Integration of serial sensory information in haptic perception of softness.

Redundant estimates of an environmental property derived simultaneously from different senses or cues are typically integrated according to the maximum likelihood estimation model (MLE): Sensory estimates are weighted according to their reliabilities, maximizing the percept’s reliability. Mechanisms underlying the integration of sequentially derived estimates from one sense are less clear. Here we investigate the integration of serially sampled redundant information in softness perception. We developed a method to manipulate haptically perceived softness of silicone rubber stimuli during bare-finger exploration. We then manipulated softness estimates derived from single movement segments (indentations) in a multisegmented exploration to assess their contributions to the overall percept. Participants explored two stimuli in sequence, using 2–5 indentations, and reported which stimulus felt softer. Estimates of the first stimulus’s softness contributed to the judgments similarly, whereas for the second stimulus estimates from later compared to earlier indentations contributed less. In line with unequal weighting, the percept’s reliability increased with increasing exploration length less than was predicted by the MLE model. This pattern of results is well explained by assuming that the representation of the first stimulus fades when the second stimulus is explored, which fits with a neurophysiological model of perceptual decisions (Deco, Rolls, & Romo, 2010)

Active Haptic Exploration of Softness: Indentation Force Is Systematically Related to Prediction, Sensation and Motivation

Active finger movements play a crucial role in natural haptic perception. For the perception of different haptic properties people use different well-chosen movement schemes (Lederman and Klatzky, 1987). The haptic property of softness is stereotypically judged by repeatedly pressing one’s finger against an objects’ surface, actively indenting the object. It has been shown that people adjust the peak indentation forces of their pressing movements to the expected stimulus’ softness in order to improve perception (Kaim and Drewing, 2011). Here, we aim to clarify the mechanisms underlying such adjustments. We disentangle how people modulate executed peak indentation forces depending on predictive vs. sensory signals to softness, and investigate the influence of the participants’ motivational state on movement adjustments. In Experiment 1, participants performed a two alternative forced-choice (2AFC) softness discrimination task for stimulus pairs from one of four softness categories. We manipulated the predictability of the softness category. Either all stimuli of the same category were presented in a blocked fashion, which allowed predicting the softness category of the upcoming pair (predictive signals high), or stimuli from different categories were randomly intermixed, which made prediction impossible (predictive signals low). Sensory signals to softness category of the two stimuli in a pair are gathered during exploration. We contrasted the first indentation (sensory signals low) and last indentation (sensory signals high) in order to examine the effect of sensory signals. The results demonstrate that participants systematically apply lower forces when softer objects (as compared to harder objects) are indicated by predictive signals. Notably, sensory signals seemed to be not as relevant as predictive signals. However, in Experiment 2, we manipulated participant motivation by introducing rewards for good performance, and showed that the use of sensory information for movement adjustments can be fostered by high motivation. Overall, the present study demonstrates that exploratory movements are adjusted to the actual perceptual situation and that in the process of fine-tuning, closed- and open-loop mechanisms interact, with varying contributions depending on the observer’s motivation

Anonymität und Mobilität - Whitepaper zum Begriffs- und Domänenverständnis des Kompetenzcluster ANYMOS – Anonymisierung für vernetzte Mobilitätssysteme

In ANYMOS werden Anforderungen und Methoden für eine Anonymisierung und anschließende Auswertung von zuvor personenbezogenen Daten untersucht. Dabei wird im Kompetenzcluster die Anwendungsdomäne Mobilität betrachtet und sich auf den Personenverkehr, da durch die Mobilität von Gütern nicht immer unmittelbar personenbezogene Daten anfallen, fokussiert. Die Notwendigkeit des Kompetenzclusters ANYMOS ergibt sich daraus, dass im Mobilitätsbereich bei zahlreichen Anwendungen große Datenmengen anfallen und es aufgrund der zu erwartenden Entwicklungen zu einem weiteren Anstieg dieser Datenmenge kommen wird. Um diese Daten in Zukunft sinnvoll nutzen zu können, ohne dabei durch die Verwendung personenbezogener Daten Persönlichkeitsrechte und/oder rechtliche Vorgaben zu verletzen, muss zunächst erforscht werden, wann diese Daten gesammelt werden und inwieweit sie auch nach einer Anonymisierung noch über einen Nutzwert verfügen. Im zweiten Abschnitt des Whitepapers wird daher zunächst Anonymität beschrieben und das Spannungsfeld zwischen juristischem und technischen Begriffsverständnis erörtert. Im dritten Abschnitt erfolgt eine Strukturierung der Mobilitätsdomäne. Dadurch soll das gemeinsame Verständnis der Begrifflichkeiten und der Relevanz der verschiedenen Themenbereiche für das Kompetenzcluster ANYMOS gefördert werden. Abschließend wird ein Ausblick – auch auf die weiteren Arbeiten in ANYMOS gegeben

