolving, intersensory conflict

Economic vs. juristic thinking in Carl Menger’s principles of economics

Austrian Economic School is increasingly being treated as one of the most significant and ever more influential bodies of ideas affecting the contemporary economic science. It is well known that Carl Menger, the founder of the Austrian School, was a lawyer by education. The paper is devoted to the degree to which his legal education influenced his economic theorizing. After a close examination of the Menger’s conceptual apparatus and the epistemological ramifications of the key notions underlying his thinking, the paper concludes that the juristic background of the far-reaching theoretical contributions contained in Menger’s Principles was truly decisive. That holds true despite the fact that Menger only exceptionally utilized the juristic vocabulary. The key ingredients of his theoretical creation? such as the individual autonomy, the coincidence of the wills in concluding a contract the effective protection of property and making transactions based on the individual motivation to further one’s own interests to the utmost? are clearly inspired and in many ways influenced by private law, particularly the doctrines underlying the Roman Law and the Austrian Civil Code

Dual proteotoxic stress accelerates liver injury via activation of p62-Nrf2

Protein accumulation is the hallmark of various neuronal, muscular, and other human disorders. It is also often seen in the liver as a major protein-secretory organ. For example, aggregation of mutated alpha1-antitrypsin (AAT), referred to as PiZ, is a characteristic feature of AAT deficiency, whereas retention of hepatitis B surface protein (HBs) is found in chronic hepatitis B (CHB) infection. We investigated the interaction of both proteotoxic stresses in humans and mice. Animals overexpressing both PiZ and HBs (HBs-PiZ mice) had greater liver injury, steatosis, and fibrosis. Later they exhibited higher hepatocellular carcinoma load and a more aggressive tumor subtype. Although PiZ and HBs displayed differing solubility properties and distinct distribution patterns, HBs-PiZ animals manifested retention of AAT/HBs in the degradatory pathway and a marked accumulation of the autophagy adaptor p62. Isolation of p62-containing particles revealed retained HBs/AAT and the lipophagy adapter perilipin-2. p62 build-up led to activation of the p62–Nrf2 axis and emergence of reactive oxygen species. Our results demonstrate that the simultaneous presence of two prevalent proteotoxic stresses promotes the development of liver injury due to protein retention and activation of the p62–Nrf2 axis. In humans, the PiZ variant was over-represented in CHB patients with advanced liver fibrosis (unadjusted odds ratio = 9.92 [1.15–85.39]). Current siRNA approaches targeting HBs/AAT should be considered for these individuals. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland

A keratin scaffold regulates epidermal barrier formation, mitochondrial lipid composition, and activity.

Keratin intermediate filaments (KIFs) protect the epidermis against mechanical force, support strong adhesion, help barrier formation, and regulate growth. The mechanisms by which type I and II keratins contribute to these functions remain incompletely understood. Here, we report that mice lacking all type I or type II keratins display severe barrier defects and fragile skin, leading to perinatal mortality with full penetrance. Comparative proteomics of cornified envelopes (CEs) from prenatal KtyI(-/-) and KtyII(-/-)(K8) mice demonstrates that absence of KIF causes dysregulation of many CE constituents, including downregulation of desmoglein 1. Despite persistence of loricrin expression and upregulation of many Nrf2 targets, including CE components Sprr2d and Sprr2h, extensive barrier defects persist, identifying keratins as essential CE scaffolds. Furthermore, we show that KIFs control mitochondrial lipid composition and activity in a cell-intrinsic manner. Therefore, our study explains the complexity of keratinopathies accompanied by barrier disorders by linking keratin scaffolds to mitochondria, adhesion, and CE formation

Can Machines Think? Interaction and Perspective Taking with Robots Investigated via fMRI

Krach S, Hegel F, Wrede B, Sagerer G, Binkofski F, Kircher T. Can Machines Think? Interaction and Perspective Taking with Robots Investigated via fMRI. PLoS ONE. 2008;3(7): e2597.Background When our PC goes on strike again we tend to curse it as if it were a human being. Why and under which circumstances do we attribute human-like properties to machines? Although humans increasingly interact directly with machines it remains unclear whether humans implicitly attribute intentions to them and, if so, whether such interactions resemble human-human interactions on a neural level. In social cognitive neuroscience the ability to attribute intentions and desires to others is being referred to as having a Theory of Mind (ToM). With the present study we investigated whether an increase of human-likeness of interaction partners modulates the participants' ToM associated cortical activity. Methodology/Principal Findings By means of functional magnetic resonance imaging (subjects n = 20) we investigated cortical activity modulation during highly interactive human-robot game. Increasing degrees of human-likeness for the game partner were introduced by means of a computer partner, a functional robot, an anthropomorphic robot and a human partner. The classical iterated prisoner's dilemma game was applied as experimental task which allowed for an implicit detection of ToM associated cortical activity. During the experiment participants always played against a random sequence unknowingly to them. Irrespective of the surmised interaction partners' responses participants indicated having experienced more fun and competition in the interaction with increasing human-like features of their partners. Parametric modulation of the functional imaging data revealed a highly significant linear increase of cortical activity in the medial frontal cortex as well as in the right temporo-parietal junction in correspondence with the increase of human-likeness of the interaction partner (computer<functional robot<anthropomorphic robot<human). Conclusions/Significance Both regions correlating with the degree of human-likeness, the medial frontal cortex and the right temporo-parietal junction, have been associated with Theory-of-Mind. The results demonstrate that the tendency to build a model of another's mind linearly increases with its perceived human-likeness. Moreover, the present data provides first evidence of a contribution of higher human cognitive functions such as ToM in direct interactions with artificial robots. Our results shed light on the long-lasting psychological and philosophical debate regarding human-machine interaction and the question of what makes humans being perceived as human

Tissue Specific Deletion of Inhibitor of Kappa B Kinase 2 with OX40-Cre Reveals the Unanticipated Expression from the OX40 Locus in Skin Epidermis

NF-κB signalling plays an essential role in T cell activation and generation of regulatory and memory populations in vivo. In the present study, we aimed to investigate the role of NF-κB signalling in post-activation T cells using tissue specific ablation of inhibitor of kappa-B kinase 2 expression, an important component of the inhibitor of kappa-B kinase complex in canonical NF-κB signalling. The OX40 antigen is expressed on activated T cells. Therefore, we used previously described mouse strain expressing Cre recombinase from the endogenous OX40 locus. Ablation of IKK2 expression using OX40Cre mice resulted in the development of an inflammatory response in the skin epidermis causing wide spread skin lesions. The inflammatory response was characterised by extensive leukocytic infiltrate in skin tissue, hyperplasia of draining lymph nodes and widespread activation in the T cell compartment. Surprisingly, disease development did not depend on T cells but was rather associated with an unanticipated expression of Cre in skin epidermis, and activation of the T cell compartment did not require Ikbk2 deletion in T cells. Employment of Cre reporter strains revealed extensive Cre activity in skin epidermis. Therefore, development of skin lesions was rather more likely explained by deletion of Ikbk2 in skin keratinocytes in OX40Cre mice

From upright to upside-down presentation: A spatio-temporal ERP study of the parametric effect of rotation on face and house processing

<p>Abstract</p> <p>Background</p> <p>While there is a general agreement that picture-plane inversion is more detrimental to face processing than to other seemingly complex visual objects, the origin of this effect is still largely debatable. Here, we address the question of whether face inversion reflects a quantitative or a qualitative change in processing mode by investigating the pattern of event-related potential (ERP) response changes with picture plane rotation of face and house pictures. Thorough analyses of topographical (Scalp Current Density maps, SCD) and dipole source modeling were also conducted.</p> <p>Results</p> <p>We find that whilst stimulus orientation affected in a similar fashion participants' response latencies to make face and house decisions, only the ERPs in the N170 latency range were modulated by picture plane rotation of faces. The pattern of N170 amplitude and latency enhancement to misrotated faces displayed a curvilinear shape with an almost linear increase for rotations from 0° to 90° and a dip at 112.5° up to 180° rotations. A similar discontinuity function was also described for SCD occipito-temporal and temporal current foci with no topographic distribution changes, suggesting that upright and misrotated faces activated similar brain sources. This was confirmed by dipole source analyses showing the involvement of bilateral sources in the fusiform and middle occipital gyri, the activity of which was differentially affected by face rotation.</p> <p>Conclusion</p> <p>Our N170 findings provide support for both the quantitative and qualitative accounts for face rotation effects. Although the qualitative explanation predicted the curvilinear shape of N170 modulations by face misrotations, topographical and source modeling findings suggest that the same brain regions, and thus the same mechanisms, are probably at work when processing upright and rotated faces. Taken collectively, our results indicate that the same processing mechanisms may be involved across the whole range of face orientations, but would operate in a non-linear fashion. Finally, the response tuning of the N170 to rotated faces extends previous reports and further demonstrates that face inversion affects perceptual analyses of faces, which is reflected within the time range of the N170 component.</p