Lymphangiosis carcinomatosa in squamous cell carcinomas of larynx and hypopharynx – value of conventional evaluation and additional immunohistochemical staining of D2-40

<p>Abstract</p> <p>Background</p> <p>Recent studies revealed a predictive value of lymphatic vessel invasion (L1) for the nodal metastasizing and poor prognosis in malignant tumors at different sites. The monoclonal antibody D2-40 (podoplanin) stains specifically endothelial cells of lymphatic vessels and improves the search for L1. However, the importance of this immunohistochemical staining was not investigated in squamous cell carcinomas (SCC) of larynx and hypopharynx.</p> <p>Aim</p> <p>This study was performed to compare the diagnostic potential of convential and immunohistochemical determination of L1 in SCC of larynx and hypopharynx with special respect to the predictive value for nodal metastasizing and prognosis.</p> <p>Methods</p> <p>119 SCCs of the larynx (n = 70) respectively hypopharynx (n = 49) were investigated. The lymphatic vessel invasion was assessed by conventional method (HE stain) and immunohistochemical staining with an antibody against D2-40 (DAKO, Germany). Immunohistochemistry was performed in accordance with manufacturer's protocol. L1 was searched microscopically in a standardized magnification (×200) in serial sections of tumor samples (1 section per cm tumor diameter).</p> <p>Results</p> <p>The immunohistochemical investigation did not show significant advantages for the prediction of regional nodal metastases. Despite a low sensitivity (< 50%) in both methods, the specifity can reach 80%. The negative predictive value in both methods seems acceptable (up to 80%), whereas the positive predictive value is not higher than 64%. Cases with L1 detected either conventionally or immunohistochemically did not show a significant shorter survival than cases with L0. However, a non-significant shorter survival was found. Only in SCC of hypopharynx, a combination of both methods revealed patients with a significant worse prognosis.</p> <p>Conclusion</p> <p>The status of lymphatic vessel invasion should be documented in standardized tumor reports. A benefit of an additional immunohistochemical investigation was not found, for the daily routine HE-stain seems sufficient.</p

The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance

The maintenance of immune tolerance requires the deletion of self-reactive T cells in the thymus. The expression of tissue-specific antigen genes (TSAs) by thymic epithelial cells is critical for this process and depends on the activity of the Autoimmune Regulator (Aire) protein, however, the molecular mechanism(s) Aire uses to target TSA gene loci are unknown. Here we identified two Aire-interacting proteins – activating transcription factor 7 interacting protein (ATF7ip) and methyl CpG binding protein 1 (MBD1) –that are required for Aire’s targeting of TSA geneloci. Moreover, Mbd1−/− mice developed pathological autoimmunity and had a defect in Aire-dependent thymic TSA gene expression underscoring the critical importance of Aire’s interaction with the ATF7ip-MBD1 protein complex in maintaining central tolerance

Induced Pluripotent Stem Cell-Derived Brain Endothelial Cells as a Cellular Model to Study Neisseria meningitidis Infection

Meningococcal meningitis is a severe central nervous system infection that occurs when Neisseria meningitidis (Nm) penetrates brain endothelial cells (BECs) of the meningeal blood-cerebrospinal fluid barrier. As a human-specific pathogen, in vivo models are greatly limited and pose a significant challenge. In vitro cell models have been developed, however, most lack critical BEC phenotypes limiting their usefulness. Human BECs generated from induced pluripotent stem cells (iPSCs) retain BEC properties and offer the prospect of modeling the human-specific Nm interaction with BECs. Here, we exploit iPSC-BECs as a novel cellular model to study Nm host-pathogen interactions, and provide an overview of host responses to Nm infection. Using iPSC-BECs, we first confirmed that multiple Nm strains and mutants follow similar phenotypes to previously described models. The recruitment of the recently published pilus adhesin receptor CD147 underneath meningococcal microcolonies could be verified in iPSC-BECs. Nm was also observed to significantly increase the expression of pro-inflammatory and neutrophil-specific chemokines IL6, CXCL1, CXCL2, CXCL8, and CCL20, and the secretion of IFN-γ and RANTES. For the first time, we directly observe that Nm disrupts the three tight junction proteins ZO-1, Occludin, and Claudin-5, which become frayed and/or discontinuous in BECs upon Nm challenge. In accordance with tight junction loss, a sharp loss in trans-endothelial electrical resistance, and an increase in sodium fluorescein permeability and in bacterial transmigration, was observed. Finally, we established RNA-Seq of sorted, infected iPSC-BECs, providing expression data of Nm-responsive host genes. Altogether, this model provides novel insights into Nm pathogenesis, including an impact of Nm on barrier properties and tight junction complexes, and suggests that the paracellular route may contribute to Nm traversal of BECs

Association Study with 77 SNPs Confirms the Robust Role for the rs10830963/G of MTNR1B Variant and Identifies Two Novel Associations in Gestational Diabetes Mellitus Development

CONTEXT: Genetic variation in human maternal DNA contributes to the susceptibility for development of gestational diabetes mellitus (GDM). OBJECTIVE: We assessed 77 maternal single nucleotide gene polymorphisms (SNPs) for associations with GDM or plasma glucose levels at OGTT in pregnancy. METHODS: 960 pregnant women (after dropouts 820: case/control: m99'WHO: 303/517, IADPSG: 287/533) were enrolled in two countries into this case-control study. After genomic DNA isolation the 820 samples were collected in a GDM biobank and assessed using KASP (LGC Genomics) genotyping assay. Logistic regression risk models were used to calculate ORs according to IADPSG/m'99WHO criteria based on standard OGTT values. RESULTS: The most important risk alleles associated with GDM were rs10830963/G of MTNR1B (OR = 1.84/1.64 [IADPSG/m'99WHO], p = 0.0007/0.006), rs7754840/C (OR = 1.51/NS, p = 0.016) of CDKAL1 and rs1799884/T (OR = 1.4/1.56, p = 0.04/0.006) of GCK. The rs13266634/T (SLC30A8, OR = 0.74/0.71, p = 0.05/0.02) and rs7578326/G (LOC646736/IRS1, OR = 0.62/0.60, p = 0.001/0.006) variants were associated with lower risk to develop GDM. Carrying a minor allele of rs10830963 (MTNR1B); rs7903146 (TCF7L2); rs1799884 (GCK) SNPs were associated with increased plasma glucose levels at routine OGTT. CONCLUSIONS: We confirmed the robust association of MTNR1B rs10830963/G variant with GDM binary and glycemic traits in this Caucasian case-control study. As novel associations we report the minor, G allele of the rs7578326 SNP in the LOC646736/IRS1 region as a significant and the rs13266634/T SNP (SLC30A8) as a suggestive protective variant against GDM development. Genetic susceptibility appears to be more preponderant in individuals who meet both the modified 99'WHO and the IADPSG GDM diagnostic criteria

Conditional transition systems with upgrades

We introduce a variant of transition systems, where activation of transitions depends on conditions of the environment and upgrades during runtime potentially create additional transitions. Using a cornerstone result in lattice theory, we show that such transition systems can be modelled in two ways: as conditional transition systems (CTS) with a partial order on conditions, or as lattice transition systems (LaTS), where transitions are labelled with the elements from a distributive lattice. We define equivalent notions of bisimilarity for both variants and characterise them via a bisimulation game. We explain how conditional transition systems are related to featured transition systems for the modelling of software product lines. Furthermore, we show how to compute bisimilarity symbolically via BDDs by defining an operation on BDDs that approximates an element of a Boolean algebra into a lattice. We have implemented our procedure and provide runtime results. This is an extended version of the TASE 2017 paper [1], including all proofs, additional examples, an extension of the formalism to account for deactivation of updates and detailed runtime results

RavN is a member of a previously unrecognized group of Legionella pneumophila E3 ubiquitin ligases

The eukaryotic ubiquitylation machinery catalyzes the covalent attachment of the small protein modifier ubiquitin to cellular target proteins in order to alter their fate. Microbial pathogens exploit this post-translational modification process by encoding molecular mimics of E3 ubiquitin ligases, eukaryotic enzymes that catalyze the final step in the ubiquitylation cascade. Here, we show that the Legionella pneumophila effector protein RavN belongs to a growing class of bacterial proteins that mimic host cell E3 ligases to exploit the ubiquitylation pathway. The E3 ligase activity of RavN was located within its N-terminal region and was dependent upon interaction with a defined subset of E2 ubiquitin-conjugating enzymes. The crystal structure of the N-terminal region of RavN revealed a U-box-like motif that was only remotely similar to other U-box domains, indicating that RavN is an E3 ligase relic that has undergone significant evolutionary alteration. Substitution of residues within the predicted E2 binding interface rendered RavN inactive, indicating that, despite significant structural changes, the mode of E2 recognition has remained conserved. Using hidden Markov model-based secondary structure analyses, we identified and experimentally validated four additional L. pneumophila effectors that were not previously recognized to possess E3 ligase activity, including Lpg2452/SdcB, a new paralog of SidC. Our study provides strong evidence that L. pneumophila is dedicating a considerable fraction of its effector arsenal to the manipulation of the host ubiquitylation pathway.Funding: This work was funded by the Intramural Research Program of the National Institutes of Health (to MPM)(Project Number: 1ZIAHD008893-07) and by the Spanish Ministry of Economy and Competitiveness Grant (to AH)(BFU2014-59759-R) and the Severo Ochoa Excellence Accreditation (to AH)(SEV-2016-0644). This study made use of the Diamond Light Source beamline I04 (Oxfordshire, UK) and ALBA synchrotron beamline BL13-XALOC, funded in part by the Horizon 2020 programme of the European Union, iNEXT (H2020 Grant # 653706). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript